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NCCN Neuroendokrin
NCCN Neuroendokrin
Neuroendocrine and
Adrenal Tumors
Version 2.2022 — December 21, 2022
NCCN.org
NCCN Guidelines for Patients® available at www.nccn.org/patients
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Version 2.2022, 12/21/22 © 2022 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.
Printed by Nathanael Mianto on 6/26/2023 9:02:55 AM. For personal use only. Not approved for distribution. Copyright © 2023 National Comprehensive Cancer Network, Inc., All Rights Reserved.
The NCCN Guidelines® are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to
treatment. Any clinician seeking to apply or consult the NCCN Guidelines is expected to use independent medical judgment in the context of individual
clinical circumstances to determine any patient’s care or treatment. The National Comprehensive Cancer Network® (NCCN®) makes no representations
or warranties of any kind regarding their content, use or application and disclaims any responsibility for their application or use in any way. The NCCN
Guidelines are copyrighted by National Comprehensive Cancer Network®. All rights reserved. The NCCN Guidelines and the illustrations herein may not
be reproduced in any form without the express written permission of NCCN. ©2022.
Version 2.2022, 12/21/22 © 2022 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.
Printed by Nathanael Mianto on 6/26/2023 9:02:55 AM. For personal use only. Not approved for distribution. Copyright © 2023 National Comprehensive Cancer Network, Inc., All Rights Reserved.
Updates in Version 2.2022 of the NCCN Guidelines for Neuroendocrine and Adrenal Tumors from Version 1.2022 include:
PDNEC-1
• Evaluation, As appropriate, fourth bullet revised: Consider MSI, MMR, and TMB testing molecular profiling of tumor tissue.
• Treatment:
Following Locoregional, unresectable, second column added after first column for treatment: If progression: Chemotherapy,
Immunotherapy, Targeted Therapy.
Following Metastatic, second column revised: If progression, consider nivolumab + ipilimumab (category 2B): Chemotherapy,
Immunotherapy, Targeted Therapy.
PDNEC-1A
• New footnote added: Tumor/somatic molecular profiling should be considered for patients with locoregional unresectable/metastatic disease
who are candidates for anti-cancer therapy to identify actionable alterations. Consider specifically testing for potentially actionable somatic
findings including, but not limited to: NTRK fusions, RET fusions, BRAF V600E mutations, MSI-H, MMR deficiency, and TMB-H. Testing on
tumor tissue is preferred; however, cell-free DNA testing can be considered if tumor tissue testing is not feasible. (Also page NE-F 5 of 9)
NE-A 1 of 5
• Required information, new bullet added: Differentiation.
NE-F 5 of 9
• Locoregional unresectable/metastatic disease: Systemic therapy
New headers added:
◊ Chemotherapy
◊ Immunotherapy
◊ Targeted Therapy
– New options added:
▪ Dabrafenib + trametinib (if BRAF V600E mutation-positive).
▪ Entrectinib (if NTRK gene fusion-positive).
▪ Larotrectinib (if NTRK gene fusion-positive).
▪ Selpercatinib (if RET gene fusion-positive).
• New footnotes added:
There are no comparative data to define optimal treatment after first-line systemic therapy.
Dabrafenib + trametinib can be considered for patients with BRAF V600E mutation-positive tumors that have progressed following prior
treatment and have no satisfactory alternative treatment options.
Entrectinib and larotrectinib can be considered for patients with NTRK gene fusion-positive tumors without a known aquired resistance
mutation, that are metastic or where surgical resection is likely to result in severe morbididty, and that have no satisfactory alternative
treatments or that have progressed following treatment.
Selpercatinib can be considered for patients with RET gene fusion-positive tumors that have progressed on or following prior systemic
treatment or who have no satisfactory alternative treatment options.
Continued
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UPDATES
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Updates in Version 2.2022 of the NCCN Guidelines for Neuroendocrine and Adrenal Tumors from Version 1.2022 include:
NE-F 9 of 9
• New references added:
Salama AKS, Li S, Macrae ER, et al. Dabrafenib and trametinib in patients with tumors with BRAFV600E mutations: Results of the NCI-MATCH
trial Subprotocol H. J Clin Oncol 2020;38:3895-3904.
Sigal DS, Bhangoo MS, Hermel JA, et al. Comprehensive genomic profiling identifies novel NTRK fusions in neuroendocrine tumors.
Oncotarget 2018;9:35809-35812.
Doebele RC, Drilon A, Paz-Ares L, et al. Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: Integrated
analysis of three phase 1-2 trials. Lancet Oncol 2020;21:271-282.
Drilon A, Laetsch TW, Kummar S, et al. Efficacy of larotrectinib in TRK fusion positive cancers in adults and children. N Engl J Med
2018;378:731-739.
Subbiah V, Wolf J, Konda B, et al. Tumour-agnostic efficacy and safety of selpercatinib in patients with RET fusion-positive solid tumours
other than lung or thyroid tumours (LIBRETTO-001): A phase 1/2, open-label, basket trial. Lancet Oncol 2022;23:1261-1273.
Updates in Version 1.2022 of the NCCN Guidelines for Neuroendocrine and Adrenal Tumors from Version 4.2021 include:
Global
• SSR revised to SSTR.
• Option revised, in most instances: octreotide LAR
• Section header revised: Extrapulmonary Poorly Differentiated Neuroendocrine Carcinoma/Large or Small Cell Carcinoma/Mixed
Neuroendocrine-Non-Neuroendocrine Neoplasm.
• Hyperaldosteronism revised to: Primary aldosteronism.
• Cushing syndrome revised to: Hypercortisolemia.
• Section header revised: Principles of Genetic Hereditary Cancer Risk Assessment and Genetic Counseling: Hereditary Endocrine Neoplasias
(NE-E)
Neuroendocrine Tumors of the Gastrointestinal Tract (Well-Differentiated Grade 1/2, Lung and Thymus)
NET-3
• Second column, second pathway revised: Tumor >2 cm or Any tumor size with incomplete resection or positive nodes/margins.
• Footnotes removed:
See Surgical Principles for Management of Neuroendocrine Tumors (NE-D). (Also page NET-4)
Some institutions will consider more aggressive treatments for 1- to 2-cm tumors with poor prognostic features. See Discussion for details.
• Footnote g revised: 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. Some institutions will consider more
aggressive treatments for 1- to 2-cm tumors with poor prognostic features. See Discussion for details.
NET-5
• Primary Treatment/Surveillance, bottom of page, option revised: Radical resection Partial or total gastrectomy (based on tumor location) with
regional lymphadenectomy (preferred) ...
Continued
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UPDATES
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Updates in Version 1.2022 of the NCCN Guidelines for Neuroendocrine and Adrenal Tumors from Version 4.2021 include:
NET-5A
• New footnote r added: For symptom and/or tumor control, octreotide LAR 20–30 mg IM or lanreotide 120 mg SC every 4 weeks. For added
symptom control, octreotide 100–250 mcg SC TID can be considered. (Also pages NET-9, NET-10, and NET-11A)
• Footnote removed: See Principles of Systemic Anti-Tumor Therapy (NE-F). (Also page NET-6)
NET-6
• Evaluation, Locoregional disease (Stage IIIA/B) pathway, option revised: Locally uUnresectable.
Bottom branch option revised: Primary Treatment of Non-Metastatic Disease option revised: See Management of Locoregional Advanced
Unresectable Disease (NET-10).
• Footnote v revised: Cytotoxic chemotherapy options include are: cisplatin + etoposide or carboplatin + etoposide.
NET-7
• Fourth option following Evaluation revised: Metastatic disease (Stage IV) or Multiple lung nodules or tumorlets and evidence of diffuse
idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH).
• Primary Therapy, bottom of page, last option revised: See Metastatic Disease (NET-11).
• Footnote y revised: Cytotoxic chemotherapy options include are: cisplatin + etoposide, carboplatin + etoposide, or temozolomide ...
• New footnote z added: See Discussion.
NET-8
• Surveillance, 12 wk–12 mo post-resection, third bullet revised: Abdominal ± pelvic multiphasic CT or MRI as clinically indicated.
NET-9
• Treatment, option following Resect primary + metastases removed: Refer to surveillance for appropriate primary disease sites (See NET-1
through NET-5).
New arrow to pathway: Abdominal/pelvic multiphasic CT or MRI every 12 wk–12 mo...
• Last column, second option revised: PRRT with 177Lu-dotatate (if SSTR-positive imaging and progression on octreotide LAR or lanreotide)
(category 1 for progressive mid-gut tumors).
• Footnotes revised:
Footnote gg: 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 Resection should be considered to reduce future obstruction, mesenteric ischemia, bleeding or perforation.
Footnote jj: If clinically significant disease progression, treatment with octreotide LAR or lanreotide should be discontinued for non-
functional tumors and continued in patients with functional tumors; those these regimens may be used in combination with any of the
subsequent options ... (Also pages NET-10, NET-11A, and NET-12)
NET-10
• Subsequent Therapy, options revised: ... Consider changing to alternate primary if progression on first-line therapy (see options from
primary therapy based on tumor grade) ...
Continued
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UPDATES
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Updates in Version 1.2022 of the NCCN Guidelines for Neuroendocrine and Adrenal Tumors from Version 4.2021 include:
NET-11
• Header revised: Management of Distant Metastases (Bronchopulmonary or Thymus) OR Multiple Lung Nodules or Tumorlets and Evidence
OF DIPNECH.
• Header revised: TREATMENT PRIMARY THERAPY
• Last column, middle option revised: If progression on first-line therapy, Cconsider changing to alternate first-line therapy if progression on
first-line therapy.
NET-11A
• Footnote pp revised: Cisplatin + etoposide, carboplatin + etoposide, or temozolomide ± capecitabine Ccan be considered for intermediate-
grade/atypical tumors with Ki-67 proliferative index and mitotic index in the higher end of the defined spectrum.
NET-12
• Surveillance, first bullet revised: Echocardiogram every 2-3 1–3 y or as clinically indicated.
• Footnote rr revised: For symptom control, octreotide 150 100–250 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 or lanreotide 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.
• Footnote tt revised: Safety and eEffectiveness of everolimus in the treatment of patients with carcinoid syndrome have has not been
established.
Neuroendocrine Tumors of the Pancreas (Well-Differentiated Grade 1/2)
PanNET-2A
• Footnote removed: See Principles of Systemic Anti-Tumor Therapy (NE-F). (Also pages PanNET-4 and PanNET-5)
• New footnote n added: For symptom and/or tumor control, octreotide LAR 20–30 mg IM or lanreotide 120 mg SC every 4 weeks. For added
symptom control, octreotide 100–250 mcg SC TID can be considered. (Also pages PanNET-4 and PanNET-5)
PanNET-3
• Footnote p revised: SSTR-based imaging only if treatment with octreotide LAR or lanreotide is planned. Octreotide LAR or lanreotide can be
considered but only if tumor expresses SSTRs should only be given if tumor demonstrates SSTRs. In the absence of SSTRs, octreotide LAR
or lanreotide can profoundly worsen hypoglycemia. (See Discussion for details).
PanNET-4
• Management of Primary Non-Metastatic Disease, option following Distal revised: Distal pancreatectomy + peripancreatic lymphadenectomy
dissection + splenectomy. (Also page PanNET-5)
PanNET-6
• Surveillance, 12 wk–12 mo post-resection:
Third bullet revised: Abdominal multiphasic CT or MRI and chest CT (± contrast) as clinically indicated.
New bullet added: Chest CT (± contrast) as clinically indicated.
PanNET-7
• Last column, fifth option revised: PRRT with 177Lu-dotatate (if SSTR-positive imaging and progression on octreotide LAR or lanreotide).
Continued
Version 2.2022, 12/21/22 © 2022 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.
UPDATES
Printed by Nathanael Mianto on 6/26/2023 9:02:55 AM. For personal use only. Not approved for distribution. Copyright © 2023 National Comprehensive Cancer Network, Inc., All Rights Reserved.
Updates in Version 1.2022 of the NCCN Guidelines for Neuroendocrine and Adrenal Tumors from Version 4.2021 include:
PanNET-7A
• Footnote bb revised: If clinically significant disease progression, treatment with octreotide LAR or lanreotide should be discontinued for
non-functional tumors and continued in patients with functional tumors; those these regimens may be used in combination with any of the
subsequent options. For details on the administration of octreotide LAR or lanreotide with 177Lu-dotatate, see NE-G.
Neuroendocrine Tumors of Unknown Primary
NUP-1
• Following Primary not discovered pathway, new option added: Well-differentiated Grade 3.
New options added: See Management of Well-Differentiated Grade 3 Locoregional Disease (WDG3-2) and Locally Advanced/Metastatic
Disease: Favorable biology (WDG3-3) or Locally Advanced/Metastatic disease: Unfavorable biology (WDG3-4).
Neuroendocrine Tumors, Well-Differentiated Grade 3
WDG3-1
• Evaluation, Recommended, third bullet revised: SSTR-PET/CT or SSTR-PET/MRI (in patients with tumors Ki ≤55%).
• Footnote f revised: 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 can be heterogeneous and treatment considerations need to
account for both pathologic and clinical features and histopathologic workup combined should dictate therapy, not solely Ki-67. (Also pages
WDG3-2, WDG3-3A, and WDG3-4)
WDG3-2
• New footnote g added: See Principles of Systemic Anti-Tumor Therapy (NE-F 4 of 9). (Also pages WDG3-3A and WDG3-4)
• Footnote h revised: Temozolomide ± capecitabine Mmay have more activity in tumors arising in pancreas compared to GI NETs. (Also page
WDG3-3A and WDG3-4)
WDG3-3
• Treatment
Following Resectable pathway, option revised: Resection of primary + metastatic sites, if feasible, with acceptable risk and toxicity profile.
Following Clinically significant tumor burden or evidence of disease progression pathway:
◊ Third option revised: PRRT with 177Lu-dotatate (if SSTR-positive).
◊ Sixth option revised: Pembrolizumab (if MSI-H, dMMR, or for TMB-H tumors ([≥10 mut/Mb]) (category 2B).
• Surveillance, second row, Every 12–24 weeks (depending on tumor biology), third bullet revised: Abdominal/pelvic MRI with contrast or
Chest/aAbdominal/pelvic multiphasic CT.
WDG3-3A
• Footnote k revised: Pembrolizumab is an option 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. (Also page WDG3-4)
• New footnote m added: For symptom and/or tumor control, octreotide LAR 20–30 mg IM or lanreotide 120 mg SC every 4 weeks. For added
symptom control, octreotide 100–250 mcg SC TID can be considered.
WDG3-4
• Treatment, Systemic therapy options, fourth bullet revised: Pembrolizumab (if MSI-H, dMMR, or for TMB-H tumors ([≥10 mut/Mb]).
• Surveillance, third bullet revised: Abdominal/pelvic MRI with contrast or chest/aAbdominal/pelvic multiphasic CT.
Continued
Version 2.2022, 12/21/22 © 2022 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.
UPDATES
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Updates in Version 1.2022 of the NCCN Guidelines for Neuroendocrine and Adrenal Tumors from Version 4.2021 include:
Extrapulmonary Poorly Differentiated Neuroendocrine Carcinoma/Large or Small Cell Carcinoma/Mixed Neuroendocrine-Non-Neuroendocrine
Neoplasm
PDNEC-1
• Tumor Type, Extrapulmonary:
Second bullet revised: Large or small cell carcinoma (other than lung).
Third bullet revised: Unknown primary (poorly differentiated) Mixed neuroendocrine-non-neuroendocrine neoplasm.
• Treatment, following Resectable pathway, bullet removed: RT alone.
• New footnote c added: Poorly differentiated neuroendocrine carcinomas are often associated with non-neuroendocrine components such as
adeno or squamous cell carcinoma. Management of these tumors is controversial. Often, chemotherapy regimens for non-neuroendocrine
components may be considered.
• Footnote e revised: Pembrolizumab can be considered for patients with mismatch repair-deficient (dMMR), microsatellite instability-high
(MSI-H), or advanced tumor mutational burden-high (TMB-H (≥10 mut/Mb) tumors (as determined by an FDA-approved test) that have
progressed following prior treatment and have no satisfactory alternative treatment options.
Adrenal Gland Tumors
AGT-1
• Evaluation:
Following Morphologic evaluation pathway, Adrenal protocol:
◊ First bullet revised: Non-contrast CT with and without contrast (if HU < +10, no further imaging).
– New sub-bullet added: If > +10 HU, proceed with contrast CT with washout.
◊ Second bullet revised: MRI with or and without contrast to determine size, heterogeneity, lipid content (MRI), contrast washout (CT), and
margin characteristics.
Following Functional evaluation pathway, Biochemical workup (See NE-C) for:
◊ Bullet removed: Suspected adrenocortical carcinoma (ACC).
◊ New bullet added: Androgen excess.
• Footnote removed: See Principles of Imaging (NE-B).
• Footnote e revised: 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 Fleseriu M, et al. Lancet Diabetes Endocrinol
2021;9:847-875). (Also page AGT-3)
• New footnote f added: ACC can oftentimes secrete multiple hormones.
AGT-2
• Additional Evaluation:
Option following Rule out pheochromocytoma pathway revised: Consider image-guided needle biopsy if clinical suspicion of
pheochromocytoma is low, metanephrines ± catecholamines are normal, and the results will impact management.
Primary aldosteronism pathway, suspect benign, option following Surgical candidate revised: Consider adrenal vein sampling for
aldosterone and cortisol.
Continued
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UPDATES
Printed by Nathanael Mianto on 6/26/2023 9:02:55 AM. For personal use only. Not approved for distribution. Copyright © 2023 National Comprehensive Cancer Network, Inc., All Rights Reserved.
Updates in Version 1.2022 of the NCCN Guidelines for Neuroendocrine and Adrenal Tumors from Version 4.2021 include:
AGT-3
• Top option following Hypercortisolemia pathway revised: Tumor <4 cm and benign-appearing lesion.
AGT-5
• Treatment, following Locoregional unresectable or Metastatic disease pathway, fourth bullet revised: Consider systemic therapy preferably
in clinical trial (See Principles of Systemic Anti-Tumor Therapy for Locoregional Unresectable or Metastatic Adrenocortical Tumors
Carcinoma [AGT-A NE-F 6 of 9]).
• Footnote w revised: 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 usually is
required with mitotane.
Paraganglioma/Pheochromocytoma
PHEO-1
• Evaluation, As appropriate, if metastatic or multifocal disease suspected, fifth bullet revised: MIBG scan with SPECT/CT.
• Footnote f revised: Both catecholamines and metanephrines/normetanephrines can produce represent false-positive results (see NE-C).
• Footnote l revised: MIBG scans are less sensitive than FDG-PET and 68Ga-DOTATATE for metastatic and multifocal paragangliomas/
pheochromocytomas. SPECT/CT imaging of involved sites is recommended. Obtain MIBG scan if considering treatment with I131-MIBG.
PHEO-2
• Page header added to top left of page: Medical Preparation For Treatment
• Primary Treatment:
Following Locally unresectable pathway, options revised:
◊ Observe, if asymptomatic or slow-growing, low-volume disease or For secreting tumors Ccontinue medical therapy alpha blockade for
secreting tumors, and:
– New bullets added:
▪ Clinical trial (preferred) or
▪ SSAs (octreotide LAR or lanreotide) or
▪ Sunitinib 37.5 mg once daily or
– Sixth bullet revised: If SSR-positive imaging: cConsider PRRT with 177Lu-dotatate, or octreotide or lanreotide (if symptomatic) (if
SSTR-positive).
Following Distant metastases pathway, options revised:
◊ Observe, if asymptomatic or slow-growing, low-volume disease or For secreting tumors Ccontinue medical therapy alpha blockade for
secreting tumors, and:
– New bullets added:
▪ SSAs (octreotide LAR or lanreotide) or
▪ Sunitinib 37.5 mg once daily or
– First bullet revised: Clinical trial, (preferred) or
– Sixth bullet revised: If SSR-positive PET imaging: cConsider PRRT with 177Lu-dotatate (if SSTR-positive) or.
Continued
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UPDATES
Printed by Nathanael Mianto on 6/26/2023 9:02:55 AM. For personal use only. Not approved for distribution. Copyright © 2023 National Comprehensive Cancer Network, Inc., All Rights Reserved.
Updates in Version 1.2022 of the NCCN Guidelines for Neuroendocrine and Adrenal Tumors from Version 4.2021 include:
PHEO-2A
• New footnote r added: See Principles of Systemic Anti-Tumor Therapy (NE-F 7 of 9).
• Footnote s revised: 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. For
symptom and/or tumor control, octreotide LAR 20–30 mg IM or lanreotide 120 mg SC every 4 weeks. For added symptom control, octreotide
100–250 mcg SC TID can be considered.
• New footnote t added: SSAs may be used for indolent, low-volume, progressing disease for antiproliferative effect and/or antisecretory
effect. Data about anti-proliferative effects are limited.
PHEO-3
• Following Locally unresectable disease or Distant metastases pathway, options under Consider imaging:
Third sub-bullet added: MIBG with SPECT/CT (if previous MIBG-positive or concern for disease progression) prior to considering
radionuclide therapy or
Fourth sub-bullet revised: FDG-PET/CT for bone-dominant disease or
Fifth sub-bullet revised: SSTR-PET/CT or SSTR-PET/MRI (if previous SSTR-positive or concern for disease progression) prior to
considering radionuclide therapy
Multiple Endocrine Neoplasia, Type 1
MEN1-2
• Fourth pathway revised: Bronchial/Thymic NETs.
MEN1-A
• Footnote 4 revised: 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 2021;111:609-630.
Multiple Endocrine Neoplasia, Type 2
MEN2-1
• Clinical Evaluation, Pheochromocytoma, bullet added: Plasma free or 24-hour urine fractionated metanephrines and normetanephrines ±
serum or 24-hour urine catecholamines.
• Treatment, top pathway revised: See NCCN Guidelines for Medullary Thyroid Carcinoma.
• Sureillance, following Parathyroidectomy, option revised: See NCCN Guidelines for Medullary Thyroid Carcinoma.
• New footnotes added:
Footnote f: See Principles of Pathology for Diagnosis and Reporting of Neuroendocrine Tumors (NE-A).
Footnote g: See Principles of Biochemical Testing (NE-C).
Footnote h: Consider medical alert ID for hormonally secreting pheochromocytomas in situ or metastatic disease.
Footnote i: 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.
Footnote j: Both catecholamines and metanephrines/normetanephrines can represent false-positive results (see NE-C).
Continued
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UPDATES
Printed by Nathanael Mianto on 6/26/2023 9:02:55 AM. For personal use only. Not approved for distribution. Copyright © 2023 National Comprehensive Cancer Network, Inc., All Rights Reserved.
Updates in Version 1.2022 of the NCCN Guidelines for Neuroendocrine and Adrenal Tumors from Version 4.2021 include:
NE-A 1 of 5
• Optional Information, fifth bullet revised: Background pathology of organ (ie, PanIN, enterochromaffin-like [ECL] cell hyperplasia).
NE-A 2 of 5
• Footnote c revised: In most mixed neuroendocrine-non-neuroendocrine neoplasms (MINENs or 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.
NE-B
• Anatomic Imaging, second bullet revised: 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 ...
NE-C 1 of 4
• First bullet revised: Some NETs can secrete specific neuroendocrine hormones. Hormonal workup should be guided by the presence
of symptoms of the excess hormone. Screening for hormones in asymptomatic individuals with asymptomatic disease is not routinely
required.
• Second bullet revised: Proton pump inhibitors (PPIs), other drugs, some medical conditions, and certain foods are known to cause false
elevations in serum gastrin and chromogranin A. To confirm diagnosis, serum gastrin 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.
• Significant changes made to table.
NE-C 2 of 4
• Pheochromocytoma/Paraganglioma, Testing:
First bullet revised: Plasma free or 24-hour urine fractionated metanephrines and normetanephrines ± serum or 24-hour urine
catecholamines.
Second bullet revised: Cervical paragangliomas: cConsider serum and urine catecholamines or methoxytyramine (the metabolite of
dopamine).
• Primary aldosteronism, Testing, first bullet revised: Screening: Suppressed renin/renin activity in association with an elevated plasma
aldosterone level (> 15 10 ng/dL).
NE-C 3 of 4
• Footnotes revised:
Footnote b: For additional information on biochemical testing for Cushing syndrome hypercortisolemia, 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. Fleseriu M, Auchus R, Bancos I,
et al. Consensus on diagnosis and management of Cushing's disease: a guideline update. Lancet Diabetes Endocrinol. 2021;9:847-875.
Footnote e: 24-hour urine for aldosterone, sodium and potassium should be considered for definitive diagnosis Oral or intravenous salt
loading and measurement of urine or plasma aldosterone to test for adequate suppression.
Continued
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Updates in Version 1.2022 of the NCCN Guidelines for Neuroendocrine and Adrenal Tumors from Version 4.2021 include:
NE-C 4 of 4
• Reference 7 was updated.
NE-D
• Second bullet, new sub-bullet added: Assess implications of pancreatoduodenectomy (Whipple procedure) in metastatic disease. In this
setting, such surgery is usually not curative and impacts liver-directed therapy long-term.
• New bullet added: In the setting of metastatic disease, resection of small bowel NET (primary tumor and mesenteric lymph nodes) should
be performed when symptoms arise from the primary tumor. In asymptomatic cases, resection should be considered to reduce future
obstruction, mesenteric ischemia, bleeding, or perforation.
• Sixth bullet revised: Cytoreductive surgery of >90% of resectable, 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 (if primary tumor
resected) may provide symptomatic relief, prevent future symptoms, and improve progression-free survival for patients with functioning
tumors. 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 ...
• Ninth bullet revised: Octreotide therapy should be administered considered parenterally prior to induction of anesthesia in patients with
functional NETs carcinoid syndrome to prevent carcinoid crisis.
NE-E 1 of 8
• Link added to bottom of page: See NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic (EVAL-A,
EVAL-B).
NE-E 3 of 8
• Option 4 revised: Criteria Recommend for Genetic Risk Evaluation and Genetic Testing for Hereditary Endocrine Neoplasia Syndromes.
Endocrine neoplasia manifestations or medical conditions associated with specific hereditary syndromes and clinical manifestations are
outlined in this table: See Tumor Associations of Hereditary Endocrine Neoplasia Syndromes (NE-E 4 of 8).
Bullet removed: Recommend evaluation in a patient with any of the following.
Fist bullet revised: Adrenal Adrenocortical carcinoma (ACC). See Hereditary Cancer Predisposition Syndromes Associated with
Adrenocortical Carcinoma (NE-E 6 of 8).
Sixth bullet revised: 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).
• New option 5 added: Consider Genetic Risk Evaluation and Genetic Testing:
New bullets added:
◊ 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.
• Footnote removed: Genetic testing may be a consideration for patients with other combinations of tumors or cancers in the patient and/or
their family members.
Continued
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Updates in Version 1.2022 of the NCCN Guidelines for Neuroendocrine and Adrenal Tumors from Version 4.2021 include:
NE-E 4 of 8
• Table heading revised: Overview Tumor Associations of Hereditary Endocrine Neoplasia Syndromes. (Also page NE-E 5 of 8)
• Multiple endocrine neoplasia type 2 (RET), Surveillance, second link revised: NCCN Guidelines for Thyroid Cancer Carcinoma (MEDU-4 and
MEDU-5).
• Footnotes moved to new reference page NE-E 8 of 8:
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. (Also page NE-E 5 of 8)
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. (Also page NE-E 7 of 8)
NE-E 5 of 8
• Footnotes moved to new reference page NE-E 8 of 8:
Miller DT, Freedenberg F, Schorry E, et al. Health supervision for children with neurofibromatosis type 1. Pediatrics 2019;143:e20190660.
(Also page NE-E 7 of 8)
The VHL Alliance. The VHL Handbook: What you need to know about VHL. 6th ed. 2020. (Also page NE-E 7 of 8)
NE-E 7 of 8
• First heading revised: Paraganglioma/Pheochromocytoma (PCC/PGL)-specific Screening Recommendations for Patients with Confirmed
Germline Hereditary Syndromes.
Hereditary (PGL/PCC) syndrome:
◊ First bullet revised: Surveillance starting at 6–8 10 years for patients with SDHB mutations and 10–15 years for patients with all other
SDHx mutations:
– Third sub-bullet revised: Cross-sectional imaging of skull base to pelvis every 2–3 years ...
– Sub-bullet added: Since SDH genes have variability in their tumor penetrance and risk for malignancy, consideration can be given to
modified screening intervals, especially for less penetrant genes such as SDHA.
von Hippel Lindau syndrome (VHL), third bullet revised: Abdominal MRI (preferred) or CT with and without IV contrast every 2–3 years
starting at age 15 years.
• Footnotes moved to new reference page NE-E 8 of 8:
Redman SP, Erez A, Druker H, et al. Von Hippel Lindau and Hereditary Pheochromocytoma/Paraganglioma Syndromes: Clinical Features,
Genetics, and Surveillance Recommendations in Childhood. Clin Cancer Res 2017;23:e68-e75.
Muth A, Crona J, Gimm O, et al. Genetic testing and surveillance guidelines in hereditary pheochromocytoma and paraganglioma. J Intern
Med 2019;285:187-204.
Tufton N, Sahdev A, Akker SA. Radiological Surveillance Screening in Asymptomatic Succinate Dehydrogenase Mutation Carriers. J Endocr
Soc 2017;1:897-907.
Neumann HPH, Young WF Jr, Eng C. Pheochromocytoma and Paraganglioma. N Engl J Med 2019;381:552-565.
• Footnotes revised:
Footnote f: Patients with SDHD, SDHAF2, and MAX patients are most at risk if the pathogenic variant was paternally inherited ...
Footnote g: Available data suggest that patients with SDHAF2 patients mutations are primarily at risk for head and neck tumors and
patients with MAX patients mutations are primarily at risk for adrenal tumors ...
Continued
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Updates in Version 1.2022 of the NCCN Guidelines for Neuroendocrine and Adrenal Tumors from Version 4.2021 include:
NE-E 8 of 8
• New reference 9 added: Amar L, Pacak K, Steichen O, et al. International consensus on initial screening and follow-up of asymptomatic SDHx
mutation carriers. Nat Rev Endocrinol 2021;17:435-444.
NE-F 1 of 9
• Header revised: Principles of Systemic Anti-Tumor Therapy: Recurrent, Locoregionally Advanced, and/or Distant Metastatic Neuroendocrine
Tumors of the Gastrointestinal Tract (Well-Differentiated Grade 1/2), Lung, and Thymus.
• First bullet revised: Systemic therapy may not be appropriate for every patient with recurrent, locoregionally advanced, and/or distant
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 liver-directed therapy for patients with liver-predominant metastases, cytoreductive
surgery, or systemic therapy, which may be appropriate considerations.
• Neuroendocrine Tumors of the Gastrointestinal Tract (Well-Differentiated Grade 1/2) table:
First colum revised: Recurrent, Locoregional Advanced Disease, and/or Distant Metastases (if progression on octreotide LAR or lanreotide)
Preferred Regimens, second bullet revised: PRRT with 177Lu-dotatate (if SSTR-positive imaging and progression on octreotide LAR/
lanreotide) (category 1 for progressive mid-gut tumors).
Useful in Certain Circumstances, under consider (listed in alphabetical order), sub-bullet revised: Cytotoxic chemotherapy, if no other
options feasible (all category 3): Anticancer agents such as 5-fluorouracil (5-FU), capecitabine, dacarbazine, oxaliplatin, streptozocin,
and temozolomide can be used in patients with progressive disease metastases for whom there are no other treatment options. (See
Discussion for details.)
• Footnotes revised:
Footnote a: 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. For symptom and/or tumor control, octreotide LAR 20–30 mg IM or lanreotide 120 mg SC every 4 weeks. For
added symptom control, octreotide 100–250 mcg SC TID can be considered.
Footnote c: If clinically significant disease progression, treatment with octreotide LAR or lanreotide should be discontinued for non-
functional tumors and continued in patients with functional tumors; these regimens and may be used in combination with any of the
systemic therapy subsequent options ... (Also page NE-F 2 of 9)
Footnote d: Safety and eEffectiveness of everolimus in the treatment of patients with carcinoid syndrome have has not been established.
(Also page NE-F 2 of 9)
Continued
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Updates in Version 1.2022 of the NCCN Guidelines for Neuroendocrine and Adrenal Tumors from Version 4.2021 include:
NE-F 2 of 9
• Header revised: Principles of Systemic Anti-Tumor Therapy: Locoregionally Advanced and/or Recurrent and/or Distant Metastatic
Neuroendocrine Tumors of the Gastrointestinal Tract (Well-Differentiated Grade 1/2), Lung, and Thymus.
• First bullet revised: Systemic therapy may not be appropriate for every patient with locoregionally advanced or recurrent and/or distant
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 liver-directed therapy for patients with liver-predominant metastases, cytoreductive
surgery, or systemic therapy, which may be appropriate considerations.
• Fifth bullet revised: For management of hormone related symptoms for GI tumors, see NET-9. For management of carcinoid syndrome, see
NET-12.
• Bronchopulmonary/Thymus Neuroendocrine Tumors table:
First column of table revised: Recurrent and/or Distant Metastases (clinically significant tumor burden and low grade/progression/
intermediate grade [atypical carcinoid] or symptomatic).
Useful in Certain Circumstances, first bullet revised: PRRT with 177Lu-dotatate (if SSTR-positive imaging and progression on octreotide
LAR or lanreotide.
• Footnote a added: For symptom and/or tumor control, octreotide LAR 20–30 mg IM or lanreotide 120 mg SQ every 4 weeks. For added
symptom control, octreotide 100–250 mcg SC TID can be considered. (Also pages NE-F 3 of 9, NE-F 4 of 9, and NE-F 7 of 9)
• Footnote removed: 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.
• Footnote f revised: Cisplatin + etoposide, carboplatin + etoposide, or temozolomide ± capecitabine Ccan be considered for intermediate-
grade/atypical tumors with Ki-67 proliferative index and mitotic index in the higher end of the defined spectrum.
NE-F 3 of 9
• Header revised: Principles of Systemic Anti-Tumor Therapy: Recurrent, Locoregionally Advanced and/or Distant Metastatic Pancreatic
Neuroendocrine Tumors (Well-Differentiated Grade 1/2).
• First bullet revised: Systemic therapy may not be appropriate for every patient with recurrent, locoregionally advanced, and/or distant
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 liver-directed therapy for patients with liver-predominant metastases, cytoreductive
surgery, or systemic therapy, which may be appropriate considerations.
• Pancreatic Neuroendocrine Tumors (Well-Differentiated Grade 1/2) table:
First column revised: Recurrent, Locoregional Advanced Disease, and/or Distant Metastases
Preferred Regimens:
◊ Second bullet revised: Octreotide LAR or lanreotide (if SSTR-positive imaging).
◊ Fifth bullet revised: PRRT with 177Lu-dotatate (if SSTR positive imaging and progression on octreotide LAR or lanreotide).
• Footnote c added: If clinically significant disease progression, treatment with octreotide LAR or lanreotide should be discontinued for non-
functional tumors and continued in patients with functional tumors; these regimens may be used in combination with any of the subsequent
options. For details on the administration of octreotide LAR or lanreotide with 177Lu-dotatate, see NE-G.
Continued
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UPDATES
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Updates in Version 1.2022 of the NCCN Guidelines for Neuroendocrine and Adrenal Tumors from Version 4.2021 include:
NE-F 4 of 9
• New Principles of Systemic Anti-Tumor Therapy: Well-Differentiated, Grade 3 Neuroendocrine Tumors page added.
NE-F 5 of 9
• Page heading revised: Principles of Systemic Anti-Tumor Therapy: Extrapulmonary Poorly Differentiated Neuroendocrine Carcinoma/Large
or Small Cell (Extrapulmonary) Carcinoma/Mixed Neuroendocrine-Non-Neuroendocrine Neoplasm.
• Table heading revised: Extrapulmonary Poorly Differentiated Neuroendocrine Carcinoma/Large or Small Cell (Extrapulmonary) Carcinoma/
Mixed Neuroendocrine-Non-Neuroendocrine Neoplasm.
Second column, last bullet added: Capecitabine (when etoposide + platinum is not feasible).
Last column, last bullet revised: Pembrolizumab (if MSI-H, dMMR, or TMB-H tumors [≥10 mut/Mb]).
NE-F 6 of 9
• Page heading revised: Principles of Systemic Anti-Tumor Therapy: for Locoregional Unresectable/Metastatic Adrenocortical Carcinoma.
(Formally page AGT-A)
• Table heading added: Locoregional Unresectable/Metastatic Adrenocortical Carcinoma.
• Footnote l revised: 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 usually is
required with mitotane.
NE-F 7 of 9
• New Principles of Systemic Anti-Tumor Therapy: Paraganglioma/Pheochromocytoma page added.
NE-F 8 of 9
• References updated.
NE-G 1 of 3
• Preparing Eligible Patients for 177Lu-dotatate, first bullet revised: Do not administer long-acting SSAs (eg, octreotide LAR, lanreotide,
octreotide) for 4–6 weeks 4 weeks prior to each 177Lu-dotatate treatment.
NE-G 2 of 3
• Second bullet revised: Aggressive antiemetic prophylaxis is recommended for patients when commercial amino acid solutions are used with
PRRT with a 5-HT3 receptor antagonist with or without an NK1 receptor blocker. See NCCN Guidelines for Antiemesis.
• Timing of SSAs (Octreotide or Lanreotide) in Relation to 177Lu-dotate, third bullet revised: There are theoretical concerns regarding the
competition between SSAs and 177Lu-dotatate for SSTR binding. Therefore, the following actions are is recommended.
First sub-bullet revised: Do not administer long-acting SSAs for 4–6 weeks 4 weeks prior to each 177Lu-dotatate treatment.
Continued
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Updates in Version 1.2022 of the NCCN Guidelines for Neuroendocrine and Adrenal Tumors from Version 4.2021 include:
NE-H 2 of 3
• Ablative Therapy changed from category 2B to category 2A.
Second bullet added: Stereotactic body radiation therapy (SBRT)/stereotactic ablative radiotherapy (SABR) (≤5 fractions) and
hypofractionated RT (6–20 fractions) using stereotactic or intensity-modulated RT/volumetric modulated arc therapy techniques with
image-guided RT can be considered for oligometastatic disease at multiple sites, including (but not limited to) liver, adrenal, bone
(including spine), lung, mediastinum, head and neck, and lymph nodes. An ablative dose is delivered to the tumor while respecting the
surrounding organ and adjacent normal tissue constraints. Generally, if this is possible in 5 or fewer fractions, SBRT/SABR techniques are
used, while hypofractionated RT is used for larger lesions or lesions next to large vessels, large airways or hollow viscous organs at risk of
complications. Motion management and image-guided RT techniques are strongly recommended to maintain RT precision and reduce the
risk of toxicity.
NE-I 1 of 2
• Symptom Management:
CS-diarrhea and flushing:
◊ Second sub-bullet revised: Telotristat ethyl 250 mg TID is can be considered specifically recommended for patients with refractory
diarrhea secondary to CS (usually with proven elevated serotonin or 5-HIAA), in combination with long-acting SSA ...
◊ Fourth sub-bullet revised: Short-acting octreotide, given subcutaneously, administered at doses of 150 100–250 mcg every 8 hours as
needed, can be prescribed to patients with suboptimal control of flushing and/or diarrhea.
◊ Fifth sub-bullet revised: Serotonin antagonists such as ondansetron can improve refractory CS diarrhea in patients with refractory symptoms
patients.
Carcinoid heart disease (CHD), sub-bullet revised: 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 patients
with symptomatic disease patients.
NE-I 2 of 2
• VIP, Management, third bullet revised: Corticosteroids can be effective in patients with SSR SSTR-refractory patients disease.
• New footnote a added: Short-acting octreotide can be added to octreotide LAR or lanreotide for rapid relief of symptoms or for breakthrough
symptoms.
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a See Principles of Pathology for Diagnosis and Reporting of Neuroendocrine Tumors (NE-A).
b For well-differentiated grade 3 NET, see WDG3-1. For poorly differentiated/large or small cell carcinomas, see PDNEC-1.
c Includes adrenal cortical tumors and incidentalomas.
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CP-1
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Recommended:
• Abdominal/pelvic multiphasic Locoregional Bowel resection(s) with See Surveillance
CT or MRIb disease regional lymphadenectomyf,g (NET-8)
As appropriate:
Jejunal/ileal/ • Somatostatin receptor (SSTR)-
colon PET/CT or SSTR-PET/MRIb,d,e
• Colonoscopy
• Chest CT with or without contrast Metastatic
• Biochemical evaluation as Metastatic Disease (NET-9)
disease
clinically indicatedc
a See Principles of Pathology for Diagnosis and Reporting of Neuroendocrine Tumors (NE-A).
b See Principles of Imaging (NE-B).
c See Principles of Biochemical Testing (NE-C).
d 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).
e SSTR PET tracers include: 68Ga-DOTATATE, 64Cu-DOTATATE, and 68Ga-DOTATOC.
f See Surgical Principles for Management of Neuroendocrine Tumors (NE-D).
g 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.
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NET-1
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Metastatic
disease Metastatic Disease (NET-9)
a See Principles of Pathology for Diagnosis and Reporting of Neuroendocrine Tumors (NE-A).
b See Principles of Imaging (NE-B).
c See Principles of Biochemical Testing (NE-C). h If endoscopic resection performed, follow-up EGD as appropriate.
d PET/CT or PET/MRI of skull base to mid-thigh with IV contrast when possible. Data are i For non-ampullary tumors, endoscopic or local excision is
limited on the optimal timing of scans following administration of SSAs. preferred. Pancreaticoduodenectomy should be considered for
e SSTR PET tracers include: 68Ga-DOTATATE, 64Cu-DOTATATE, and 68Ga-DOTATOC. ampullary tumors not amenable to endoscopic or local excision.
f See Surgical Principles for Management of Neuroendocrine Tumors (NE-D). j Invasion into muscle (see Staging, ST-2).
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NET-2
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No surveillance
Tumor ≤2 cm Simple appendectomyg,f indicated
Metastatic
disease Metastatic Disease (NET-9)
a See
Principles of Pathology for Diagnosis and Reporting of Neuroendocrine Tumors (NE-A).
b See Principles of Imaging (NE-B).
d 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.
e SSTR PET tracers include: 68Ga-DOTATATE, 64Cu-DOTATATE, and 68Ga-DOTATOC.
f 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.
g 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. Some institutions will consider more aggressive treatments for 1- to 2-cm tumors with poor prognostic features. See
Discussion for details.
h Greater than 12 lymph nodes should be retrieved.
i Data are limited on survival benefit from right hemicolectomy.
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NET-3
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a See Principles of Pathology for Diagnosis and Reporting of Neuroendocrine Tumors (NE-A).
b See Principles of Imaging (NE-B).
c See Principles of Biochemical Testing (NE-C).
d 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.
e SSTR PET tracers include: 68Ga-DOTATATE, 64Cu-DOTATATE, and 68Ga-DOTATOC.
j For 1- to 2-cm tumors, consider examination under anesthesia (EUA) and/or EUS with radical resection if muscularis propria invasion or node positive.
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NET-4
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Footnotes
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NET-5
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NET-5A
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a See Principles of Pathology for Diagnosis and Reporting of Neuroendocrine Tumors (NE-A).
b See Principles of Imaging (NE-B).
c See Principles of Biochemical Testing (NE-C).
d 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.
e SSTR PET tracers include: 68Ga-DOTATATE, 64Cu-DOTATATE, and 68Ga-DOTATOC.
k See Surgical Principles for Management of Neuroendocrine Tumors (NE-D).
n See Principles of Hereditary Cancer Risk Assessment and Genetic Counseling (NE-E).
t 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.
u Chemoradiation is thought to have most efficacy for tumors with atypical histology or tumors with higher mitotic and proliferative indices (eg, Ki-67).
v Cytotoxic chemotherapy options are: cisplatin + etoposide or carboplatin + etoposide.
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NET-6
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NET-7
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12 wk–12 mo post-resection:
• H&P
• Consider biochemical markers as clinically
indicated (See NE-C)c See Management of Locoregional
• Abdominal ± pelvic multiphasic CT or MRIb GI tract Advanced Disease and/or Distant
• Chest CT with or without contrast for primary Metastases (NET-9)
lung/thymus tumors (as clinically indicated for
primary GI tumors)b
See Management of Locoregional
>1 y post-resection to 10 y: Bronchopulmonary/ Unresectable Disease (NET-10)
• Every 12–24 mo Disease recurrenceee thymus or
H&P See Management of Distant
Consider biochemical markers as clinically Metastases (NET-11)
indicated (See NE-C)c
Abdominal ± pelvic multiphasic CT or MRIb
Chest CT with or without contrast for primary
lung/thymus tumors (as clinically indicated Carcinoid See Management of Carcinoid
for primary GI tumors)b syndrome Syndrome (NET-12)
>10 y:
• Consider surveillance as clinically indicatedb,dd
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NET-8
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b See Principles of Imaging (NE-B). ff Noncurative debulking surgery might be considered in select cases.
c See Principles of Biochemical Testing (NE-C). gg Resection should be considered to reduce future obstruction, mesenteric ischemia, bleeding, or
d PET/CT or PET/MRI of skull base to mid-thigh with IV contrast perforation.
when possible. Data are limited on the optimal timing of scans hh Treatment with octreotide LAR or lanreotide will likely only benefit those patients who are SSTR-
following administration of SSAs. positive.
e SSTR PET tracers include: 68Ga-DOTATATE, 64Cu-DOTATATE, ii In select cases, it may be appropriate to proceed to front-line systemic therapy or liver-directed
and 68Ga-DOTATOC. therapy prior to or concurrently with octreotide LAR or lanreotide.
k See Surgical Principles for Management of Neuroendocrine jj If clinically significant disease progression, treatment with octreotide LAR or lanreotide should be
Tumors (NE-D). discontinued for non-functional tumors and continued in patients with functional tumors; these
r For symptom and/or tumor control, octreotide LAR 20–30 mg IM
regimens may be used in combination with any of the subsequent options. For details on the
or lanreotide 120 mg SC every 4 weeks. For added symptom administration of octreotide LAR or lanreotide with 177Lu-dotatate, see NE-G.
control, octreotide 100–250 mcg SC TID can be considered. kk See Principles of Peptide Receptor Radionuclide Therapy (PRRT) with 177Lu-dotatate (NE-G).
w See Principles of Systemic Anti-Tumor Therapy (NE-F). ll See Principles of Liver-Directed Therapy for Neuroendocrine Tumor Metastases (NE-H).
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NET-9
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r For symptom and/or tumor control, octreotide LAR 20–30 mg IM or lanreotide 120 mg SC every 4 weeks. For added symptom control, octreotide 100–250 mcg SC TID
can be considered.
u Chemoradiation is thought to have most efficacy for tumors with atypical histology or tumors with higher mitotic and proliferative indices (eg, Ki-67).
jj If clinically significant disease progression, treatment with octreotide LAR or lanreotide should be discontinued for non-functional tumors and continued in patients with
functional tumors; these regimens may be used in combination with any of the subsequent options. For details on the administration of octreotide LAR or lanreotide
with 177Lu-dotatate, see NE-G.
kk See Principles of Peptide Receptor Radionuclide Therapy (PRRT) with 177Lu-dotatate (NE-G).
mm For symptom control, consider addition of focal therapy (ie, endobronchial therapy debulking, ablation).
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NET-10
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Footnotes
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NET-11
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NET-11A
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b See Principles of Imaging (NE-B). rr For symptom control, octreotide 100–250 mcg SC TID or octreotide LAR 20–30
c See Principles of Biochemical Testing (NE-C). mg IM or lanreotide 120 mg SC every 4 weeks. Dose and frequency may be further
w See Principles of Systemic Anti-Tumor Therapy (NE-F). increased for symptom control as needed. Therapeutic levels of octreotide would not
jj If clinically significant disease progression, treatment with
octreotide LAR or be expected to be reached for 10–14 days after LAR injection. Short-acting octreotide
lanreotide should be discontinued for non-functional tumors and continued in can be added to octreotide LAR or lanreotide for rapid relief of symptoms or for
patients with functional tumors; these regimens may be used in combination breakthrough symptoms.
with any of the subsequent options. For details on the administration of ss Evaluate for pancreatic exocrine deficiency and bile acid diarrhea.
octreotide LAR or lanreotide with 177Lu-dotatate, see NE-G. tt Effectiveness of everolimus in the treatment of patients with carcinoid syndrome has
qq See Principles of Hormone Control (NE-I). not been established.
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NET-12
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PanNET-1
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Footnotes
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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PanNET-2
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PanNET-2A
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PanNET-3
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PanNET-4
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PanNET-5
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12 wk–12 mo post-resection:
• H&P
• Consider biochemical markers as
clinically indicatedc
• Abdominal multiphasica CT or MRI
• Chest CT (± contrast) as clinically
indicated
>1 y post-resection to a maximum of 10 y:
• Every 6–12 mo See Management of Locoregional Advanced Disease
Disease recurrencey and/or Distant Metastases (PanNET-7)
H&P
Consider biochemical markers as
clinically indicatedc
Abdominal multiphasica CT or MRI
Chest CT (± contrast) as clinically
indicated
>10 y:
• Consider surveillance as clinically
indicatedx
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PanNET-6
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EVALUATION TREATMENT
If complete
• Abdominal ± resection Resect metastases + primarycc See Surveillance (PanNET-6)
pelvic multiphasic possibleh,aa
CT or MRIa
and chest CT • Observe with markers If disease progressionbb:
(± contrast) as and abdominal/pelvic Clinical trial
clinically indicated multiphasica CT or MRI Clinically or
Asymptomatic,
• SSTR-PET/CT or every 12 wk–12 mo and significant Everolimusee (category 1 for progressive
low tumor
SSTR-PET/MRIa,d,e chest CT (± contrast) progressive disease)
burden, and
• Biochemical as clinically indicated disease, or
stable disease
evaluation as • Consider octreotide see below Sunitinibee (category 1 for progressive
clinically indicated LARdd,ee or disease)
(See NE-C)c lanreotidedd,ee or
• Consider tumor If disease Temozolomide + capecitabineee
classification/ Manage clinically progression, or
grade (See NE-A)z significant symptoms consider PRRT with 177Lu-dotatate (if SSTR-positive
Symptomatic and progression on octreotide LAR or
or as appropriate octreotide
(PanNET-1, PanNET-2, LARdd,ee or lanreotide)ee,gg
Clinically or
significant PanNET-3, PanNET-4, lanreotidedd,ee
and PanNET-5) (if not already Other cytotoxic chemotherapyee
tumor burden or
or receiving)
Consider belzutifan in the setting of germline
Clinically VHL alteration in patients with progressive
significant or
PanNETsee,hh
progressive or
diseasebb Consider alternative front-line therapy Consider liver-directed therapy for liver-
(see options for disease progression)ee,ff predominant diseaseii,jj
or
Palliative RT for symptomatic bone metastases
Footnotes
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PanNET-7
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PanNET-7A
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See Management of
Bronchopulmonary/Thymus
Locoregional Advanced Disease
(NET-8)
Well- and/or
Primary not
differentiated Distant Metastases (NET-10)
discoveredf
grade 1/2g,h or
See Management of
Gastrointestinal Tract Locoregional
Tumor-directed localizing
Advanced Disease and/or Distant
studies:
Metastases (NET-11)
• Chest CT with or
without contrast and
multiphasic abdominal/ See Management of Well-
pelvic CT or MRIc Differentiated Grade 3
Biopsy-proven Locoregional Disease (WDG3-2)
NETs of • SSTR-PET/CT or
SSTR-PET/MRIc,d,e and
unknown Well- Locally Advanced/Metastatic
primaryb,f • Consider FDG-PET/CT
differentiated Disease: Favorable Biology
and brain imaging (CT
grade 3 (WDG3-3)
or MRI) with contrast
in poorly differentiated or
carcinomas only Locally Advanced/Metastatic
• Consider EGD or EUS Disease: Unfavorable Biology
and/or colonoscopy (WDG3-4)
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NUP-1
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Recommended:
• Multiphasic abdominal/pelvic CT or MRI with
contrast ± chest CT as clinically indicated
• Pathology review
• SSTR-PET/CT or SSTR-PET/MRIb,c (in patients Locoregional
with tumors Ki ≤55%) (Resectable) See WDG3-2
Well- As appropriate
differentiated • FDG-PET/CT
Favorable biology (eg,
Grade 3 • Biochemical evaluation as clinically indicated
relatively low Ki-67f
neuroendocrine (See NE-C)
[<55%], slow growing, See WDG3-3
tumors • Consider tumor mutational burden (TMB)
positive SSTR-based PET
testingd Locally imaging)
• Consider assessment of p53, Rb, p16 by advanced/
histopathologic analysis or molecular profiling Metastatic
if uncertain about differentiation Unfavorable biology (eg,
• Genetic counseling and testing for inherited relatively high Ki-67f
genetic syndromes (only for duodenal or [≥55%], faster growing, See WDG3-4
pancreatic NET)e negative SSTR-based PET
imaging)
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WDG3-1
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WDG3-2
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Footnotes
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WDG3-3
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FOOTNOTES
a See Principles of Imaging (NE-B).
c SSTR PET tracers include: 68Ga-DOTATATE, 64Cu-DOTATATE, and 68Ga-DOTATOC.
f 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 can be heterogeneous and treatment considerations need to account for both pathologic and clinical features.
g See Principles of Systemic Anti-Tumor Therapy (NE-F 4 of 9).
h Temozolomide ± capecitabine may have more activity in tumors arising in the pancreas compared to GI NETs.
i Clinical trials are preferred due to a lack of data from prospective clinical trials to guide therapy.
j 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).
k 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.
l See Principles of Liver-Directed Therapy for Neuroendocrine Tumor Metastases (NE-H).
m For symptom and/or tumor control, octreotide LAR 20–30 mg IM or lanreotide 120 mg SC every 4 weeks. For added symptom control, octreotide 100–250 mcg SC
TID can be considered.
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WDG3-3A
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WDG3-4
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Footnotes
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PDNEC-1
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PDNEC-1A
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History of prior or
current malignancy
with risk of or See Additional Evaluation (AGT-2)
suspicion of
adrenal metastasis
a See d If unenhanced is < +10 HU, then the tumor is probably benign. If unenhanced is > +10
Principles of Pathology for Diagnosis and Reporting of
Neuroendocrine Tumors (NE-A). HU, then use enhanced and washout. If >60% absolute washout in 15 minutes, the tumor
b See Principles of Biochemical Testing (NE-C). is likely to be benign; if <60%, the tumor is possibly malignant. (Caoili E, et al. Radiology
c For benign-appearing lesions, refer to the following guidelines for the 2002;222:629-633).
e For benign-appearing lesions, refer to the Endocrine Society's Clinical Practice Guidelines
management of adrenal incidentalomas: Zeiger MA, et al. Endocrine
practice: Official Journal of the American College of Endocrinology and for the Treatment of Cushing's Syndrome (Fleseriu M, et al. Lancet Diabetes Endocrinol
the American Association of Clinical Endocrinologists 2009;15 Suppl 2021;9:847-875).
f ACC can oftentimes secrete multiple hormones.
1:1-20; Fassnacht M, et al. Eur J Endocrinol 2016;175:G1-G34.
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AGT-1
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Considerh image-
guided needle biopsy See functional
History of prior or Adrenal cortical tissue
if clinical suspicion of evaluation (AGT-1)
current malignancy pheochromocytoma
Rule out pheochromocytoma
with risk of or
(See NE-C)b is low, metanephrines
suspicion of ± catecholamines are
adrenal metastasis normal, and the results See NCCN disease-specific
Metastasis from
will impact management other site discovered treatment guidelines
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AGT-2
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Hypercortisolemiae
Apparent localized
disease, locally Open
resectable disease, Adrenalectomy
Tumor >4 cmk or • FDG-PET/CTj or regionally for suspected See
inhomogeneous, irregular • Chest CT with or advanced disease malignancyl,m Adrenocortical
margins, local invasion, without contrastj Carcinoma
or other malignant • Abdominal/pelvic CT (AGT-5)
imaging characteristics or MRI with contrast
Metastatic disease
e For benign-appearing lesions, refer to the Endocrine Society's Clinical Practice Guidelines for the Treatment of Cushing's Syndrome (Fleseriu M, et al. Lancet Diabetes
Endocrinol 2021;9:847-875).
j See Principles of Imaging (NE-B).
k Some centers may use 6 cm as cutoff.
l Perioperative management should include stress-dose steroids (eg, methylprednisolone or hydrocortisone).
m May require removal of adjacent structures (ie, liver, kidney, pancreas, spleen, diaphragm) for complete resection.
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AGT-3
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AGT-4
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j See Principles of Imaging (NE-B). t Ifbulky disease, or <90% is removable, surgery can be reconsidered following response
o Staging workup, see AGT-4. to systemic therapy.
p See Principles of Hereditary Cancer Risk Assessment and Genetic u See Principles of Liver-Directed Therapy for Neuroendocrine Tumor Metastases (NE-H).
Counseling (NE-E). v High-risk local recurrence features include: positive margins, Ki-67 >10%, rupture of
q FDA-approved test recommended for determination of TMB. capsule, large size, and high grade.
r May require removal of adjacent structures (ie, liver, kidney, pancreas, w Monitor mitotane blood levels. Some institutions recommend target levels of 14–20 mcg/
spleen, diaphragm) for complete resection. mL if tolerated. Steady-state levels may be reached several months after initiation of
s It is important to achieve negative margins and avoid breaching the mitotane. Life-long hydrocortisone ± fludrocortisone replacement usually is required with
tumor capsule. There may be an increased risk for local recurrence and mitotane.
peritoneal spread when done with a minimally invasive approach. x Mitotane may have more benefit for control of hormone symptoms than control of tumor.
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AGT-5
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Recommended:
• Plasma free or 24-hour urine fractionated metanephrines and
normetanephrinesb,d,e ± serum or 24-hour urine catecholaminesf
• Adrenal protocol CT (abdomen/pelvis)
• Genetic counseling and testing for inherited genetic syndromesh
Pheochromocytoma/
paraganglioma As appropriate, if metastatic or multifocal disease suspected:i See Primary Treatment (PHEO-2)
• Abdominal/pelvic multiphasic CT or MRIg
• SSTR-PET/CT or SSTR-PET/MRIe,j,k
• FDG-PET/CT (skull base to mid-thigh)
• Chest CT with or without contrast
• MIBG scan with SPECT/CTl
a See Principles of Pathology for Diagnosis and Reporting of Neuroendocrine Tumors (NE-A).
b See Principles of Biochemical Testing (NE-C).
c Consider medical alert ID for hormonally secreting pheochromocytomas and paragangliomas in situ or metastatic disease.
d 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.
e For cervical paraganglioma, consider measuring serum and/or 24-hour urine fractionated catecholamines (for dopamine).
f Both catecholamines and metanephrines/normetanephrines can represent false-positive results (see NE-C).
g See Principles of Imaging (NE-B).
h See Principles of Hereditary Cancer Risk Assessment and Genetic Counseling (NE-E).
i Data on the role of functional imaging in pheochromocytoma/paraganglioma are evolving and the preferred method remains unclear.
j PET/CT or PET/MRI of skull base to mid-thigh with IV contrast when possible.
k SSTR PET tracers include: 68Ga-DOTATATE, 64Cu-DOTATATE, and 68Ga-DOTATOC.
l MIBG scans are less sensitive than FDG-PET and 68Ga-DOTATATE for metastatic and multifocal paragangliomas/pheochromocytomas. SPECT/CT imaging of
involved sites is recommended. Obtain MIBG scan if considering treatment with I131-MIBG.
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PHEO-1
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Footnotes
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PHEO-2
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FOOTNOTES
c Consider medical alert ID for hormonally secreting pheochromocytomas and paragangliomas in situ or metastatic disease.
k SSTR PET tracers include: 68Ga-DOTATATE, 64Cu-DOTATATE, and 68Ga-DOTATOC.
m 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.
n 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.
o HSA iobenguane I 131 is an FDA-approved option.
p Data are limited on the use of PRRT with 177Lu-dotatate in this setting. See Principles of PRRT with 177Lu-dotatate (NE-G).
q CVD = cyclophosphamide, vincristine, and dacarbazine.
r See Principles of Systemic Anti-Tumor Therapy (NE-F 7 of 9).
s For symptom and/or tumor control, octreotide LAR 20–30 mg IM or lanreotide 120 mg SC every 4 weeks. For added symptom control, octreotide 100–250 mcg SC TID
can be considered.
t SSAs may be used for indolent, low-volume, progressing disease for antiproliferative effect and/or antisecretory effect. Data about anti-proliferative effects are limited.
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PHEO-2A
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SURVEILLANCEu
12 wk–12 mo post-resection:v
• H&P, blood pressure, and markersb
• Consider chest CT (± contrast) and abdominal/pelvic CT or MRI with contrast
>1 y post-resection up to 10 y:
Resectable disease • H&P, blood pressure, and markersb
(post-resection) Years 1–3: every 6–12 mou
Years 4+ up to 10 y: annuallyu
• Consider chest CT (± contrast) and abdominal/pelvic CT or MRI with contrast
>10 y:
• Consider surveillance as clinically indicated
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PHEO-3
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PanNET:d
• Recommended
Biochemical evaluation as clinically See Treatment of PanNETs Specific
indicated (See NE-C) to MEN1 Patients (MEN1-A)
Clinical diagnosis of and See MEN1
MEN1 Abdominal ± pelvic multiphasic CT or Surveillance
MRIc See appropriate sporadic PanNET
• Genetic workup and treatment (PanNET-1 (MEN1-2)
counseling • As appropriate through PanNET-5)
and testing for EUS
inherited genetic • SSTR-PET/CT or SSTR-PET/MRIc,e,f
syndromesa
Pituitary:
• Recommended
Consider referral to
Pituitary or sella MRI with contrast
endocrinology for further workup
Biochemical evaluation as
clinically indicated (See NE-C) See MEN1
Surveillance
Bronchial/Thymic: (MEN1-2)
• Chest CT with contrast and abdominal/
See appropriate bronchopulmonary/
pelvic multiphasic CT or MRI
thymus workup and treatment (NET-6)
• Biochemical evaluation as clinically
indicated (See NE-C)
a See Principles of Hereditary Cancer Risk Assessment and Genetic Counseling (NE-E). e PET/CT or PET/MRI of skull base to mid-thigh with IV contrast when
b Preference of scan will depend on institutional practice/protocol. Sestamibi may not be possible. Data are limited on the optimal timing of scans following
as sensitive since often the patient has hyperplasia. See Principles of Imaging (NE-B). administration of SSAs.
c See Principles of Imaging (NE-B). f SSTR PET tracers include: 68Ga-DOTATATE, 64Cu-DOTATATE, and
d van Treijen MJC, et al. J Endocr Soc 2018;2:1067-1088. 68Ga-DOTATOC.
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MEN1-1
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MEN1 SURVEILLANCEg,h
Patients with MEN1 should be screened for all of the following tumor types:
• If calcium rises:
PTH
Parathyroid:
25-OH vitamin D
• Calcium annually
Re-image with neck ultrasound and/or parathyroid sestamibi
with SPECT scan (SPECT-CT preferred) or 4D-CTb,h
PanNET:
• Follow previously elevated serum hormones or as symptoms See appropriate sporadic PanNET workup and treatment
indicate (PanNET-1 through PanNET-5)
• Consider abdominal/pelvic CT or MRIc,h with contrast every 1–3 y
• Consider serial EUS
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
b 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).
c See Principles of Imaging (NE-B).
g Consider referral to an endocrinologist.
h For prolonged surveillance, studies without radiation are preferred.
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MEN1-2
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1 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.
2 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.
3 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.
4 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. Neuroendocrinology
2021;111:609-630.
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MEN1-A
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Parathyroid:
• Serum calcium
Clinical diagnosis • If calcium elevated:
of MEN2 PTH and 25-OH vitamin D See NCCN Guidelines for
• Genetic Imagingb (neck Parathyroidectomyl Thyroid Carcinoma
counseling ultrasound, parathyroid
and testing for sestamibi with SPECT
inherited genetic scan, or 4D-CT)
syndromesa
Pheochromocytomac,d,e,f,g,h
• Plasma free or 24-hour urine
fractionated metanephrines
See Pheochromocytoma Guidelines (PHEO-1)
and normetanephrinesg,i
± serum or 24-hour urine
catecholaminesj
a See Principles of Hereditary Cancer Risk Assessment and Genetic Counseling (NE-E).
b 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).
c Evaluation of pheochromocytoma should be done before the administration of any anesthetic or invasive procedure.
d More likely to be multifocal.
e For synchronous bilateral pheochromocytomas, a bilateral adrenalectomy is recommended.
f See Principles of Pathology for Diagnosis and Reporting of Neuroendocrine Tumors (NE-A).
g See Principles of Biochemical Testing (NE-C).
h Consider medical alert ID for hormonally secreting pheochromocytomas in situ or metastatic disease.
i 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.
j Both catecholamines and metanephrines/normetanephrines can represent false-positive results (see NE-C).
k For the treatment of synchronous tumors, surgical resection of pheochromocytoma should take priority over thyroidectomy for medullary thyroid cancer.
l 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.
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MEN2-1
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2019 WHO Classification and Grading Criteria for Neuroendocrine Neoplasms of the Gastrointestinal Tract and
Hepatopancreatobiliary Organs
a 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 mm2 (ie, in a total area of 10 mm2); 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.
b Poorly differentiated NECs are not formally graded but are considered high grade by definition.
c In most mixed neuroendocrine-non-neuroendocrine neoplasms (MINENs or 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.
References
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.
NE-A
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PRINCIPLES OF IMAGING
Anatomic Imaging • Octreotide SPECT/CT is much less sensitive for defining SSTR-
• Cross-sectional imaging should include the primary site of disease. positive disease than SSTR-PET/CT, and typically cannot be
Either CT or MRI is appropriate. done in combination with multiphase CT or MRI. Therefore,
• The liver is a common metastatic site for NET, and these metastatic SSTR-PET/CT or SSTR-PET/MRI is preferred.
lesions are often hypervascular. Therefore, multiphasic imaging should • In selected cases where high-grade NET or poorly differentiated
be performed whenever possible. Following arterial-phase imaging of neuroendocrine carcinoma is documented or suspected or
the liver, imaging of the abdomen and pelvis can be performed in the where disease is growing rapidly, FDG-PET/CT may be useful to
portal-venous phase of enhancement. Oral contrast may be helpful to identify high-grade active disease.
delineate discrete lesions within the bowel. • As with SSTR-PET/CT, combining FDG-PET with dual-phase liver
• Without a known tumor or specific clinical concern, imaging of the chest CT or MRI is preferred.
is optional for GI NET and imaging of the brain is generally not required Surveillance
for well-differentiated NET. • After potentially curative surgery, surveillance is recommended
• For metastatic well-differentiated NET, anatomic imaging should for at least 10 years for most patients. In certain cases,
generally be performed every 12 weeks–12 months based on clinical or surveillance may be extended beyond 10 years based on risk
pathologic signs of aggressiveness. factors such as age and risk of recurrence. However, data are
• Consider MRI over CT to minimize radiation risk. limited on the optimal surveillance schedule beyond 10 years.
• MRI preferred for pregnant patients.
Transthoracic Echocardiogram (ECHO)b to Assess for Carcinoid
Functional Imaginga (NET-related) Heart Disease
• Evaluation with SSTR imaging to assess receptor status and distant • Echocardiogram (transthoracic echocardiography, TTE) is
disease is appropriate. This is especially important for determining important for the evaluation of carcinoid heart disease and
whether a patient may benefit from SSTR-directed therapy. should include morphologic evaluation of the valves (especially
SSTR-based imaging options include SSTR-PET/CT or SSTR-PET/MRI, tricuspid and pulmonic) and the right heart.
or octreotide SPECT/CT (only if SSTR-PET is not available)
Appropriate SSTR-PET tracers include 68Ga-DOTATATE, 68Ga-
DOTATOC, or 64Cu-DOTATATE.
SSTR-positive if uptake in measurable lesions is greater than liver.
• Whenever possible, SSTR-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 SSTR-
negative as well as those that are SSTR-positive.
a Data on the role of functional imaging in pheochromocytoma/paraganglioma is evolving and the preferred method remains unclear.
b 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.
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NE-B
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Pituitary Tumor Pituitary (part of May be asymptomatic, depends on • Serum IGF-1 (category 2B)
MEN1) the hormone secreted • Serum prolactin
• LH/FSH
• Alpha subunits
• TSH (free T4)
• Screen for hypercortisolemia
Hypercortisolemiab Adrenal, pituitary, Central weight gain, striae, • Screen for hypercortisolemia with 1 of the following testsd:
or ectopic (often hypertension, hyperglycemia, 1 mg overnight dexamethasone suppression test
bronchial or depression, hirsutism 2–3 midnight salivary cortisols
thymic) 24-hour urinary free cortisol
• Confirmatory testing if positive
• Plasma ACTH
Footnotes
References
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.
NE-C
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References
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.
NE-C
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NE-D
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See NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic (EVAL-A, EVAL-B)
References
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.
NE-E
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References
a 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;543:65-71). References
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.
NE-E
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Multiple endocrine neoplasia type Medullary thyroid cancer (≤98%) MEN2A: See MEN2-1 and
2 (RET)d Pheochromocytoma (≤50%) • Cutaneous lichens NE-E (7 of 8)2
Parathyroid adenoma/hyperplasia (≤25% amyloidosis NCCN Guidelines for Thyroid
MEN2A, rare in MEN2B) • Hirschsprung disease Carcinoma (MEDU-4 and
MEN2B: MEDU-5)
• Intestinal ganglioneuromas
• Mucosal neuromas
• Marfanoid habitus
Note: This resource is not intended to be an exhaustive list of hereditary endocrine neoplasias. Specific scenarios may warrant consideration of less
common conditions such as Carney complex, Carney triad, Currarino syndrome, or polycythemia-paraganglioma-somatostatinoma syndrome.
b 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.
c 10% of cases have de novo MEN1 mutations.
d 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.
References
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.
NE-E
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e 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.
References
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.
NE-E
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Lynch syndrome (MLH1, EPCAM/MSH2, Colon, endometrial, gastric, ovarian, and other NCCN Guidelines for Genetic/Familial High-Risk
MSH6, PMS2) cancers Assessment: Breast, Ovarian, and Pancreatic
Multiple endocrine neoplasia type 1 Parathyroid adenoma/hyperplasia, duodenal/ See MEN1-2 and MEN1-A
(MEN1) pancreatic neuroendocrine tumors, pituitary
adenomas, bronchial/thymic carcinoids
Familial adenomatous polyposis (APC) Colon polyposis/cancer, duodenal/periampullary NCCN Guidelines for Genetic/Familial High-Risk
polyposis/cancer, thyroid cancer Assessment: Colorectal
References
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.
NE-E
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Paraganglioma/Pheochromocytoma (PGL/PCC)-specific Screening Recommendations for Patients with Confirmed Germline Hereditary
Syndromes5-8
Hereditary PGL/PCC syndromef,9
• Surveillance starting at 6–10 years for patients with SDHB mutations and 10–15 years for patients with all other SDHx mutations:
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 2–3 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.g
Since SDH genes have variability in their tumor penetrance and risk for malignancy, consideration can be given to modified screening
intervals, especially for less penetrant genes such as SDHA.
Multiple endocrine neoplasia type 22
• 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 2–3 years starting at age 15 years.
f Patients with SDHD, SDHAF2, and MAX mutations 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.
g Available data suggest that patients with SDHAF2 mutations are primarily at risk for head and neck tumors and patients with MAX mutations are primarily at risk for
adrenal tumors. Therefore, consideration can be given to more targeted imaging in these cohorts.
References
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.
NE-E
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a For symptom and/or tumor control, octreotide LAR 20–30 mg IM or lanreotide 120 mg SC every 4 weeks. For added symptom control, octreotide 100–250 mcg SC TID
can be considered.
b The PROMID trial showed an antitumor effect of octreotide LAR in advanced neuroendocrine tumors of the midgut.3 The CLARINET trial showed an antitumor effect of
lanreotide in advanced, well-differentiated metastatic grade 1 and grade 2 GEP NETs.4
c If clinically significant disease progression, treatment with octreotide LAR or lanreotide should be discontinued for non-functional tumors and continued in patients with
functional tumors; these regimens may be used in combination with any of the subsequent options. For details on the administration of octreotide LAR or lanreotide
with 177Lu-dotatate, see NE-G.
d Effectiveness of everolimus in the treatment of patients with carcinoid syndrome has not been established.
e See Principles of PRRT with 177Lu-dotatate (NE-G).
References
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.
NE-F
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Recurrent and/or • Clinical trial • None • PRRT with 177Lu-dotatate (if SSTR-positive
Distant Metastases • Everolimusd,1,2 (category 1 for and progression on octreotide LAR or
(clinically significant bronchopulmonary NET) lanreotide)e
tumor burden and low • Octreotide LARa,3 or • Temozolomide5,6 ± capecitabinef,7,8
grade/progression/ lanreotidea,4 (if SSTR-positive • Cisplatin + etoposidef,9,10
intermediate grade and/or hormonal symptoms) • Carboplatin + etoposidef,10,11
[atypical carcinoid] or
symptomatic)
a For symptom and/or tumor control, octreotide LAR 20–30 mg IM or lanreotide 120 mg SC every 4 weeks. For added symptom control, octreotide 100–250 mcg SC TID
can be considered.
c If clinically significant disease progression, treatment with octreotide LAR or lanreotide should be discontinued for non-functional tumors and continued in patients with
functional tumors; these regimens may be used in combination with any of the subsequent options. For details on the administration of octreotide LAR or lanreotide
with 177Lu-dotatate, see NE-G.
d Effectiveness of everolimus in the treatment of patients with carcinoid syndrome has not been established.
e See Principles of PRRT with 177Lu-dotatate (NE-G).
f Cisplatin + etoposide, carboplatin + etoposide, or temozolomide ± capecitabine can be considered for intermediate-grade/atypical tumors with Ki-67 proliferative index
and mitotic index in the higher end of the defined spectrum.
References
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.
NE-F
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a For symptom and/or tumor control, octreotide LAR 20–30 mg IM or lanreotide 120 mg SC every 4 weeks. For added symptom control, octreotide 100–250 mcg SC TID
can be considered.
h 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).
i Pembrolizumab can be considered for patients with dMMR, MSI-H, or advanced TMB-H tumors (as determined by an FDA-approved test) that have progressed
following prior treatment and have no satisfactory alternative treatment options.
j Temozolomide ± capecitabine may have more activity in tumors arising in the pancreas compared to GI NETs.
References
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.
NE-F
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p See Discussion for further information regarding the phase III FIRM-ACT trial.
q 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 usually is required with mitotane.
r Mitotane may have more benefit for control of hormone symptoms than control of tumor.
References
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.
NE-F
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Paraganglioma/Pheochromocytoma
Locally Unresectable Distant Metastases
• Clinical trial (preferred) • Clinical trial (preferred)
• SSAs (octreotide LAR or lanreotide)a,s • SSAs (octreotide LAR or lanreotide)a,s
• Sunitinib 37.5 mg once daily • Sunitinib 37.5 mg once daily
• HSA iobenguane I 131t or other 131I-MIBG (requires prior positive • Systemic chemotherapy (eg, CVDw or temozolomide)
MIBG scan) • HSA iobenguane I 131t or other 131I-MIBG (requires prior positive
• Consider PRRT with 177Lu-dotatate (if SSTR-positive)u,v MIBG scan)
• Consider PRRT with 177Lu-dotatate (if SSTR-positive)u,v
a For symptom and/or tumor control, octreotide LAR 20–30 mg IM or lanreotide 120 mg SC every 4 weeks. For added symptom control, octreotide 100–250 mcg SC TID
can be considered.
s SSAs may be used for indolent, low-volume progressing disease for antiproliferative effect and/or antisecretory effect. Data about anti-proliferative effects are limited.
t HSA iobenguane I 131 is an FDA-approved option.
u SSTR PET tracers include: 68Ga-DOTATATE, 64Cu-DOTATATE, and 68Ga-DOTATOC.
v Data are limited on the use of PRRT with 177Lu-dotatate in this setting. See Principles of PRRT with 177Lu-dotatate (NE-G).
w CVD = cyclophosphamide, vincristine, and dacarbazine.
References
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.
NE-F
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Continued
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.
NE-F
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Key Eligibility:
• Well-differentiated NET
• SSTR expression of NET as detected by SSTR-PET/CT or SSTR-PET/MRa,b,c
• Adequate bone marrow, renal, and hepatic function
Preparing Eligible Patients for 177Lu-dotatate
• Do not administer long-acting SSAs (eg, octreotide LAR, lanreotide) for 4 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: flushing, 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 effective 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:
IV infusion of amino acids is a critical part of 177Lu-dotatate therapy for nephroprotection.
a See Principles of Imaging (NE-B).
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.
c SSTR PET tracers include: 68Ga-DOTATATE, 64Cu-DOTATATE, and 68Ga-DOTATOC.
Continued
Note: All recommendations are category 2A unless otherwise indicated. References
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.
NE-G
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References
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.
NE-G
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Continued
References
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.
NE-H
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References
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.
NE-H
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Carcinoid Syndrome
• Carcinoid syndrome (CS) primarily occurs in patients with metastatic well-differentiated 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 flushing, diarrhea, wheezing (rare), and carcinoid heart disease (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 flushing is less well understood.
Refractory flushing or diarrhea is defined as suboptimal symptom control in the setting of long-acting SSAs (octreotide LAR or lanreotide) used in
approved doses.
It is important to note that diarrhea can be multifactorial: other common causes include direct side effects from SSAs, pancreatic exocrine insufficiency
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 flushing • Non CS-diarrhea
Long-acting SSAs (octreotide LAR and lanreotide) are highly active for control of In patients who develop diarrhea/steatorrhea exacerbation while
both flushing and diarrhea. on SSA, a trial of pancreatic enzymes for pancreatic exocrine
Telotristat 250 mg TID can be considered specifically for patients with refractory insufficiency should be considered.
diarrhea secondary to CS (usually with proven elevated serotonin or 5-HIAA), Patients with persistent diarrhea after ileocecectomy or
in combination with long-acting SSA. Symptomatic benefit can sometimes be cholecystectomy, especially if associated with urgency, can
delayed for several weeks after initiation of the drug. be treated empirically with bile acid binding drugs such as
Patients who experience symptom exacerbation towards the end of each 4-week cholestyramine.
SSA cycle can often benefit from more frequent administration (ie, every 3 weeks). For patients with presumed short-gut syndrome, suggest referral to
Dose escalation can also sometimes benefit patients with refractory symptoms. appropriate gastroenterologist expert.
Short-acting octreotide, given subcutaneously, administered at doses of 100–250 Nonspecific antidiarrheals (ie, loperamide, diphenoxylate/atropine,
mcg every 8 hours as needed, can be prescribed to patients with suboptimal tincture of opium) and cyproheptadine can be beneficial for
control of flushing and/or diarrhea. management of refractory diarrhea, regardless of cause.
Serotonin antagonists such as ondansetron can improve refractory CS diarrhea in • Carcinoid heart disease (CHD)
patients with refractory symptoms. CHD should be monitored by a cardiologist with expertise in
Treatments that effectively cytoreduce secretory metastatic tumors are likely to the disease as the echocardiographic diagnosis of CHD can be
palliate hormonal symptoms. For patients with liver-dominant disease, surgical challenging. Valve replacement (typically tricuspid and pulmonary) is
cytoreduction or hepatic arterial embolization are highly effective at control of indicated for patients with symptomatic disease.
flushing and/or diarrhea. PRRT with 177Lu-dotatate has been associated with
delay in diarrhea progression.
Nonspecific antidiarrheals (ie, loperamide, diphenoxylate/atropine, tincture of
opium) and cyproheptadine can be beneficial for management of refractory
diarrhea, regardless of cause.
Cyproheptadine can be considered for control of flushing for patients who cannot
tolerate SSA.
Hormone Management
Gastrin • Manage gastric hypersecretion with high-dose PPIs, generally given two times a day.
• Consider octreotide LARa or lanreotide.
Insulin • Stabilize glucose levels with diet and/or diazoxide or everolimus.
• Octreotide LARa or lanreotide can be considered but only if tumor expresses SSTRs. In the absence of
SSTRs, octreotide LARa or lanreotide can profoundly worsen hypoglycemia.
VIP • Octreotide LARa or lanreotide are the first-line management for control of hormone symptoms.
• Correct electrolyte imbalance (K+, Mg2+, HCO3-) and dehydration.
• Corticosteroids can be effective in patients with SSTR-refractory disease.
Glucagon • Octreotide LARa or lanreotide are the first-line management for control of hormone symptoms.
• Treat hyperglycemia and diabetes, as appropriate.
a Short-acting octreotide can be added to octreotide LAR or lanreotide for rapid relief of symptoms or for breakthrough symptoms.
M Distant Metastasis
M0 No distant metastasis
M1 Distant metastasis
M1a Metastasis confined to liver
M1b Metastases in at least one extrahepatic site (e.g., lung, ovary,
nonregional lymph node, peritoneum, bone)
Continued
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.
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ST-1
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M Distant Metastasis
M0 No distant metastasis
M1 Distant metastases
M1a Metastasis confined 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
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.
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ST-2
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M Distant Metastasis
M0 No distant metastasis
M1 Distant metastasis
M1a Metastasis confined to liver
M1b Metastases in at least one extrahepatic site (e.g., lung,
ovary, nonregional lymph node, peritoneum, bone) Continued
M1c Both hepatic and extrahepatic metastases
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(2017) published by Springer International Publishing.
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ST-3
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M Distant Metastasis
M0 No distant metastasis
M1 Distant metastasis
M1a Metastasis confined to liver
M1b Metastases in at least one extrahepatic site (e.g., lung, ovary,
nonregional lymph node, peritoneum, bone) Continued
M1c Both hepatic and extrahepatic metastases
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(2017) published by Springer International Publishing.
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ST-4
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M Distant Metastasis
M0 No distant metastasis
M1 Distant metastases
M1a Metastasis confined 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 Continued
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(2017) published by Springer International Publishing.
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ST-5
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M Distant Metastasis
M0 No distant metastasis
M1 Distant metastasis
M1a Metastasis confined 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
Continued
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(2017) published by Springer International Publishing.
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ST-6
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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
Continued
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(2017) published by Springer International Publishing.
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ST-7
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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
Continued
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ST-8
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Continued
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(2017) published by Springer International Publishing.
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ST-9
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Continued
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(2017) published by Springer International Publishing.
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ST-10
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Continued
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(2017) published by Springer International Publishing.
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ST-11
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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.
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ST-12
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CAT-1
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Discussion This discussion section corresponds to the NCCN Guidelines for Neuroendocrine and Adrenal Tumors. Last updated: December 14th, 2021.
Table of Contents
Overview ........................................................................................ MS-2 Pheochromocytomas/Paragangliomas ........................................MS-36
Literature Search Criteria and Guidelines Update Methodology . MS-2 Multiple Endocrine Neoplasia .....................................................MS-40
Histologic Classification and Staging of Neuroendocrine and MEN1 .........................................................................................MS-40
Adrenal Tumors ............................................................................. MS-3
MEN2 and Familial MTC.............................................................MS-44
Histologic Classification ............................................................... MS-3
Future Trial Design ......................................................................MS-47
Staging ........................................................................................ MS-4
References ...................................................................................MS-48
Pathologic Reporting .................................................................... MS-5
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MS-1
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An analysis of the SEER database estimated that the incidence of NETs in Appropriate diagnosis and treatment of NETs often involves collaboration
the United States was 6.98 cases per 100,000 people in the year 2012.2 between specialists in multiple disciplines, using specific biochemical,
This analysis suggested that the incidence of NETs is increasing, and that radiologic, and surgical methods. Specialists include pathologists,
the prevalence of individuals with NETs in the United States may exceed endocrinologists, radiologists (including nuclear medicine specialists), and
170,000. Other independent analyses of the SEER database also found medical, radiation, and surgical oncologists.
that the incidence of GI NETs increased from 1975 to 2008.3,4 The
These guidelines discuss the diagnosis and management of both sporadic
reasons for this increase are unclear, although it seems likely that
and hereditary neuroendocrine and adrenal tumors and are intended to
improved diagnosis and classification is one factor.5
assist with clinical decision-making. Most of the guideline sections pertain
Most NETs seem to be sporadic and risk factors for sporadic NETs are to well-differentiated, low- to intermediate-grade tumors, although well-
poorly understood. NETs may also arise in the context of inherited genetic differentiated high-grade tumors and poorly differentiated/ large or small
syndromes, including multiple endocrine neoplasia types 1 (MEN1), 2 cell carcinomas are also addressed (see Poorly Differentiated
(MEN2), and 4 (MEN4), and succinate dehydrogenase (SDHx) mutations. Neuroendocrine Carcinomas/Large or Small Cell Carcinomas or Unknown
NETs have also been associated with other conditions, including von Primary, below). Medical practitioners should note that unusual patient
Hippel-Lindau (VHL) disease, tuberous sclerosis complex, and scenarios (presenting in <5% of patients) are not specifically discussed in
neurofibromatosis.6,7 MEN1, associated with mutations in the menin gene, these guidelines.
is characterized by multiple tumors of the parathyroid, pituitary, and
Literature Search Criteria and Guidelines Update
pancreatic glands.8 MEN2, associated with mutations in the RET proto- Methodology
oncogene, is characterized by the development of medullary thyroid
Prior to the update of this version of the NCCN Guidelines for
cancer, pheochromocytoma (often bilateral), and hyperparathyroidism.9
Neuroendocrine Tumors, an electronic search of the PubMed database
NETs have also been associated with other conditions, including VHL
was performed to obtain key literature published in the field since the
disease, tuberous sclerosis complex, and neurofibromatosis.6,7
previous Guidelines update, using the following search terms:
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MS-2
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MS-3
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and/or counted in the areas of highest activity referred to as “hot spots”. A Staging
key recommendation is that tumor differentiation, mitotic rate, and Ki-67 NETs are staged according to the AJCC tumor (T), node (N), metastasis
index should all be included in the pathology report. Doing so allows the (M) staging system. The AJCC introduced its first TNM staging system for
treating physician to factor these data into the clinical picture to make the classification of NETs in its 7th edition of the AJCC Cancer Staging
appropriate treatment decisions in GI and pancreatic NENs. The current Manual.37 The T and N definitions and other staging definitions were
grading of lung NENs does not rely on Ki-67.27 revised in the 8th edition of the AJCC Cancer Staging Manual. 38 The 8th
edition also added the first staging system for thymic tumors and adrenal
The classification of lung and thymus NETs varies from that of
NETs (including staging for pheochromocytoma and paraganglioma).38
gastroenteropancreatic NETs in some classification systems, and in
NETs of the stomach, duodenum/ampulla, jejunum/ileum, appendix,
particular does not include Ki-67 and includes the assessment of necrosis.
colon/rectum, and pancreas have separate staging systems. The
Well-differentiated NETs of the lung and thymus are considered typical
association of tumor stage with prognosis has been confirmed in analyses
(low-grade, <2 mitoses/10 HPF and no necrosis) or atypical (intermediate
of the SEER database and the National Cancer Database.39-45 An analysis
grade, 2–10 mitosis/10 HPF and/or foci of necrosis), using histologic
of 691 patients with jejunal-ileocecal NETs treated at the Moffitt Cancer
criteria.28
Center between 2000 and 2010 revealed 5-year survival rates of 100%,
High-grade, poorly differentiated lung and thymus NECs are of either small 100%, 91%, and 72% for stages I through IV, respectively, further
cell or large cell cytology, with greater than 10 mitoses/10 HPF and validating the TNM staging system.36 Of note, however, this analysis also
extensive foci of necrosis.26,29-31 suggested that, unlike other malignancies, primary tumor size and depth of
invasion had little bearing on survival in early-stage disease.33 Similar
Considerable debate remains as to the most appropriate Ki-67 proliferative results were reported in a separate analysis of 6792 small intestine NETs
threshold for the determination of tumor grade and consequent treatment in the SEER database, which found that outcomes were similar for
decisions.32,33 A retrospective database review of 252 patients with high- patients with T1 and T2 tumors.46 These results have been supported in
grade GI NEC suggested that platinum-based chemotherapy is most additional analyses, confirming that the presence of lymph node and
active in those with a Ki-67 index of greater than or equal to 55%.34 These distant metastases have the strongest effect on survival.47,48
results suggest that a higher Ki-67 cutoff than is currently recommended
may be more appropriate to classify tumors as high grade. Conversely, for NETs of the lungs and bronchi are staged in the same manner as more
low-grade tumors, some studies have suggested that the currently common lung carcinomas. As in lung carcinoma, more advanced tumor
accepted cutoff may be too low. An analysis of data from 274 patients with stage for NETs of the lungs and bronchi is associated with worse
pancreatic NETs found that a 5% Ki-67 cutoff (rather than 2%) was the prognosis.37,38
optimal prognostic indicator.35 A comparable analysis based on 691
The TNM staging system for the classification of pancreatic NETs in the
patients with jejunal-ileocecal NETs similarly found that a threshold of 5
8th edition of the AJCC Cancer Staging Manual is separate from exocrine
mitoses/10 HPF provided better prognostic information than one of 2
pancreatic carcinoma.37,38 The primary tumor (T) is differentiated based on
mitoses/10 HPF.36
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size and involvement of major vessels or other organs (see Staging in the paragangliomas. In a validation study, the NETest demonstrated high
guidelines). A retrospective analysis of 425 patients with pancreatic NETs sensitivity (>95%) in patients with well-differentiated, metastatic NETs.55
treated at the Moffitt Cancer Center between 1999 and 2010 validated the The molecular basis of NETs remains poorly understood, and additional
AJCC 2017 classification system, with 5-year overall survival (OS) rates of molecular predictors of outcome remain investigational. One study found
92%, 84%, 81%, and 57% for stages I through IV, respectively (P < that overexpression of mammalian target of rapamycin (mTOR) or its
.001).49 Although the trends of this analysis are consistent with population- downstream targets was associated with shorter OS in 195
based studies, the survival rates from this analysis were significantly neuroendocrine tissue samples (15% were located in the pancreas; 85%
higher than those seen in population-based studies.50,51 For example, in were GI carcinoids).56 Small bowel carcinoid (neuroendocrine) tumors
the SEER database analysis of pancreatic NETs, the 5-year survival rate have been found to have recurrent mutations in the cyclin-dependent
for patients with metastatic disease was only 19.5%.51 kinase inhibitor, CDKN1B (p27),57 and loss of CDKN1B expression has
been reported to be an adverse prognostic factor in
Pathologic Reporting gastroenteropancreatic NETs.58 Circulating tumor cells (CTCs) have also
In addition to information on histologic classification and stage, the margin been studied as possible prognostic markers, based on the idea that
status (positive or negative) and the presence of vascular or perineural tumor cells in the blood would be indicative of more disseminated disease.
invasion should be included in the pathology report; some studies have Another study found that the presence of greater than or equal to 1 CTC in
suggested that these factors may also have prognostic significance.52,53 7.5 mL of blood was independently associated with worse progression-
free survival (PFS) and OS in patients with varyingly pretreated metastatic
Whether or not tumors are associated with symptoms of hormone NETs from various primary sites.59
hypersecretion (”functioning” or “non-functioning”) is a clinical rather than
histologic diagnosis. The presence of hormone-staining granules without a More research is required, however, before these and other new
clinical syndrome does not make a tumor “functioning.” Thus, functional molecular assays are routinely used in the clinic. A multinational
status is usually not included in the pathology report. consensus meeting of experts concluded that, to date, no single currently
available biomarker is sufficient as a diagnostic, prognostic, or predictive
Other Potential Prognostic Markers marker in patients with NETs.60
Chromogranin A is a secreted protein that may be elevated in patients with
NETs; elevated levels have been associated with poorer prognosis. In Principles of Genetic Risk Assessment and Counseling
select cases, chromogranin A may have prognostic value but treatment In the 2021 guidelines, the panel included a new principles of genetic risk
decisions are not based solely on changes in chromogranin. The assessment and counseling for hereditary endocrine neoplasias. This
neuroendocrine neoplasms test (NETest) is a blood-based biomarker test section outlines how to go about genetic counseling, provides an overview
that measures the expression level of multiple analytes.54 It can help in the of clinical manifestations associated with these disorders, and advises the
identification of small bowel, pancreas, and bronchopulmonary readers of resources that can be accessed for more information (eg, how
neuroendocrine neoplasms, as well as pheochromocytomas and to find a genetic counselor, see Principles of Genetic Risk Assessment
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and Counseling in the algorithm). Recommendations are provided Genetic Risk Assessment and Counseling in the algorithm). Additional
regarding pre-test counseling, considerations when determining the most screening recommendations are also provided for patients with hereditary
appropriate testing strategy, post-test counseling, and criteria for genetic paraganglioma/pheochromocytoma, MEN2, and VHL syndrome.
risk evaluation for hereditary endocrine neoplasia syndromes.
Sporadic Neuroendocrine Tumors
Genetic risk evaluation is recommended in patients with any of the Neuroendocrine Tumors of the Gastrointestinal Tract (Well-
following: 1) adrenocortical carcinoma (ACC); 2) Differentiated Grade 1/2), Lung, and Thymus
paraganglioma/pheochromocytoma; 3) gastrinoma (duodenal/pancreatic
Approximately one-third of neuroendocrine (carcinoid) tumors arise in the
or type 2 gastric NET); 4) multifocal pancreatic NETs; 5) parathyroid
lungs or thymus, and two-thirds arise in the GI tract. Sites of origin within
adenoma or primary hyperparathyroidism before age 30, multiple
the GI tract include the stomach, small intestine, appendix, and rectum.1,2
parathyroid adenomas, multigland hyperplasia (without obvious secondary
The prognosis for patients with NETs varies according to the stage at
causes), or recurrent primary hyperparathyroidism; 6) clinical suspicion for
diagnosis, histologic classification, and primary site of the tumor (see
MEN2 due to the presence of medullary thyroid cancer or other
Histologic Classification and Staging of Neuroendocrine and Adrenal
combination of MEN2-related features; 7) a mutation identified on tumor
Tumors, above).
genomic testing that has clinical implications if also identified in the
germline (eg, tumor analysis shows a mutation in BRCA1/2 or mismatch NETs of the GI tract, lung, or thymus may secrete various hormones and
repair (MMR) gene); 8) a close blood relative with a known pathogenic vasoactive peptides. Bronchial and thymic NETs have been associated
variant/likely pathogenic variant in a cancer susceptibility gene; 9) a first- with adrenocorticotropic hormone (ACTH) production and are a cause of
degree relative meeting one of the above criteria but not available for Cushing syndrome.61,62 NETs arising in the small intestine or appendix are
testing; and 10) clinical suspicion for MEN1 due to 2 or more of the more commonly associated with carcinoid syndrome, related to the
following, or 1 of the following and a family history of 1 or more of the secretion of serotonin, histamine, or tachykinins into the systemic
following: primary hyperparathyroidism, duodenal/pancreatic NET, pituitary circulation causing episodic flushing and diarrhea.63 Approximately 50% to
adenoma, or foregut carcinoid (bronchial, thymic, or gastric). Genetic risk 66% of patients with carcinoid syndrome develop valvular cardiac
evaluation should be considered at any age in patients with complications consisting of tricuspid regurgitation and/or pulmonary
duodenal/pancreatic NET. stenosis.64
Genetic syndromes covered in this section include hereditary The metabolic products released by intestinal NETs are rapidly destroyed
paraganglioma/pheochromocytoma syndrome; MEN1, MEN2, and MEN4; by liver enzymes in the portal circulation. Thus, the classical syndrome,
neurofibromatosis type 1; tuberous sclerosis complex; and VHL syndrome. occurring in approximately 8% to 28% of patients with NETs,65,66 is not
Some resources are also listed for hereditary cancer predisposition usually observed unless liver metastases or rarely retroperitoneal disease
syndromes associated with ACCs such as Li-Fraumeni syndrome, Lynch have occurred, in which case hepatic metastases release metabolic
syndrome, MEN1, and familial adenomatous polyposis (see Principles of products directly into the systemic circulation via the hepatic veins.
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These guidelines address seven major subtypes of NETs of the GI tract, Imaging in NETs recommends the use of SSR PET over 111In-DPTA
lung, and thymus: 1) jejunal/ileal/colon, 2) duodenal, 3) appendix, 4) rectal, scintigraphy.69-71,76 Unless otherwise indicated, the preferred SSR-based
5) gastric, 6) bronchopulmonary, and 7) thymus. imaging in this discussion includes SSR-PET/CT or SSR-PET/MRI
Evaluation of Neuroendocrine Tumors of the Gastrointestinal Tract (Well-
imaging using 68Ga-DOTATATE, 68Ga-DOTATOC, or 64Cu-DOTATATE.
Differentiated Grade 1/2), Lung, and Thymus SSR scintigraphy using 111In-octreotide (with SPECT/CT) is appropriate
Patients who present with suspected NETs of the GI tract, lung, or thymus only if SSR-PET is not available. SSR-PET imaging is more sensitive than
should be evaluated with imaging studies to assess disease burden and SSR scintigraphy for determining SSR status. Data are limited on whether
possible primary location. Commonly used techniques include CT and long-acting SSR inhibition interferes with 68Ga-DOTATATE PET/CT
MRI. NETs of the GI tract, lung, and thymus are highly vascular and can scans, but one study77 showed that timing does not make a difference.
appear isodense with liver on conventional CT scan, depending on
Additional imaging recommendations vary by disease site and include
contrast phase. Multiphase CT or MRI scans with contrast should
colonoscopy, endoscopic ultrasound (EUS), and/or
therefore be used for evaluation of liver metastasis. Chest CT scans with
esophagogastroduodenoscopy (EGD) as appropriate for duodenal and
or without contrast are also recommended as appropriate to assess for
gastric NETs; endorectal ultrasound for rectal NETs; and bronchoscopy
lung metastases.
and brain MRI, as appropriate for bronchopulmonary NETs.
Because most NETs overexpress high-affinity receptors for
Biochemical evaluation can also be helpful in the initial diagnostic
somatostatin,63,67 a peptide hormone generated by the hypothalamus that
evaluation, particularly in patients who have clinical symptoms that are
blocks the release of growth hormones,68 somatostatin receptor (SSR)-
suggestive of hormone hypersecretion. Evaluation of serotonin secretion,
based imaging may be considered in the initial evaluation of patients with
using a 24-hour urine or plasma collection for 5-hydroxyindoleacetic acid
NETs. Such imaging can provide useful information on overall tumor
(5-HIAA), is generally recommended in patients with metastatic lung or GI
burden and location; additionally, positive imaging confirms the presence
NETs, particularly if carcinoid syndrome, manifested by symptoms of
of SSRs, which can have therapeutic implications. A major advance in
flushing and diarrhea, is suspected. Screening for hormones in
imaging NETs came with the 2016 FDA approval of PET/CT imaging using
asymptomatic individuals is not routinely recommended.
the radiolabeled somatostatin analog gallium-68 (68Ga) DOTATATE.
Several studies have shown the diagnostic utility, safety, specificity, and Chromogranin A is sometimes used as a biochemical marker in non-
high sensitivity of 68Ga-DOTATATE PET/CT.69-73 A systematic review and functioning tumors. Whereas one meta-analysis calculated the sensitivity
meta-analysis of 22 studies determined that 68Ga-DOTATATE had a and specificity of chromogranin A to be 73% and 95%, respectively, for
pooled sensitivity and specificity of 91% and 94%, respectively, for the diagnosis of NETs,78 others have questioned its value. Chromogranin A is
initial diagnosis of NETs.74 One study even showed that it was able to elevated in patients with renal or hepatic impairment and in patients
more correctly identify patients for peptide receptor radiotherapy than receiving proton pump inhibitors (PPIs), and in general should not be
111
indium-diethylenetriaminepentaacetic acid (111In-DPTA) scintigraphy.75 relied upon in isolation as a diagnostic test. In 2021, the panel removed
The 2018 Appropriate Use Criteria for Somatostatin Receptor PET chromogranin A from the algorithm as it lacks specificity and test values
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can fluctuate, which can lead to false-positive results. Unlike chromogranin Gastric Neuroendocrine Tumors
A, the NETest scores are not impacted by the use of PPIs.54 However, the Three types of gastric NETs are recognized: type 1 (associated with
panel did not include NETest in the algorithm as there are no randomized chronic atrophic gastritis or high gastric pH); type 2 (associated with
or phase II data for NETest. While these tests can be useful for select antrum-sparing type A Zollinger-Ellison syndrome); and type 3 (sporadic
patients, test results alone should not be used to guide treatment and unifocal)80 Types 1 and 2 gastric NETs are both associated with
decisions. hypergastrinemia; the major difference between them is that patients with
type 1 gastric NETs generally have antrum-sparing atrophic gastritis with a
Genetic counseling and testing for inherited genetic syndromes should be
loss of the usual negative feedback loop on the gastrin-producing cells of
considered. A workup for Cushing syndrome and carcinoid syndrome
the antrum by acid, resulting in hypergastrinemia and excess stimulation
(discussed in Evaluation and Treatment of Cushing Syndrome, below)
of the endocrine cells of the fundus, and patients with type 2 gastric NETs
may also be indicated in cases of bronchopulmonary or thymic NETs if
have evidence of acid hypersecretion secondary to gastrinoma (Zollinger-
signs and symptoms of hypercortisolemia are suspected. Details of the
Ellison syndrome).80 Type 1 gastric NETs pursue an indolent course, with
evaluation and diagnosis of a patient with Cushing syndrome from a
a rate of metastases of less than 5%. Evidence suggestive of type 1
bronchial NET have been published.79
disease includes a histologic diagnosis of atrophic gastritis on gastric
Management of Locoregional Disease biopsy, elevated gastric pH, vitamin B12 deficiency, and positive anti-
The management of locoregional NETs of the GI tract, lung, and thymus intrinsic factor antibodies (not all tests need to be done to make a
depends on tumor size, primary site, and the general condition of the diagnosis). For rare type 1 tumors that are greater than 2 cm, the workup
patient. Resection is the primary treatment approach for most localized should include multiphasic CT or MRI of the abdomen performed with
NETs of the GI tract, lung, and thymus. Although symptoms of hormone contrast. Type 2 tumors are rare and occur in the setting of gastrinoma in
hypersecretion are more common in patients with metastatic disease, for which elevated gastrin levels produce gastric neuroendocrine hyperplasia
patients with locoregional disease and symptoms of hormone and multifocal gastric NETs. A SEER-based analysis of 3523 patients with
hypersecretion, symptom control with octreotide or lanreotide is gastric neuroendocrine neoplasms found a 5-year OS rate of 53.7%.81
paramount. Octreotide and lanreotide also may be considered for tumor
Endoscopic surveillance and endoscopic resection of prominent tumors is
control in patients with locoregional disease who have SSR-positive
recommended for patients with locoregional type 1 gastric NETs every 2 to
imaging (see Management of Locoregional Advanced and/or Distant
3 years or as clinically indicated. For locoregional type 2 gastric NETs, the
Metastatic Gastrointestinal Tract (Well-Differentiated Grade 1/2),
primary gastrinoma should, in general, be resected. If the primary tumor is
Neuroendocrine Tumors or of the Bronchopulmonary or Thymic
not resected, endoscopic surveillance and endoscopic resection of
Neuroendocrine Tumors, below). Specific recommendations for
prominent gastric NETs should be considered and/or octreotide or
management of NET subtypes are described herein.
lanreotide can be given. Gastric acid hypersecretion should be managed
with high-dose PPIs. Patients with non-metastatic gastric NETs and
normal gastrin levels (type 3) often have more aggressive tumors and are
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usually treated with radical resection of the tumor and regional stage I, II, or low-grade IIIA, patients may be monitored under surveillance
lymphadenectomy. For early-stage, smaller tumors, endoscopic or wedge procedures as described (see Surveillance of Resected Neuroendocrine
resection can be considered if there is no evidence of regional Tumors of the Gastrointestinal Tract (Well-Differentiated Grade 1/2), Lung,
lymphadenopathy on EUS or other imaging.82 Endoscopic resection and Thymus, below). If the stage IIIA disease is intermediate grade,
should be reserved for small (<1 cm), superficial, low-grade tumors. observation is an option. Cytotoxic chemotherapy (category 2B) may be
considered and includes cisplatin with etoposide, carboplatin with
Thymic Neuroendocrine Tumors etoposide, or temozolomide. There are limited data on the effectiveness of
The 5-year survival rate of thymic NETs is 62%.83 Localized (stage I–II) adjuvant therapy in this setting. Response rates in small studies with less
and locoregional (stage III A/B) NETs in the thymus are generally treated than 40 patients with atypical NETs found a 19% to 22% response rate
with surgical resection without adjuvant therapy if they have been when patients were treated with any chemotherapy.87-89 Otherwise,
completely resected with negative margins. There are limited data on the efficacy has been extrapolated from small cell lung cancer trials.90-92
utility of radiation with or without cytotoxic chemotherapy in patients with
unresectable disease or in the setting of incomplete resection or positive Management of Locoregional Disease, Bronchopulmonary or Thymic
margins.84,85 Observation may be considered for patients with incomplete Neuroendocrine Tumors
resection and/or positive margins. Radiation therapy (RT) (category 3) is If surgical resection is not medically feasible for patients with low-grade,
considered in select cases by some panel members to be an option for stage IIIA/B/C bronchopulmonary disease or stage IIIA/B thymic disease,
low-grade (typical carcinoid) tumors. If tumors are intermediate grade then observation (if asymptomatic) or systemic therapy are recommended.
(atypical carcinoid), treatment with RT with or without systemic therapy Systemic therapy options include octreotide or lanreotide, if the patient is
should be considered given evidence that radiation and cytotoxic SSR-positive and/or has hormonal symptoms, everolimus, temozolomide
chemotherapy appear to have greater efficacy in tumors with higher with or without capecitabine, and RT. If the stage IIIA/B/C
mitotic and proliferative indices. For atypical carcinoid or intermediate bronchopulmonary disease or stage IIIA/B thymic disease in this setting is
disease, the data are extrapolated from small cell lung cancer intermediate grade (atypical carcinoid), additional treatment options from
recommendations. Cytotoxic chemotherapy options include cisplatin with those listed above include RT in the presence or absence of concurrent
etoposide or carboplatin with etoposide. systemic therapy (cisplatin/etoposide or carboplatin/etoposide), or
systemic therapy alone.87,88,93 Observation is also an option (if
Bronchopulmonary Neuroendocrine Tumors asymptomatic and non-progressive).
Neuroendocrine tumors are most commonly located in the lung or
bronchus and account for 30.6% of NETs.86 Surgery, including lobectomy Neuroendocrine Tumors of the Duodenum, Small Intestine, and Colon
or other anatomic resection and mediastinal node dissection or sampling, For non-functioning, localized lesions arising in the duodenum, endoscopic
is recommended for patients with stage I, II, and IIIA bronchopulmonary resection is preferred if feasible. Transduodenal local excision with
tumors. If surgery is contraindicated, thermal ablation or stereotactic body regional lymphadenectomy, and pancreatoduodenectomy are other
RT (SBRT) is recommended. If surgery is feasible and the disease is in options for primary treatment of non-metastatic duodenal NETs. If
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endoscopic resection was performed, follow-up upper endoscopy (EGD) based imaging may be considered if there are equivocal CT findings. If no
should be performed as appropriate. distant disease is identified, a right hemicolectomy should be considered.
Results from a systematic review and meta-analysis with 261 patients
For patients presenting with tumors in the jejunum, ileum, or colon, suggest that a right hemicolectomy was beneficial in appendiceal NETs
surgical resection(s) of the bowel with regional lymphadenectomy is greater than 2 cm.98 Additionally, a small proportion of appendiceal NETs
recommended. The surgical procedure should include careful examination may also contain evidence of adenocarcinoma (ie, “adenocarcinoid” or
of the entire bowel, because multiple synchronous lesions may be present. “goblet cell carcinoid”). These tumors should be managed according to the
In addition, the proximity to or involvement of the superior mesenteric NCCN Guidelines for Colon Cancer (available at www.NCCN.org).
artery and superior mesenteric vein should be assessed during surgery.
Neuroendocrine Tumors of the Rectum
Appendiceal Neuroendocrine Tumors An analysis of the SEER database revealed that patients with NET tumors
Most appendiceal NETs are identified incidentally, during appendectomy of the rectum had the best prognosis (HR, 1.87; 95% CI, 1.76-1.98). 86 The
performed for appendicitis. Most appendiceal NETs have well- treatment of rectal lesions is based on the size of the primary tumor. For
differentiated histology, and for most appendiceal tumors less than or small (<1 cm) and incidental lesions, complete endoscopic resection with
equal to 2 cm, simple appendectomy is sufficient because metastases are negative margins may be sufficient, but for resection with indeterminate
uncommon.94,95 margins and low grade (G1), endoscopy at 6 to 12 months by endoscopy
is recommended to assess for residual disease. If endoscopy results
However, some controversy exists regarding the management of
determine residual disease or intermediate grade after endoscopy, or if the
appendiceal NETs measuring less than 2 cm with more aggressive
small incidental tumors have indeterminate margins and intermediate
histologic features. A population-based study analyzing the SEER
grade (G2), the pathway for all other rectal tumors should be followed. All
database found evidence that lymph node metastases can develop in
other rectal lesions should be staged using rectal MRI or endorectal
some patients with appendiceal NETs 2 cm or smaller.96 Some NCCN
ultrasound. If the lesion is less than or equal to 2 cm or minimally invasive
Member Institutions thus consider more aggressive treatment for 1- to 2-
(T1), endoscopic or transanal excision is recommended. Given the higher
cm tumors with poor prognostic features, such as lymphovascular or
risk of invasion with larger tumors, examination under anesthesia (EUA)
mesoappendiceal invasion or atypical histologic features. In a
and/or EUS before the procedure should be considered for tumors 1 to 2
retrospective case series that included 79 patients with appendiceal
cm in size. A retrospective review found that metastases were present in
carcinoid (neuroendocrine) tumors, small-vessel invasion was a risk factor
66% of 87 patients with well-differentiated rectal NETs of 11 to 19 mm.99
for metastases in patients with tumors less than 2 cm.97
Tumors larger than 2 cm or that are node positive, those with invasion of
Patients with tumors greater than 2 cm, an incomplete resection, or
the muscularis propria (T2–T4), or those associated with lymph node
positive nodes/margins are at risk for locoregional or distant metastases.
metastases should be treated with low anterior resection or, in rare cases,
These patients should be staged with abdominal/pelvic CT or MRI scans
an abdominoperineal resection.100
with intravenous (IV) contrast. To make an unequivocal diagnosis, SSR-
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Surveillance of Resected Neuroendocrine Tumors of the Gastrointestinal review and meta-analysis revealed a predictive role of urinary 5-HIAA for
Tract (Well-Differentiated Grade 1/2), Lung, and Thymus mortality.105 During monitoring of patients after treatment of a NET,
Surveillance of bronchopulmonary and GI NETs should include complete decreasing levels of 5-HIAA indicate a response to treatment, whereas
patient history and physical (H&P) examination and a multiphasic CT or an increasing or excessive concentration indicates that the treatment has not
MRI scan with contrast (usually abdominal with or without pelvis). For been successful. However, a patient with symptoms may still have a NET
patients with primary lung and thymic tumors, chest CT scans with or even if the concentration of 5-HIAA is normal. Diet and a variety of drugs
without contrast are recommended. Surveillance imaging of the chest may can affect the 5-HIAA test. Therefore, patients should be advised not to
also be considered if clinically indicated in patients with primary GI tumors. eat avocados, bananas, cantaloupe, eggplant, pineapples, plums,
Most patients with NETs of the jejunum/ileum/colon; duodenum, rectum, tomatoes, hickory nuts/pecans, plantains, kiwi, dates, grapefruit,
and thymus; and type 3 gastric NETs with normal gastrin levels should be honeydew, or walnuts for 48 hours before the start of and during urine
reevaluated 12 weeks to 12 months after resection (earlier if the patient is collection. Medications that can increase 5-HIAA include acetaminophen,
symptomatic). After 1-year post-resection, follow-up should occur every 12 ephedrine, diazepam, nicotine, glyceryl guaiacolate (an ingredient found in
to 24 months for up to 10 years post-resection. After 10 years, surveillance some cough medicines), and phenobarbital.
should be considered as clinically indicated. If initial scans are negative,
the frequency of follow-up scans may decrease. For high-grade tumors, SSR-based imaging or 18F-fluorodeoxyglucose (FDG)-PET/CT scans (for
more frequent surveillance may be appropriate. high-grade tumors) are not routinely recommended for surveillance after
definitive resection, but may be indicated to assess disease location and
Relevant biochemical evaluations can also be performed based on pre- disease burden for comparison in cases of subsequent possible
resection findings. Elevated levels of chromogranin A have been recurrence.
associated with recurrence.101-103 In addition, an analysis of a large
prospective database showed that chromogranin A levels elevated twice In specific cases, follow-up recommendations for patients with resected GI
the normal limit or higher were associated with shorter survival times for NETs differ from the above general recommendations. For rectal tumors
patients with metastatic NETs (HR, 2.8; 95% CI, 1.9–4.0; P < .001).104 smaller than 1 cm and negative margins, prognosis is excellent and no
Chromogranin A levels can be elevated in several concurrent medical follow-up is usually required. Follow-up endoscopies with rectal MRI or
conditions, including renal or hepatic insufficiency, and are also commonly endorectal ultrasound are recommended for rectal tumors that are
elevated in the setting of concurrent PPIs. Several panelists therefore between 1 and 2 cm, 6 and 12 months after primary therapy, and then as
caution that rising chromogranin A levels in an asymptomatic patient with clinically indicated.
a tumor that looks stable on imaging does not necessarily indicate that a
patient should be initiated on a new therapy. For appendiceal tumors 2 cm or smaller without aggressive features, no
surveillance is indicated. Patients with small, well-differentiated
5-HIAA, a metabolite of serotonin, in a 24-hour urine or plasma sample appendiceal NETs are at very low risk for recurrence,106-108. However,
may also be considered as a biochemical marker in some cases, because recurrences have rarely been reported even after resection of
particularly in patients with metastatic small-intestinal NETs. A systematic
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small appendiceal tumors, any patients with symptoms of hormone differentiated or have atypical histology. If carcinoid syndrome is
hypersecretion should be more fully evaluated. suspected, a cardiology consultation and echocardiogram are
recommended to assess whether the patient has carcinoid heart disease,
For hypergastrinemic patients with type 1 gastric NETs, follow-up and SSR-based imaging may be considered to assess the SSR status of
endoscopies are recommended every 2 to 3 years or as clinically NETs.112 The echocardiogram may include a comprehensive assessment
indicated. For hypergastrinemic patients with type 2 gastric NETs, follow- of the right-sided and left-sided valves using two-dimensional, color-flow
up endoscopies should be considered. If clinically indicated, imaging and continuous wave Doppler assessment, standard assessment of right
studies should also be performed. Because gastrin levels remain and left heart size and function, and two-dimensional and color-flow
persistently high in patients with atrophic gastritis, gastrin levels are assessment of the atrial septum with an agitated saline injection if left-
generally uninformative in patients with type 1 gastric NETs. After baseline sided valve disease is present.113 The comprehensive assessment of the
gastrin, the panel does not recommend following gastrin and right-sided and left-sided valves has three components: 1) tricuspid valve
chromogranin A levels for type 1 tumors. assessment using parasternal inflow, short axis, and apical 4-chamber
views; 2) pulmonary valve assessment using parasternal outflow, short
Evaluation of Locoregional Advanced Disease and/or Distant Metastatic
Gastrointestinal Tract (Well-Differentiated Grade 1/2), Bronchopulmonary, axis, and apical or subcoastal outflow views; and 3) left-sided valves using
and Thymic Neuroendocrine Tumors standard parasternal and apical views.
Baseline imaging recommendations for patients suspected to have distant
metastatic disease include multiphase technique CT or MRI.109,110 The Twenty-four-hour urine or plasma 5-HIAA may also be considered, and
most common sites of metastases from intestinal NETs include then repeated over time to monitor subsequent disease progression. As
regional/mesenteric lymph nodes, liver, and bones. When evaluating previously mentioned, if carcinoid syndrome is suspected, evaluation of
locoregional advanced and/or metastatic NETs of the GI tract, lung, and serotonin secretion, using a 24-hour urine or plasma collection for 5-HIAA,
thymus, or for suspected carcinoid syndrome, abdominal/pelvic is recommended. Bronchial and thymic tumors may also be associated
multiphasic CT or MRI scans with IV contrast and chest CT scans with with hypersecretion of ACTH that causes the development of Cushing
contrast are recommended. Chest CT scans may be performed with or syndrome;114 therefore, if clinically indicated, patients should be screened
without contrast when evaluating for metastases from primary tumors in for hypercortisolemia. If Cushing syndrome is suspected, see discussion
other sites. below (see Evaluation and Treatment of Cushing Syndrome, below).
SSR-based imaging, if not already done, is recommended to assess the Management of Locoregional Advanced and/or Distant Metastatic
Gastrointestinal Tract (Well-Differentiated Grade 1/2) Neuroendocrine
SSR status of locoregional advanced and/or metastatic NETs of the GI Tumors
tract, lung, or thymus, if treatment with octreotide or lanreotide is being
considered. Poorly differentiated bronchopulmonary or thymic tumors may Somatostatin Analogs for Control of Symptoms and Tumor Growth
have less avidity for 68Ga-DOTATATE PET/CT;111 therefore, FDG- Patients who have metastatic NETs and carcinoid syndrome should be
PET/CT or PET/MRI may be considered for NETs that are poorly treated with octreotide or lanreotide.115 The long-acting release (LAR)
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formulation of octreotide is commonly used for the chronic management of controlled phase III trial of 135 patients with metastatic NETs and a
symptoms in patients with carcinoid syndrome. Standard doses of documented history of carcinoid syndrome, who were experiencing an
octreotide LAR are 20 to 30 mg intramuscularly every 4 weeks. Dose and average of 4 or more BMs a day while receiving stable-dose somatostatin
frequency may be further increased for symptom control as needed. analog therapy for at least 3 months prior to enrollment in the study.128
Therapeutic levels are not achieved for 10 to 14 days after LAR injection. Patients were randomized to receive placebo, telotristat ethyl (250 mg), or
Octreotide (usually 150–250 mcg subcutaneously three times daily) can telotristat ethyl (500 mg) in a 1:1:1 ratio three times per day orally for 12
be added to octreotide LAR for rapid relief of symptoms or for weeks during a double-blind treatment period. From baseline to week 12,
breakthrough symptoms.116-118 mean BM frequency reductions per day for placebo, telotristat ethyl (250
mg), and telotristat ethyl (500 mg) were -0.9, -1.7, and -2.1, respectively.
Lanreotide has a similar mechanism of action as octreotide, but is In addition, both telotristat dosages significantly decreased mean urinary
administered as a deep subcutaneous injection. Several studies have 5-HIAA compared to placebo at week 12 (P < .001).128 Compared to
shown it to be effective at controlling symptoms of hormone secretion in placebo, treatment with telotristat at either dosage did not result in a
patients with GI NETs, gastrinomas, or tumors secreting vasoactive statistically significant change in the number of observed flushing
intestinal polypeptide (VIPomas).119-123 The multinational phase III ELECT episodes;128 therefore, additional options should be considered to manage
trial randomized 115 patients with carcinoid syndrome who were either other symptoms associated with carcinoid syndrome. In the TELEPRO
naïve to or responsive to octreotide to receive 120 mg of lanreotide or real-world study, patients given telotristat ethyl had a decrease in diarrhea
placebo and evaluated the number of days patients required use of rescue and other carcinoid syndrome symptoms.129 Additional therapies that may
octreotide.124 Patients in the lanreotide arm required less frequent rescue be considered to achieve disease control are hepatic arterial embolization,
octreotide than those in the placebo arm (33.7% vs. 48.5%; P = .017). cytoreductive surgery for liver-predominant disease, or other systemic
Overall, lanreotide treatment improved symptom control, irrespective of therapy based on disease site.
prior octreotide use.124,125
During treatment for carcinoid syndrome, a cardiology consultation and
If carcinoid syndrome is poorly controlled, telotristat may be considered for echocardiogram to assess whether the patient has carcinoid heart disease
persistent symptoms (eg, diarrhea), after ruling out non-carcinoid should also be performed every 2 to 3 years,115 or as clinically indicated.
syndrome causes. Patients should be evaluated for pancreatic exocrine Cardiac heart disease is frequent in patients with carcinoid syndrome; in
deficiency and bile acid diarrhea. Telotristat or telotristat ethyl is a small- one study, 59% of patients with carcinoid syndrome were diagnosed with
molecule tryptophan hydroxylase (TPH) inhibitor, which decreases urinary tricuspid regurgitation.130,131 A study of 250 patients with carcinoid
5-HIAA levels and the frequency of bowel movements (BMs) in patients syndrome showed that patients with 5-HIAA levels of 300 μmol or greater
with carcinoid syndrome.126,127 It was approved by the FDA in February (57 mg) over 24 hours and with 3 or more flushing episodes per day were
2017 and the recommendation to use telotristat for persistent diarrhea in more likely to have carcinoid heart disease.132 To monitor disease control
this context is based on the results of the TELESTAR study. The and/or progression, surveillance imaging of the abdomen and pelvis using
TELESTAR study was a multicenter, randomized, double-blind, placebo-
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multiphasic CT or MRI every 12 weeks to 12 months and chest CT scans months (95% CI, 30.9–68.0).137 The difference in the reported median PFS
with or without contrast should be performed as clinically indicated. between the PROMID and CLARINET studies is likely explained by a
difference in the study populations, as the majority of the patients enrolled
In patients with GI tract primary tumors who have clinically significant in the CLARINET trial had stable disease in the 3 to 6 months before
tumor burden or progressive disease, initiation of either octreotide LAR or randomization.136 The long-term efficacy and safety of lanreotide was
lanreotide is recommended to potentially control tumor growth if they are demonstrated in a 48-week phase II trial with Japanese patients with
not already receiving it. The recommendation to consider octreotide LAR NETs.138 Stable disease was observed in 71.4% of patients while
in these patients is based on the results of the PROMID study, a placebo- progressive disease was observed in 21.4% of patients.
controlled phase III trial of 85 patients with metastatic midgut NETs
(proliferative index, Ki-67, up to 2%), which showed median times to tumor Patients with clinically significant progression of metastatic
progression of 14.3 and 6 months in the octreotide LAR and placebo bronchopulmonary and GI NETs can pursue several other options, as
groups, respectively (P = .000072).133 After 6 months of treatment, stable discussed below.
disease was observed in 66.7% of patients in the octreotide LAR group
and in 37.2% of patients in the placebo group. Results of long-term Resection of Metastatic Disease
survival of patients in the PROMID study134 found that median OS was not In some cases, patients with limited hepatic metastases or other sites of
significantly different between the arms (83.7 months in the placebo arm disease can undergo complete resection of the primary tumor and
and 84.7 months in the octreotide arm; HR, 0.83; 95% CI, 0.44–1.46; P = metastases with curative intent. One study of 172 patients who underwent
.51).135 However, post-study treatment included octreotide LAR in 38 of 43 hepatic resection of metastatic NETs showed that long-term survival can
patients in the placebo arm, possibly confounding interpretation of long- be achieved in selected cases: the reported 10-year OS rate was
term survival results. 50.4%.139 A systematic review reported 5-year OS rates ranging from 41%
to 100% in patients undergoing hepatic resection.140 Most patients with
The recommendation that lanreotide be considered for control of tumor resected metastatic disease, however, will eventually experience
growth in patients with clinically significant tumor burden or progressive recurrence.141,142 Noncurative debulking surgery can also be considered in
disease is based on results of the CLARINET study. The CLARINET study select cases, especially if the patient is symptomatic either from tumor
randomized 204 patients with locally advanced or metastatic bulk or hormone production.
nonfunctioning pancreatic or intestinal NETs (proliferative index, Ki-67, up
to 10%) to receive either lanreotide or placebo and followed patients for Resection of the primary site in the setting of unresectable metastases is
PFS. Results from this trial showed that treatment with lanreotide for 2 generally not indicated if the primary site remains asymptomatic and is
years resulted in an improvement in PFS over placebo (PFS, not reached relatively stable.140 However, taking a careful history is recommended as
vs. 18 months; HR, 0.47; 95% CI, 0.30–0.73; P < .001).136 Subsequent surgery may be an option for asymptomatic patients with previous,
data from a pre-planned interim analysis of the open-label extension of the intermittent obstructions. A retrospective study did not find a survival
CLARINET study estimated PFS in patients treated with lanreotide at 32.8 improvement of resecting asymptomatic primary small bowel tumors.143
However, it is not uncommon for patients with small bowel primary tumors
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to experience symptoms of intermittent abdominal pain from episodic 1 for bronchopulmonary NET) is a recommended treatment option.
bowel obstruction or bowel ischemia related to the primary tumor and However, the safety and effectiveness of everolimus in the treatment of
surrounding fibrosis. Palliative small bowel resection is recommended in patients with carcinoid syndrome have not been established. Everolimus is
these patients. an inhibitor of mTOR and was well tolerated and showed evidence of
antitumor effect in patients with advanced NETs when given with
If resection is performed and future treatment with octreotide or lanreotide octreotide LAR in a phase II trial.161 In the randomized phase III RADIANT-
is anticipated, a prophylactic cholecystectomy can be considered given the 2 trial, 429 patients with advanced NETs and carcinoid syndrome were
association between long-term treatment with somatostatin analogs and randomized to receive octreotide LAR with everolimus or placebo.162
the development of biliary symptoms and gallstones.115 Based on central review, patients receiving octreotide plus everolimus had
a median PFS of 16.4 months, compared with 11.3 months for patients
Liver-Directed Therapies for Metastatic Neuroendocrine Tumors of the
Gastrointestinal Tract (Well-Differentiated Grade 1/2) receiving octreotide alone (P = .026). This difference in the primary
endpoint of PFS did not, however, meet the predefined threshold for
For patients with locoregional advanced, liver-predominant, progressive
statistical significance. An open-label extension of the RADIANT-2 trial
disease or patients with poorly controlled carcinoid syndrome, liver-
allowed patients who had progressed or completed the double-blind core
directed therapies are recommended, mainly with the palliative goals of
phase to take everolimus plus octreotide LAR. The median OS was not
extending life and relieving hormonal symptoms.144-147
statistically different for patients receiving everolimus plus octreotide LAR
Cytoreductive surgery or ablative therapies such as radiofrequency (29.2 months) or placebo plus octreotide LAR (during the open-label
ablation (RFA) or cryoablation may be considered if near-complete extension; 35.2 months) at the final cutoff date.163 Adverse events
treatment of tumor burden can be achieved (category 2B).148-152 Ablative associated with everolimus included stomatitis, rash, fatigue, and
therapy in this setting is non-curative. Data on the use of these diarrhea.162,163 Other side effects have also been described.164-166
interventions are emerging. For unresectable liver metastases, hepatic
A subsequent trial, RADIANT-4, was an international, double-blind,
regional therapy (arterial embolization,153 chemoembolization,154-156 or
placebo-controlled, phase 3 trial that randomized 302 patients with
radioembolization [category 2B])156-160 is recommended. No single
progressive, non-functional lung or GI NETs 2:1 to receive everolimus or
modality of embolization therapy has been shown to be superior to
placebo.167 In contrast to RADIANT-2, patients in RADIANT-4 were not
another, but there is a difference in both long-term and short-term
receiving a somatostatin analog at the time of study enrollment and
toxicities among the different modalities. Palliative RT is recommended for
concurrent somatostatin analog was not a study requirement. Median PFS
symptomatic bone metastases.
was 11.0 months (95% CI, 9.2–13.3) in the everolimus arm and 3.9
Everolimus for Advanced Neuroendocrine Tumors of the Gastrointestinal months (95% CI, 3.6–7.4) in the placebo arm. The hazard ratio for
Tract (Well-Differentiated Grade 1/2), Lung, and Thymus progression or death was 0.48 (95% CI, 0.35–0.67; P < .001). Drug-
For patients with progressive metastatic GI tract NETs or intermediate related grade 3/4 adverse events included stomatitis (9% vs. 0%),
grade (atypical carcinoid) bronchopulmonary NETs, everolimus (category infections (7% vs. 0%), diarrhea (7% vs. 2%), anemia (4% vs. 1%), fatigue
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(3% vs. 1%), and hyperglycemia (3% vs. 0%). A real-world report A phase II trial assessed bevacizumab plus capecitabine and included 49
highlights the outcomes of 169 pretreated patients with advanced NETs of patients with advanced and/or metastatic GI NETs.176 A PFS of 23.4
the pancreas (n = 85) or other sites (n = 84) who received everolimus months was reported, with 18% of patients achieving a partial response
through a compassionate use program.168 An increased risk of adverse and 70% achieving stable disease. Similar results were seen in 2 small
events in patients who had received previous radiolabeled peptide therapy trials of FOLFOX (fluorouracil, leucovorin, oxaliplatin) and CAPEOX
or chemotherapy was noted. An exploratory analysis of a subgroup of (capecitabine, oxaliplatin) combined with bevacizumab where a PFS of
patients with advanced, progressive, well-differentiated, non-functional 19.3 months and 16.7 months, respectively, was reported.177 However,
lung NETs from RADIANT-4 reported improved PFS by central review these findings have not been confirmed in phase III studies.
(HR, 0.50; 95% CI, 0.28–0.88) in the everolimus arm (9.2 months)
compared to the placebo arm (3.6 months).169 Additionally, a secondary The panel lists cytotoxic chemotherapy (namely 5-FU, capecitabine,
endpoint analysis of RADIANT-4 found that health-related quality-of-life dacarbazine, oxaliplatin, streptozocin, and temozolomide) for progressive
outcomes were maintained in patients receiving everolimus and placebo, NETs of the GI tract as a category 3 recommendation. While some
with no significant difference between them.170 panelists believe the toxicity of systemic therapy does not warrant its
widespread use in this population, others believe that it is an important
Systemic Therapy for Advanced Neuroendocrine Tumors of the alternative for patients without other options for treatment. For patients
Gastrointestinal Tract (Well-Differentiated Grade 1/2), Lung, and Thymus with clinically significant bronchopulmonary or thymic tumor burden that is
Cytotoxic chemotherapy: The benefits associated with cytotoxic low or intermediate grade, temozolomide either administered alone or in
chemotherapy in patients with advanced NETs appear, at best, to be combination with octreotide or lanreotide is an option to manage tumor
modest. Tumor response rates are generally low, and no PFS benefit has burden and any associated symptoms.87,178 In a retrospective study of 31
been clearly demonstrated.171 patients with progressive metastatic bronchial NETs, temozolomide
monotherapy was associated with partial responses in 14% of patients.178
Capecitabine was tested in patients with metastatic carcinoid A small retrospective study examined the combination of temozolomide
(neuroendocrine) tumors in a phase II trial; no objective responses were and capecitabine in patients with advanced lung NETs. The results
reported, although 13 of 19 patients were reported to have experienced showed an objective response rate (ORR) of 30%, with a median OS of 68
stable disease.172 The combination of capecitabine and oxaliplatin was months (95% CI, 35.3 months–100.7 months) and a median PFS of 13
assessed in a phase II study, with response rates of 23% in patients with months (95% CI, 4.4 months–21.6 months).179 Another study comprising
poorly differentiated NETs and 30% in well-differentiated disease.173 5- 33 patients with advanced pulmonary carcinoids treated with
fluorouracil (5-FU) was assessed in the phase III E1281 trial in temozolomide and capecitabine reported a median OS of 30.4 months and
combination with streptozocin or doxorubicin.174 Response rates in both a median PFS of 9.0 months.180
arms were around 16%. Dacarbazine was given following progression,
with a response rate of 8%. Responses to temozolomide in advanced
NETs are rare.175
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Radiolabeled Somatostatin Analogs for Advanced Neuroendocrine disease response rate of 29% to 31% and a combined disease control rate
Tumors of the Gastrointestinal Tract (Well-Differentiated Grade 1/2), of 74% to 81%.195 NCCN recommends considering PRRT with 177Lu-
Lung, and Thymus dotatate as a treatment option for some patients with advanced and/or
Several early studies initially reported that treatment with radiolabeled metastatic GI tract, bronchopulmonary, and thymic NETs that are SSR-
somatostatin analogs was associated with tumor responses in patients positive with imaging. Treatment with 177Lu-dotatate is recommended for
with advanced NETs.181-185 A prospective phase II study of radiopeptide patients with unresectable GI NETs that have progressed if there was
therapy in 90 patients with metastatic NETs refractory to octreotide SSR-positive imaging and progression on octreotide and lanreotide
showed that treatment was associated with improvement in symptoms; (category 1 for mid-gut tumors). Treatment with 177Lu-dotatate is also
radiographic regression, however, was relatively uncommon.186 Numerous recommended for patients with bronchopulmonary or thymic NETs, SSR-
large, non-randomized cohort analyses have also reported encouraging positive imaging, and disease progression while taking octreotide or
survival rates with this approach.187-189 lanreotide, if the tumor is either low grade (typical) with clinically significant
tumor burden, or intermediate grade (atypical). Please see Principles of
A recent phase III study, NETTER-1, randomized 229 patients with
Peptide Receptor Radionuclide Therapy (PRRT) with 177Lu-dotatate in
advanced midgut NETs to receive treatment with either 177Lu-dotatate or
the algorithm for practical guidance and information, including patient
high-dose octreotide. Results of this study showed that treatment with
eligibility, patient preparation for treatment, dose and administration of
177Lu-dotatate was associated with a significant improvement in PFS (not
177Lu-dotatate, post-treatment instructions, and timing of somatostatin
reached vs. 8.4 months; P < .0001).190 Objective tumor responses were
analogues.
observed in 18% of patients who received 177Lu-dotatate versus 3% in
the control group (P < .001). Another recent study examined the long-term For patients with locoregional advanced disease and/or distant
efficacy, survival, and toxicity of 177Lu-dotatate in a group of 610 Dutch metastases of the GI tract, following progression on octreotide or
patients with metastatic gastroenteropancreatic and bronchial NETs.191 lanreotide, everolimus and PRRT with 177Lu-dotatate are preferred
PFS and OS for all patients were 29 months [95% CI, 26–33 months] and regimens while the cytotoxic chemotherapy regimens listed above are
63 months (95% CI, 55–72 months), respectively.191 Other smaller studies “useful in certain circumstances.”
also found improved OS (58.8 months, n = 114)192 and median PFS (20.1
months with typical disease and 15.7 months with atypical disease; n = Use of Somatostatin Analogs with 177Lu-dotatate
34)193 with peptide receptor radionuclide therapy (PRRT) treatment in Most patients treated with PRRT will have progressed on first-line
patients with advanced bronchopulmonary NETs. somatostatin analog treatment. Patients with hormonally functional tumors
should continue octreotide or lanreotide along with 177Lu-dotatate. It is
PRRT with 177Lu-dotatate was approved by the FDA in January 2018 for unclear whether patients with nonfunctional tumors benefit from
the treatment of adult patients with unresectable, low- or intermediate- continuation of somatostatin analog treatment during and after 177Lu-
grade, locally advanced or metastatic gastroenteropancreatic NETs.194 A dotatate treatment. A recent study looked at whether 68Ga-DOTATATE
meta-analysis of 18 studies with 1920 patients with unresectable uptake before or after long-acting somatostatin analog treatment was
metastatic NETs treated with 177Lu-dotatate PRRT found a pooled
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affected in patients with NETs and found that the uptake in the primary multiphasic CT or MRI scans every 3 to 6 months. Alternatively, these
tumor and metastatic sites were not compromised.77 However, there are patients can be treated with octreotide and lanreotide (if the patient is
still theoretical concerns regarding the competition between somatostatin SSR-positive and/or has hormonal symptoms). No clear consensus exists
analogs and 177Lu-dotatate for SSR binding. Somatostatin analog on the timing of octreotide or lanreotide initiation in asymptomatic patients
treatment interruption may not be necessary, but the panel recommends with metastatic NETs and low tumor burden. Although initiation of
the following adjustments. Concomitant use of long-acting somatostatin octreotide or lanreotide is an option in these patients, deferring initiation
analogs such as lanreotide and octreotide is not recommended in the 4 to until evidence of tumor progression is seen may also be appropriate in
6 weeks prior to each treatment with 177Lu-dotatate. Additionally, short- selected patients. The phase 3 RADIANT-2 trial included 44/429 patients
acting somatostatin analogs should be stopped 24 hours before each with lung NETs and only nine of these were atypical carcinoids.89
177Lu-dotatate treatment. Somatostatin analogs (short- and long-acting) However, this study did not stratify according to the type of tumor; 33
can be resumed 4 to 24 hours after each 177Lu-dotatate treatment. IV patients received octreotide LAR + everolimus and 11 patients received
infusion of amino acids is a critical part of 177Lu-dotatate therapy for octreotide LAR + placebo. As with GI primary tumors above, there is no
nephroprotection. clear consensus on the timing of initiation of octreotide or lanreotide in
such patients and either approach may be appropriate in selected
Liver Transplantation Considered Investigational for Liver Metastases of patients.
Neuroendocrine Tumors of the Gastrointestinal Tract (Well-Differentiated
Grade 1/2) A clinical trial is preferred for patients with clinically significant tumor
Several series have now reported the results of liver transplantation burden and low grade (typical carcinoid) disease, evidence of disease
patients with carcinoid tumors whose metastases are confined to the progression, intermediate grade (atypical carcinoid) disease, or
liver.196-201 Results from a multicenter database of 85 patients at 28 symptomatic disease. Observation can be considered if asymptomatic or
centers who underwent liver transplantation for NETs were also for tumors on the lower end of the proliferative index-defined spectrum.
reported.202 A meta-analysis showed that, while 5-year survival rates are Treatment options include initiation of octreotide or lanreotide, if the
encouraging, the majority of patients undergoing liver transplantation patient is SSR-positive and/or has hormonal symptoms. Additional options
ultimately develop recurrence.203 The panel acknowledged the include initiation of everolimus (based on the results of the RADIANT 4
considerable associated risks and deemed liver transplantation to be study, described above) (category 1 for bronchopulmonary NET with
investigational and not part of routine care at this time. distant metastases), PRRT with 177Lu-dotatate (if the patient is SSR-
positive and progresses on octreotide and lanreotide), and liver-directed
Management of Distant Metastatic Bronchopulmonary or Thymic
Neuroendocrine Tumors therapy for liver-predominant disease. Cisplatin/etoposide,
Lung NETs include a spectrum from low-grade typical NETs to carboplatin/etoposide, or temozolomide, 178 with or without
intermediate-grade atypical NETs.204 If patients present with capecitabine,179,180 can be considered for intermediate grade (atypical
asymptomatic, low tumor burden that is low grade (typical carcinoid), they tumors) with Ki-67 proliferative index and mitotic index in the higher end of
can be observed with chest CT scans with contrast and abdominal/pelvic the defined spectrum.87 For symptom control, the addition of focal therapy,
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such as endobronchial therapy debulking or ablation, can be considered. somatostatinomas (80%–90%) are associated with a relatively high risk for
A clinical trial, everolimus, octreotide, and lanreotide are preferred metastases.206 The remaining rare pancreatic NETs include VIPoma and
treatment options while PRRT with 177Lu-dotatate and the chemotherapy cholecystokinin-producing tumors.207
regimens are listed as “useful in certain circumstances.”
Pancreatic NETs occurring in patients with MEN1 are typically multiple
Although rare, some patients may present with multiple lung nodules or and require different treatment strategies from those used for patients
tumorlets and widespread peripheral airway neuroendocrine cell with sporadic pancreatic NETs, which are usually solitary (see MEN1,
hyperplasia. In this case, a diagnosis of diffuse idiopathic pulmonary below). Gastrinoma and insulinoma are the most common pancreatic
neuroendocrine cell hyperplasia (DIPNECH) can be made.204 This NETs in patients with MEN1.208
condition is generally indolent, and patients can be observed with chest
CT scans without contrast every 12 to 24 months or as clinically indicated. Evaluation of Neuroendocrine Tumors of the Pancreas (Well-Differentiated
Grade 1/2)
If patients are symptomatic, treatment with octreotide or lanreotide (if
The recommended evaluation also includes an abdominal multiphasic CT
SSR-positive and/or chronic cough/dyspnea is not responsive to inhalers)
or MRI scan (with or without pelvis). A chest CT scan with or without
is recommended.
contrast may be included as appropriate. SSR-based imaging and EUS
Neuroendocrine Tumors of the Pancreas (Well-Differentiated Grade can also be considered if additional imaging is needed.209 Consideration of
1/2) genetic counseling and testing for inherited genetic syndromes is
According to a population-based study, malignant pancreatic NETs recommended for all patients with pancreatic NETs. Personal and family
account for approximately 1% of pancreatic cancers by incidence and 10% history should also be evaluated in patients with pancreatic NETs for the
of pancreatic cancers by prevalence.205 Although the peak incidence of possibility of MEN1 (see Multiple Endocrine Neoplasia, below) or other
occurrence is between ages 40 and 69 years, a significant number of hereditary syndromes as appropriate.
patients diagnosed with pancreatic NETs are younger than 35 years.205,206
Hormone-secreting tumors, even when very small, may result in significant
Based on an analysis of pancreatic NETs in the SEER database from
clinical symptoms, and lesion identification can be difficult.210 These cases
1973 to 2000, the annual incidence per 1 million was 1.8 in females and
often require additional imaging, such as EUS and somatostatin
2.6 in males.51 An estimated 40% to 91% of pancreatic NETs are
scintigraphy.
nonfunctional. The remainder manifest with clinically evident hormonal
symptoms.12,51 Consistent with these numbers, analysis of the NCCN Because many pancreatic NETs secrete hormones, biochemical
NETs Outcomes Database found that 22% of patients with pancreatic evaluation should also be considered in patients with pancreatic NETs.206
NETs have a hormonal syndrome.65 Of these functioning tumors, up to Biochemical evaluation is generally guided by the presence of symptoms
70% are insulinomas, and only 10% are associated with metastases. that might indicate excess hormone secretion. Screening for hormones in
Approximately 15% are glucagonomas. Gastrinomas and asymptomatic individuals is not routinely recommended. However,
somatostatinomas account for another 10%; gastrinomas and chromogranin A is non-specific and is often elevated in all NETs. The
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range of symptoms associated with hormonal secretion is diverse. Classic gastrinoma includes measurement of serum gastrin levels.215 Diagnosis of
syndromes include those associated with insulinomas, which secrete gastrinoma can be confounded by the concurrent use of PPIs, which will
insulin, resulting in fasting or nocturnal hypoglycemia. Gastrinomas elevate serum gastrin levels. Importantly, most patients who are found to
secrete gastrin, and patients often present with recurrent peptic ulcers. have an elevated level of serum gastrin do not have a gastrinoma but
Glucagonomas are associated with the development of hyperglycemia or have achlorhydria or are receiving PPIs or antacids. To confirm diagnosis,
diabetes mellitus and/or migratory necrolytic erythema. Patients with gastrin levels must be measured after the patient is off PPI therapy for at
somatostatinomas may also present with hyperglycemia or diabetes least 1 week.216
mellitus and/or diarrhea/steatorrhea. VIPomas are characterized by watery
diarrhea, hypokalemia, and achlorhydria (WDHA syndrome) from Imaging with abdominal multiphasic CT/MRI scan (with or without pelvis)
secretion of VIP. The guidelines describe appropriate tests for each of with IV contrast is recommended. Other tests, such as SSR-based
these situations. Non-functioning tumors are not accompanied by any imaging, chest CT scan with or without contrast, EUS, and other
symptoms or hormone secretion, but often have elevated pancreatic biochemical tests may be performed as appropriate. Approximately 70% of
polypeptide (PP; category 3) and chromogranin A. PP has more utility than patients with MEN1 and gastrinoma have tumors situated in the
chromogranin A and can be useful in a prognostic setting but test results duodenum.
alone should not be used to guide treatment decisions.
Evaluation of Insulinomas
Chromogranin A levels are elevated in 60% or more of patients with either Insulinomas should be suspected in people who have hypoglycemia
functioning or nonfunctioning pancreatic endocrine tumors.211-213 In (generally fasting or nocturnal) and a pancreatic mass. However, some
addition, analysis of a large prospective database found that chromogranin insulinomas can be small and not visible on imaging and so should be
A levels elevated twice the normal limit or higher were associated with suspected in persons presenting with hypoglycemia. Evaluation with a 72-
shorter survival times for patients with metastatic NETs (HR, 2.8; 95% CI, hour fast, which tests serum insulin, pro-insulin, and C-peptide during
1.9–4.0; P < .001).104 Chromogranin A was also found to be a prognostic concurrent hypoglycemia, is the gold standard.217 An insulin level greater
factor in a prospective study of patients treated with everolimus.214 Care than 3 mcIU/mL (usually >6 mcIU/mL), C-peptide concentrations of at
should be taken in measuring chromogranin A and interpreting the results, least 0.6 ng/mL, and proinsulin levels of greater than or equal to 5 pmol/L
because spuriously elevated levels of chromogranin A have been reported when fasting blood glucose is less than 55 mg/dL is suspicious for
in patients using PPIs, those with renal or liver failure, those with insulinoma.217 Other biochemical tests may be performed as appropriate.
hypertension, and those with chronic gastritis. Other causes of hypoglycemia, such as adrenal insufficiency and
malnutrition, and other causes of non–insulin-mediated hypoglycemia
Evaluation of Gastrinomas should be ruled out prior to performing a 72-hour fast. The Endocrine
Gastrinoma should be suspected in patients with severe and refractory Society Guidelines on Hypoglycemia have details regarding the general
gastroduodenal ulcers or symptoms such as dyspepsia, usually workup for hypoglycemia.217
accompanied by diarrhea. Evaluation of a patient with suspected
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Imaging with abdominal, with or without pelvis, multiphasic CT with with or without contrast can be performed. SSR-based imaging and EUS
contrast or MRI is recommended to localize insulinomas. Some can be performed as appropriate if the tumor is not able to be localized or
insulinomas are too small to be imaged with CT or MRI, and in those there is concern for metastatic disease. Genetic counseling and testing for
cases EUS can be useful. If imaging is negative, then insulinomas can inherited genetic syndromes should be considered.
often be localized by injecting calcium into selective pancreatic arteries
Primary Treatment of Locoregional Resectable Neuroendocrine Tumors of
and measuring the insulin levels in the right (usually) or left hepatic vein
the Pancreas (Well-Differentiated Grade 1/2)
(Imamura-Doppman procedure).218 Most experts recommend this test only
Resection is the primary treatment approach for localized pancreatic NETs
for patients with persistent or recurrent insulin-mediated hypoglycemia and
when possible, and can result in excellent outcomes. Exceptions to
when other localization tests are equivocal or negative.
surgery include patients with other life-limiting comorbidities or high
Ninety percent of insulinomas pursue an indolent course and can be cured surgical risk, particularly if tumors are small and indolent.
surgically. To rule out metastatic disease, chest CT scans with or without
Preoperative Management
contrast and SSR-based imaging can also be done. However, insulinomas
Surgical resection is the optimal treatment for locoregional pancreatic
are less consistently octreotide-avid than other pancreatic NETs, and
endocrine tumors. Before excision, however, any symptoms of hormonal
SSR-based imaging may consequently be less useful as an imaging
excess must be treated. Octreotide or lanreotide can be used for symptom
technique in insulinomas than in other tumor subtypes. SSR-based
control in most pancreatic NET subtypes.115 Octreotide or lanreotide
imaging should be performed if octreotide or lanreotide is being
should be used with caution in patients with insulinoma, because they can
considered as a treatment for metastatic disease. Octreotide or lanreotide
also suppress counterregulatory hormones such as growth hormone,
should only be administered to patients whose tumors are SSR-positive.
glucagon, and catecholamines. In this situation, octreotide and lanreotide
Patients with insulinoma should be carefully monitored when receiving
can precipitously worsen hypoglycemia and can result in fatal
octreotide or lanreotide because in some cases these drugs can
complications.219 Octreotide and lanreotide should not be used in patients
profoundly worsen hypoglycemia (see Preoperative Management,
with insulinoma who have a negative result by SSR-based imaging.
below).219
In addition, specific measures are often recommended based on
Evaluation of Glucagonomas and VIPomas
symptoms. For insulinomas, it is important to stabilize glucose levels with
For patients with recent-onset diabetes, cachexia, and/or a necrolytic
diet and/or diazoxide and/or everolimus. For gastrinomas, gastrin
erythematous skin rash and a pancreatic mass, the panel recommends a
hypersecretion may be treated with high-dose PPIs. For patients with
blood test for glucagon and blood glucose. For suspected VIPomas with
glucagonoma, treatment of hyperglycemia and diabetes is necessary,
characteristic watery diarrhea, testing for VIP and electrolytes is
especially to control blood sugars prior to surgery. All patients who might
recommended. For both glucagonomas and VIPomas, abdominal, with or
require splenectomy should receive preoperative trivalent vaccine (ie,
without pelvis, multiphase contrast-enhanced CT or MRI scans with IV
pneumococcus, haemophilus influenzae b, meningococcal group c).
contrast is recommended to identify the primary tumors. Chest CT scans
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procedures are safe for patients with insulinomas and may be associated head of the pancreas, and with distal pancreatectomy and splenectomy if
with shorter hospital stays.230 they are distally localized. Resection for larger (>2 cm) or malignant-
appearing tumors should include total removal of the tumor with negative
Surgical Management of Glucagonomas margins (including adjacent organs) and regional lymph nodes.
Most glucagonomas are malignant and calcified and located in the tail of
the pancreas, with regional node involvement. The recommended Surveillance of Resected Pancreatic Neuroendocrine Tumors (Well-
Differentiated Grade 1/2)
treatment is distal pancreatectomy with splenectomy and resection of the
Disease recurrence has been observed in 21% to 42% of patients with
peripancreatic lymph nodes. For tumors in the pancreatic head,
pancreatic NETs and can occur after many years.233-235 Higher lymph node
pancreatoduodenectomy with resection of the peripancreatic lymph nodes
ratio and Ki-67 status may indicate a higher chance of recurrence.233
is recommended. Small (<2 cm) peripheral glucagonomas are rare;
Patients should undergo follow-up 12 weeks to 12 months after resection,
enucleation or local excision with peripancreatic lymph dissection may be
or earlier if the patient presents with symptoms. After 1-year post-
considered for small peripheral tumors of the head or distal pancreas. A
resection, follow-up should occur every 6 to 12 months for up to 10 years
hypercoagulable state has been reported in 10% to 33% of patients with
post-resection with an H&P. Appropriate biochemical markers can be
glucagonoma.231,232 Therefore, perioperative anticoagulation can be
considered as clinically indicated. After 10 years, surveillance should be
considered because of the increased risk of pulmonary emboli.
considered as clinically indicated.236 Abdominal multiphasic CT or MRI
Surgical Management of VIPomas should be performed. Chest CT scans (with or without contrast) can be
Distal VIPomas are treated with distal pancreatectomy with resection of performed as clinically indicated. These surveillance recommendations
peripancreatic lymph nodes and with or without splenectomy. may also apply to cases where observation of patients with metastatic
Pancreatoduodenectomy with dissection of peripancreatic nodes is disease has been chosen. Less frequent surveillance may be appropriate
recommended for tumors in the head of the pancreas. Small (<2 cm) for low-risk tumors such as well-differentiated stage I pancreatic NETs.
peripheral VIPomas are rare; enucleation or local excision with SSR-based imaging or FDG-PET/CT scans are not recommended for
peripancreatic lymph dissection may be considered for small peripheral routine surveillance.
tumors of the head or distal pancreas.
The optimal duration of surveillance is unknown. In one study of 123
Surgical Management of Other Pancreatic Neuroendocrine Tumors patients with resected sporadic pancreatic NETs, most recurrences
(Well-Differentiated Grade 1/2) occurred within 5 years of resection, and all recurrences occurred within
The treatment recommendations for tumors secreting hormones such as 10 years.237 In select cases, including resectable locoregional or
somatostatinoma, ACTH, parathyroid hormone-related peptide (PTHrP), oligometastatic recurrence, surgical resection may be considered.
and PP are similar to those for nonfunctioning tumors. Tumors that are
small (<2 cm) and peripheral can be enucleated or resected, with or
without regional lymphadenectomy. Deeper, larger (>2 cm), or invasive
tumors are treated with pancreatoduodenectomy if they are located in the
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Management of Locoregional Advanced and/or Metastatic Neuroendocrine abdominal and pelvic multiphasic CT or MRI scans every 12 weeks to 12
Tumors of the Pancreas (Well-Differentiated Grade 1/2) months until clinically significant disease progression occurs. Chest CT
To evaluate the extent of locoregional advanced disease and/or distant scans with or without contrast may also be performed if clinically indicated.
metastases, multiphasic CT or MRI scans with IV contrast of the In addition, however, treatment with lanreotide or octreotide can be
abdomen, with or without pelvis, should be performed. SSR-based considered (see discussion below). The optimal time to begin therapy in
imaging is also recommended. A chest CT scan with or without contrast this patient population is not known.
and appropriate biochemical evaluation may be carried out if clinically
indicated. Metastases in patients with NETs of the pancreas, when they For symptomatic patients with unresectable disease, those who initially
develop, often occur first in the liver. In patients with limited hepatic present with clinically significant tumor burden, or those with clinically
disease, surgical excision of both the primary tumor and liver metastases significant disease progression, octreotide or lanreotide should be
should be considered with curative intent when possible and can be considered if patients are not already receiving treatment with these
performed in a staged or synchronous fashion. A meta-analysis reported options. Several different options can be considered if the disease
that 5-year OS ranges from 41% to 100% in this patient population.140 continues to progress. Systemic options include targeted therapy
Noncurative debulking surgery can also be considered in select cases. (everolimus [category 1 for progressive disease], sunitinib [category 1 for
When performing staged pancreatoduodenectomy and liver resection, progressive disease], and consideration of belzutifan [in the setting of
hepatectomy should be considered before pancreatic resection to reduce germline VHL alteration in patients with progressive pancreatic NETs]);
the risk of perihepatic sepsis from the contaminated biliary tree.238 PRRT with 177Lu-dotatate if SSR-positive imaging and progression on
Although resection may provide clinical benefit, most patients with octreotide or lanreotide) temozolomide/capecitabine or treatment with
metastatic disease will experience recurrence.141,142 Additional resection or other cytotoxic chemotherapy; or palliative RT for symptomatic bone
ablation may be possible. A study of 172 patients who had liver resection metastases. The options above, as well as liver-directed therapies, are
of metastatic NETs (55 with the primary tumor in the pancreas) showed discussed in more detail in the following sections. These regimens were
that significant long-term survival can be achieved after recurrence in also preference stratified. Everolimus, octreotide, lanreotide, sunitinib,
many patients, with a 10-year OS rate of 50.4%.139 temozolomide/capecitabine, and PRRT with 177Lu-dotatate are preferred
treatment options. Cytotoxic chemotherapy options, for patients with bulky,
If resection is performed for advanced NETs and future treatment with symptomatic, and/or progressive disease are listed as “other
octreotide or lanreotide is anticipated, cholecystectomy is recommended recommended” regimens and include 5-FU/doxorubicin/streptozocin,
given the association between long-term treatment with somatostatin streptozocin/doxorubicin, streptozocin/5-FU, FOLFOX, and CAPEOX.
analogs and the development of biliary symptoms and gallstones.115 Consideration of belzutifan is a “useful in certain circumstances” option.
Unfortunately, most patients who present with advanced pancreatic NETs Somatostatin Analogs
have unresectable disease. For selected patients with unresectable
Patients with pancreatic NETs and symptoms of hormone hypersecretion
disease who are asymptomatic and have low tumor burden and stable
should, in most cases, receive treatment with either lanreotide or
disease, observation can be considered, with marker assessment and
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octreotide and/or other medication to manage their symptoms as associated with everolimus is independent of prior or concurrent
previously described. Patients without hormone-related symptoms who somatostatin analog therapy or prior chemotherapy.167,240,241 Everolimus
have uptake with somatostatin scintigraphy can also be considered for can also be considered to stabilize glucose levels for patients with
treatment with octreotide or lanreotide. Results from the CLARINET study, insulinomas.242 Adverse events associated with everolimus include
in which 204 patients with gastroenteropancreatic NETs (including both stomatitis, hyperglycemia, and, in rare cases, pneumonitis.239 Other side
carcinoid and pancreatic NETs) were randomized to receive treatment effects have also been described.164-166 One report highlighted the
with either lanreotide or placebo, showed that treatment with lanreotide outcomes of 169 pretreated patients with advanced NETs of the pancreas
was associated with in an improvement in PFS (PFS, not reached vs. 18 (n = 85) or other sites (n = 84) who received everolimus through a
months; HR, 0.47; 95% CI, 0.30–0.73; P < .001).136 Although no compassionate use program.168 A higher risk of adverse events was noted
randomized studies to date have directly shown an antitumor effect of in patients with previous radiolabeled peptide therapy and chemotherapy.
octreotide in pancreatic NETs, the PROMID trial showed an improvement
in its primary endpoint of time to tumor progression (14.3 vs. 6 months; P Sunitinib, administered orally at a dose of 37.5 mg once daily, was
= .000072) in carcinoid (neuroendocrine) tumors of the midgut.133 compared with placebo in a multicenter randomized study of patients with
Lanreotide and octreotide share the same mechanism of action, and the advanced, progressive, metastatic pancreatic NETs.243 The study was
panel believes that either lanreotide or octreotide are appropriate options designed to enroll 340 patients but was discontinued after enrollment of
for tumor control in this setting. 171 patients, before the predefined efficacy analysis. At discontinuation,
patients who received sunitinib had a median PFS duration of 11.4
Additional therapies can be given in place of or in addition to octreotide or months, compared with 5.5 months for patients receiving placebo (P <
lanreotide, as discussed below. .001). The ORR seen with sunitinib was 9.3%.243 A large proportion of
patients on the placebo arm subsequently received sunitinib at
Molecularly Targeted Therapies progression, and no significant difference in OS was observed between
The molecularly targeted agents everolimus and sunitinib have been the arms.244 Long-term treatment (median 87.1 weeks) did not alter the
confirmed to have antitumor activity and to improve PFS in patients with safety profile.245 Adverse events associated with sunitinib include fatigue
advanced pancreatic NETs. In addition, data have shown the clinical and, in rare cases, congestive heart failure.246 Other side effects have also
benefits of belzutifan in patients with pancreatic NETs not requiring been described, including diarrhea, mucositis, and weakness.247-249
immediate surgery, in the setting of germline VHL.
A phase II study evaluated belzutifan in 61 patients with germline VHL
Everolimus, administered orally at a dose of 10 mg once daily, was alterations who had localized/nonmetastatic renal cell carcinoma and
evaluated in a multicenter study (RADIANT-3) enrolling 410 patients with allowed the presence of VHL disease-associated tumors in other organ
advanced, progressive, pancreatic NETs.239 In this study, the median PFS systems.250 The study excluded patients with prior systemic anticancer
duration for patients randomized to everolimus was 11.0 months, therapy, including anti-vascular endothelial growth factor (VEGF) therapy,
compared with 4.6 months for patients receiving placebo (P < .001). patients needing immediate surgical intervention for tumor treatment, or
Subset analyses of RADIANT-3 suggested that the PFS benefit
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patients with evidence of metastatic disease on screening imaging, but Oral temozolomide-based therapy is also used in patients with advanced
included patients with pancreatic NETs and central nervous system pancreatic NETs. Temozolomide has been administered using different
hemangioblastomas. Data showed that belzutifan resulted in an ORR of schedules, either alone or in combination with other agents.175,254-257 A
91% in 22 patients with pancreatic NETs, as assessed by an independent retrospective series reported that the combination of temozolomide with
review committee using RECIST, version 1.1. Fourteen percent of patients capecitabine was associated with an objective radiographic response rate
achieved a complete response. The median time to response and median of 70% and a median PFS of 18 months.257 Another retrospective review
duration of response for these patients were 5.5 months (range, 2.5 of the temozolomide and capecitabine combination reported a 61%
months–16.4 months) and not reached (range, 2.9+ months–22.3+ months), response rate in 18 patients, with 1 surgically proven complete pathologic
respectively, with responses still ongoing at the time to data cutoff (median response.258 A meta-analysis of 384 patients with advanced
follow-up of 21.8 months [range, 20.2 months–30.1 months] for all patients). neuroendocrine neoplasms reported an OS greater than 12 months and a
The most common grade 3 adverse events were anemia (8%), 73% disease control rate.259 Another study with 32 patients found that the
hypertension (8%), and fatigue (5%) across all patients. combination treatment led to a median OS of 24 months and improved
PFS.260
Cytotoxic Chemotherapy for Advanced Pancreatic Neuroendocrine
Tumors (Well-Differentiated Grade 1/2) Temozolomide-based combination regimens have also been formally
Cytotoxic chemotherapy is another option for patients with locoregional evaluated in prospective, phase II studies. One such study assessed the
advanced or metastatic pancreatic NETs. While a number of regimens safety and efficacy of temozolomide administered with bevacizumab, a
have been associated with antitumor activity in this setting, there is no monoclonal antibody targeted against VEGF.254 Five of the 15 patients
panel consensus on which cytotoxic chemotherapy regimen is best. The (33%) with pancreatic NETs had a radiographic response (with no
alkylating agents streptozocin and temozolomide appear to have the most responses in the 19 patients with carcinoid tumors), and the toxicity was
antitumor activity in pancreatic NETs. acceptable. The combination of temozolomide with everolimus has also
been studied and found to be safe, with partial responses observed in
Streptozocin is FDA approved for use in patients with advanced pancreatic
40% of patients with pancreatic NETs.261
NETs. The combination of doxorubicin and streptozocin was initially
reported to be associated with an overall response rate of 69% and a These results suggest that the activity of temozolomide in pancreatic
survival benefit in a relatively small randomized study of patients with NETs is at least comparable to that of streptozocin, and support its use in
advanced pancreatic NETs.251 A retrospective review from MD Anderson pancreatic NETs. The combination of temozolomide with everolimus has
Cancer Center reported an ORR of 39% with the combination of 5-FU, also been studied. There is no current consensus, however, on the optimal
doxorubicin, and streptozocin.252 A phase II trial assessed bevacizumab temozolomide dosing regimen or whether temozolomide should be
combined with 5-FU and streptozocin.253 A PFS of 23.7 months was administered alone or in combination with other agents.
reported, with 56% of patients achieving a partial response and 44%
achieving stable disease. Other cytotoxic agents appear to be less active than streptozocin or
temozolomide in pancreatic NETs. 5-FU was assessed in the phase II/III
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E1281 trial in combination with streptozocin or doxorubicin in patients with The panel recommends PRRT with 177Lu-dotatate as a treatment option
NETs of various locations, including the pancreas.174 Response rates in for patients with locoregional advanced pancreatic NETs and/or distant
both arms were around 16%. Dacarbazine was given following metastases who have symptomatic disease, clinically significant tumors
progression, with a response rate of 8%. Other studies have also shown burden, or clinically significant progressive disease, and disease
the combination of 5-FU and streptozocin to be effective in this progression with positive SSR imaging.
setting.262,263 One study with 88 patients with pancreatic NETs found a
partial response rate of 31%, a median PFS of 9 months, and an OS of 30 Liver-Directed Therapies
months,264 while a smaller study obtained a disease control rate of 78% Liver-directed therapies may be considered in patients with progressive
with the use of FOLFOX.265 The combination of capecitabine and liver-predominant metastatic disease, to reduce tumor bulk and relieve
oxaliplatin was assessed in a phase II study, with response rates of 23% symptoms of hormone hypersecretion.146 The panel lists cytoreductive
in patients with poorly differentiated NETs and 30% in well-differentiated surgery or ablative therapy (ie, RFA,152 cryotherapy, microwave149,151)
disease.173 As oxaliplatin-based chemotherapy has shown some promising (category 2B) as recommendations for these patients. Although some
results,266 more studies are needed to expand these findings. groups report that the risks of cytoreductive surgery outweigh its
benefits,268 others have reported good outcomes.269,270
Radiolabeled Somatostatin Analogs for Advanced Pancreatic
Neuroendocrine Tumors (Well-Differentiated Grade 1/2) Additional options include hepatic regional therapies including bland
Treatment with radiolabeled somatostatin analogs has been reported to hepatic arterial embolization,153 radioembolization,157-160 and
result in tumor responses in patients with advanced pancreatic NETs.181-185 chemoembolization.271 Whereas embolization in general is considered an
Numerous large, non-randomized cohort analyses have also reported effective approach in patients with liver-predominant disease,144,145,147 only
encouraging survival rates with this approach.188,189,191 Most recently, the limited data compare the various embolization techniques, and the optimal
study of 177Lu-dotatate in a group of 610 Dutch patients with metastatic embolization approach remains uncertain. After any prior biliary
gastroenteropancreatic NETs and bronchial NETs included 133 patients instrumentation, there are increased risks of infectious complications
with pancreatic NETs.191 Patients with a primary NET in the pancreas had associated with liver-directed therapies.272
the longest OS (71 months) and six patients had a complete response.191
In general, these studies have enrolled only patients with evidence of high Liver Transplantation Considered Investigational
tumoral SSR expression. A randomized study of high-dose octreotide Several series have now reported the results of liver transplantation in
versus 177Lu-dotatate has been reported in patients with advanced patients with pancreatic NETs whose metastases are confined to the
midgut NETs, and results from this study suggest this approach is both liver.196-201,273 A meta-analysis showed that, while 5-year survival rates are
safe and associated with improved PFS in this setting.190 Prospective, encouraging, the majority of patients undergoing liver transplantation
randomized studies of radiolabeled somatostatin analogs have not yet ultimately develop recurrence.203 The panel acknowledged the
been completed in patients with advanced pancreatic NETs.267 considerable associated risks and deemed liver transplantation to be
investigational and not part of routine care at this time.
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Neuroendocrine Tumors of Unknown Primary Colonoscopy can also be considered, especially in cases of well-
A SEER database analysis reported high incidence rates for NETs with an differentiated liver metastases, to identify possible primary tumors in the
unknown primary site of 0.84 per 100,000 persons.1,2 When a NET of small intestine or colon.278 It is not uncommon for small bowel NETs to be
unknown primary is diagnosed, attempts are usually first made to identify small and difficult to visualize, although in some cases imaging may
the origin of the neoplasm to help guide treatment decisions.274,275 If the demonstrate an associated mesenteric mass. Exploratory surgery is
primary tumor cannot be identified, treatment decisions are generally generally not recommended for purely diagnostic purposes. However, if a
guided by tumor histology (see Histologic Classification and Staging of small bowel primary tumor is suggested by symptoms and radiologic
Neuroendocrine and Adrenal Tumors, above). Many of these tumors are findings and if metastases are completely resectable, surgery can be
poorly differentiated and aggressive.276 considered.278
Evaluation of Neuroendocrine Tumors of Unknown Primary Primary Treatment of Neuroendocrine Tumors of Unknown Primary
The initial evaluation of a patient with biopsy-proven NETs of unknown NETs of unknown primary should be treated presumptively as
primary includes family history, clinical manifestations, laboratory studies, gastroenteropancreatic NETs. If the primary tumor is not identified, poorly
imaging studies, and/or immunohistochemical studies. Family history is differentiated NETs should be treated as described for Poorly
particularly relevant as it may identify affected relatives and patients who Differentiated Neuroendocrine Carcinomas/Large or Small Cell
are at increased risk for multiple endocrine tumors, such as patients with Carcinomas or Unknown Primary, below. In the absence of a primary
MEN1 or MEN2. tumor identified in the pancreas, well-differentiated tumors should be
treated similarly to typical grade 1/2 NETs, as described above.
Given the differences in systemic treatment approaches for carcinoid and
pancreatic NETs, establishing whether a patient has a primary pancreatic Well-Differentiated Grade 3 Neuroendocrine Tumors
NET can have important treatment implications. Potential primary sites Well-differentiated G3 NETs were introduced as a new category in the
may be investigated with imaging studies, such as chest CT scans with or 2017 WHO classification update of pancreatic NENs, and in the 2019
without contrast, and multiphasic abdominal and pelvic CT or MRI scans. WHO classification for digestive system (gastroenteropancreatic) NENs
Many express specific receptors for amines or peptides (eg, SSRs), and (including unknown primary tumors). These encompass tumors that have
SSR-based imaging may be helpful in localizing primary NETs.70,277 a high proliferation rate, with a mitotic index greater than 20 or a Ki-67
Ultrasound or EUS of the pancreas is useful for patients with possible index greater than 20%, and a well-differentiated morphology.279 These
insulinomas or other NETs of the pancreas. In addition, radionucleotide occur mostly in the pancreas, stomach, and colon, although they can
bone imaging (bone scan) is recommended to evaluate patients suspected occur at any primary site. Well-differentiated G3 tumors have a better
of having metastatic bone disease. An FDG-PET/CT or PET/MRI scan and prognosis than poorly differentiated NECs, but a worse prognosis when
brain imaging with contrast (CT or MRI) can occasionally be useful in compared to G1–G2 well-differentiated NETs.25 The results from two
finding a primary tumor, but are less sensitive in well-differentiated NETs studies showed that patients with well-differentiated G3 NETs had a
and should only be considered in cases of poorly differentiated tumors.
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significantly higher median OS (41–99 months vs. 17 months) compared histopathologic workup should dictate therapy, not solely Ki-67. For
to patients with poorly differentiated NECs.280,281 locoregional (resectable) disease, resection is recommended, along with
regional lymphadenectomy, if feasible, regardless of tumor biology.286
Evaluation of Well-Differentiated Grade 3 Neuroendocrine Tumors
Patient factors should be considered.
Imaging with multiphasic abdominal/pelvic CT or MRI scans with contrast,
with or without chest CT scans (if clinically indicated), and SSR-based For resectable locoregional disease with unfavorable biology, a clinical
PET imaging (SSR-PET) is recommended. SSR-based PET imaging trial is preferred. Neoadjuvant chemotherapy can also be given on a case-
should include PET/CT or PET/MRI of the skull base to mid-thigh with IV by-case basis and options include temozolomide with or without
contrast (both arterial and portal venous phase), when possible. Data are capecitabine, oxaliplatin-based therapy (FOLFOX or CAPEOX),
limited on the optimal timing of SSR scans following administration of cisplatin/etoposide, or carboplatin/etoposide. Temozolomide may have
somatostatin analogs. FDG-PET/CT scans can be performed as more activity in tumors arising in the pancreas. Following the completion of
appropriate if SSR PET imaging is negative. There are some instances neoadjuvant chemotherapy, the patient should undergo resection with
where FDG PET is useful in patients with positive SSR PET. Biochemical regional lymphadenectomy if feasible.
evaluation should be performed if the patient has symptoms suggestive of
a secretory tumor. Pathology review is recommended and assessment of For resectable locally advanced or metastatic disease with favorable
p53, Rb, and p16, by histopathologic analysis or molecular profiling, can biology, resection of the primary and metastatic sites may be performed, if
be considered if there is uncertainty about the tumor’s degree of feasible. The treatment for unresectable locally advanced or metastatic
differentiation, as a mutation in these genes would suggest a poorly tumors depends on the degree of tumor burden. If the patient is
differentiated NEC.282-284 SSR 2A staining may also be helpful.285 Genetic asymptomatic with low tumor burden, observation with a short interval
counseling and testing for inherited genetic syndromes is recommended follow-up scan is an option for select patients; otherwise, octreotide or
only for duodenal or pancreatic NETs. lanreotide is recommended if the patient is SSR-positive and/or has
hormonal symptoms. There are multiple treatment modalities if the patient
Primary Treatment of Well-Differentiated Grade 3 Neuroendocrine Tumors has a clinically significant tumor burden or evidence of disease
Treatment recommendations are based on the biology of the tumor. A progression. Octreotide or lanreotide is recommended if the patient is
tumor with favorable biology typically possesses Ki-67 less than 55%, is SSR-positive and/or has hormonal symptoms. Enrollment in a clinical trial
slow-growing, and may yield a positive SSR-based PET result. A tumor is preferred. Other recommended treatment options include PRRT with
with unfavorable biology typically has Ki-67% greater than or equal to 177Lu-dotatate, everolimus, sunitinib (pancreas only), chemotherapy, or
55%, is faster-growing, and may yield a negative SSR-based PET result. liver-directed therapy (for liver-predominant disease). Chemotherapy
Importantly, the data informing the appropriate Ki-67 cutoff are limited and options consist of temozolomide with or without capecitabine,260
variability/heterogeneity of Ki-67 in a given tumor and over time in serial oxaliplatin-based therapy (FOLFOX, CAPEOX), cisplatin/etoposide, or
biopsies make decision-making less straightforward in this entity carboplatin/etoposide. Pembrolizumab (category 2B) is also an option for
compared to other NENs. The combination of clinical course and patients with advanced tumor mutational burden-high (TMB-H) tumors
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(≥10 mutations/Mb), as determined by an FDA-approved test, that have Surveillance of Well- Differentiated Grade 3 Neuroendocrine Tumors
progressed following prior treatment and have no satisfactory alternative Surveillance for resectable locoregional, locally advanced, or metastatic
treatment options.287,288 There is some concern with the TMB cutoff. In disease consists of a routine patient H&P examination along with
some cancers, compared to a TMB-low status, a TMB-H status did not appropriate imaging studies (abdominal/pelvic MRI scans with contrast or
result in a higher objective response rate (ORR) in patients treated with an abdominal/pelvic multiphasic CT, and chest CT scans as clinically
immune checkpoint inhibitor,289 especially after additional cohort indicated) every 12 to 24 weeks for the first 2 years and every 6 to 12
stratification.290 Please see Principles of Peptide Receptor Radionuclide months thereafter, for up to 10 years. Surveillance for resectable
Therapy (PRRT) with 177Lu-dotatate in the algorithm for practical locoregional disease depends on the tumor biology and Ki-67%. Patients
guidance and information, including patient eligibility, patient preparation with unresectable locally advanced or metastatic disease with favorable
for treatment, dose and administration of 177Lu-dotatate, post-treatment biology should be monitored every 12 to 24 weeks (depending on tumor
instructions, and timing of somatostatin analogues. biology), with an H&P and a chest CT with or without contrast and an
abdominal/pelvic MRI with contrast or a chest/abdominal/pelvic
In the event of locally advanced or metastatic disease with unfavorable multiphasic CT scan. SSR-PET/CT or SSR-PET/MRI or FDG PET/CT
biology, a clinical trial is a preferred option. Other recommended options scans and biochemical markers are also recommended as clinically
include chemotherapy (as described above) and the combination of indicated. Patients with unresectable locally advanced or metastatic
nivolumab and ipilimumab (category 2B).291 Pembrolizumab is also an disease with unfavorable biology should follow the same surveillance
option for patients with advanced TMB-H tumors, as determined by an recommendations (except for SSR imaging) but should be followed every
FDA-approved test, that have progressed following prior treatment and 8 to 12 weeks (depending on tumor biology).
have no satisfactory alternative treatment options.287,288 Additional
chemotherapy options in this setting include irinotecan-based therapies Poorly Differentiated Neuroendocrine Carcinomas/Large or Small
(eg, FOLFIRI, cisplatin/irinotecan, FOLFIRINOX). The addition of liver- Cell Carcinomas or Unknown Primary
directed therapies, including embolization, selective internal RT, ablation, Although rare, extrapulmonary poorly differentiated NECs can occur in a
and SBRT, can be considered in selected cases with residual liver- wide variety of organs. They are characterized by a high mitotic index and
predominant disease after systemic therapy. Palliative RT is high Ki-67 index. The most aggressive of these tumors histologically
recommended for symptomatic bone metastases. resemble classic small cell carcinoma of the lung. The most frequent
organs involved are the cervix, esophagus, pharynx and larynx, colon,
Evolving data suggest that well-differentiated tumors with intermediate Ki- rectum, prostate, pancreas, and bladder.293 Most extrapulmonary poorly
67 levels (in the 20%–55% range) may not respond as well to differentiated NECs are aggressive and require combined multimodality
platinum/etoposide as patients with higher Ki-67 (>55%).34 A few studies treatment, usually following a treatment paradigm that parallels the
reported that treatment with platinum-based chemotherapy yielded almost treatment of small cell lung cancer. These tumors are rarely associated
no response (0%–2% response rate).280,281,292 with a hormonal syndrome. Gastrointestinal tumors with mixed histology of
poorly differentiated adenocarcinoma can be treated according to the
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NCCN Guidelines for Colon Cancer and Pancreatic Adenocarcinoma carboplatin/etoposide). For unresectable locoregional disease, concurrent
(available at www.NCCN.org). or sequential radiotherapy in combination with chemotherapy, or
chemotherapy alone are recommended. If metastatic disease is present,
Results from a SEER database analysis of NECs found that 9% were chemotherapy alone is recommended.
extrapulmonary.293 The median survival for all NECs was 7.7 months.
Compared to other primary NECs (26.0%), the survival was lower for lung Cytotoxic chemotherapy regimens, such as cisplatin/etoposide294,295 or
NECs (5.6%) and GI NECs (13.1%) at 5 years. The median survival of carboplatin/etoposide,296 FOLOFOX,297 FOLFIRI,298 and temozolomide
patients with GI NECs was 7.5 months, with patients with small intestine with or without capecitabine,299 are generally used as primary treatment for
tumors doing better (25.1 months) than patients with pancreatic tumors resectable, locoregional unresectable, or metastatic disease. For
(5.7 months). The median survival for patients with unknown primary locoregional unresectable or metastatic disease, additional chemotherapy
NECs was 2.5 months. options include cisplatin/irinotecan,295 carboplatin/irinotecan, and
FOLFIRINOX.300,301 The efficacy of second-line or later lines of
Evaluation of Poorly Differentiated/Large or Small Cell Carcinomas or
chemotherapy is very limited and survival is short.302 The combination of
Unknown Primary
ipilimumab and nivolumab (category 2B) can be considered if the disease
CT scans of the chest, abdomen, and pelvis or CT scans of the chest and
progresses following chemotherapy.291,303 The results of one phase II
MRI of the abdomen and pelvis are recommended as baseline staging
study (S1609 DART) revealed an ORR of 44% in patients with non-
studies. Brain imaging with MRI or CT scan with contrast and FDG-PET
pancreatic high-grade NECs (including lung primaries) treated with
should be performed as clinically indicated, and should be considered
combined ipilimumab and nivolumab.303 Subsequent data from an
routinely in poorly differentiated NECs of the thorax and neck. Biochemical
additional cohort of patients (N = 19) with high-grade NENs (median Ki-67
markers are recommended if symptoms are suggestive of a secretory
80%) revealed an ORR of 26% and a 6-month PFS of 32%.304 The median
tumor. SSR imaging is not part of the routine evaluation of poorly
PFS was 2.0 months and the median OS was 8.7 months. The subgroup
differentiated NECs. Tumor biomarkers such as microsatellite instability
analysis of the CA209-538 trial, centered on patients with advanced NENs
(MSI), MMR, and TMB testing (by an FDA-approved test) should be
that received the combined treatment, demonstrated an ORR of 24%.291
considered as they can aid in assessing targeted therapy options.
The median PFS was 4.8 months and the OS was 14.8 months. Immune-
Primary Treatment of Extrapulmonary Poorly Differentiated/Large or Small related toxicity occurred in 66% of cases. Importantly, preliminary data
Cell Neuroendocrine Carcinomas or Unknown Primary from the multi-cohort phase II study (N = 123) of durvalumab plus
For resectable poorly differentiated/large or small cell NECs, poorly tremelimumab for patients with NENs of gastroenteropancreatic or lung
differentiated of unknown primary, treatment options depend on the origin suggested only modest activity (irRECIST ORR 9.1%) in G3
disease site. Such options include surgical resection and adjuvant gastroenteropancreatic NENs.305
chemotherapy with or without radiotherapy, neoadjuvant chemotherapy
with or without radiation and resection, chemotherapy alone, RT alone, Finally, pembrolizumab can also be considered for patients with MMR-
and definitive chemoradiation (with cisplatin/etoposide or deficient, MSI-high, or advanced TMB-high (as determined by an FDA-
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approved test) tumors that have progressed following prior treatment and enlargement, hyperglycemia, and hypokalemia. Aldosterone-secreting
have no satisfactory alternative treatment options.287,288,306 tumors may present with hypertension, weakness, and hypokalemia.
Androgen-secreting tumors in females may induce hirsutism, virilization,
Surveillance of Poorly Differentiated/Large or Small Cell Carcinomas or
deepening of the voice, and oligo/amenorrhea.308 In males, estrogen-
Unknown Primary
secreting tumors may induce gynecomastia and testicular atrophy.
For patients with resectable disease, surveillance after treatment
Hormonally inactive ACCs typically produce symptoms related to tumor
completion consists of a routine H&P along with appropriate imaging
burden, including abdominal pain, back pain, early satiety, and weight
studies (chest CT with or without contrast and abdominal/pelvic MRI with
loss.308
contrast or chest/abdominal/pelvic multiphasic CT) every 12 weeks for the
first year and every 6 months thereafter. However, patients with Evaluation and Treatment of Adrenal Gland Tumors
locoregional, unresectable disease and with metastatic disease should be All patients with adrenal gland tumors need biochemical evaluation and
monitored more closely every 6 to 16 weeks with an H&P and appropriate appropriate imaging. Biochemical evaluation to evaluate for
imaging studies as described. hyperaldosteronism, Cushing syndrome, pheochromocytoma, and
suspected ACC should be done with every adrenal mass. Comprehensive
Adrenal Gland Tumors
guidelines for the workup of adrenal tumors, adrenal incidentalomas,
Adrenocortical carcinomas are rare (incidence, 0.7–2 per million).307,308 hyperaldosteronism, Cushing syndrome, and pheochromocytoma and
ACC has a bimodal age distribution, with peak incidences in early paraganglioma are published through the Endocrine Society320-322 and the
childhood and the fourth to fifth decades of life. Females are more European Society of Endocrinology (ESE).323,324
frequently affected (55%–60%).307,309 Most cases are sporadic; however,
ACCs have been observed in association with several hereditary NCCN recommends doing a morphologic evaluation of adrenal nodules
syndromes, including Li-Fraumeni syndrome, Lynch syndrome, Beckwith- with adrenal protocol CT, or MRI with or without contrast, to determine the
Wiedemann syndrome, MEN1, and familial adenomatous polyposis.8,310-315 size, heterogeneity, lipid content (with MRI), contrast washout (with CT),
The underlying mechanisms of carcinogenesis in sporadic ACCs have not and margin characteristics. If the Hounsfield unit (HU) attenuation value is
been fully elucidated; however, inactivating somatic mutations of the p53 less than 10 on unenhanced CT, then the tumor is probably benign. If the
tumor suppressor gene (chromosome 17p13316,317) and alterations at the HU attenuation value is greater than 10 on unenhanced CT, then
11p15 locus (site of the IGF2 gene318,319) seem to occur frequently. enhanced CT and washout at 15 minutes is recommended. If the absolute
washout value is greater than 60% at 15 minutes, the tumor is likely
Approximately 60% of patients present with evidence of adrenal steroid benign; if less than 60%, the tumor is possibly malignant.325,326 Functional
hormone excess, with or without virilization.308 Signs and symptoms evaluation should be done as noted above. Most ACCs secrete multiple
associated with hypersecretion of cortisol, called Cushing syndrome, hormones; therefore, if imaging is suspicious for adrenal cortical
include weight gain, weakness (primarily in proximal muscles), carcinoma, evaluation for sex steroid in addition to the above evaluation is
hypertension, psychiatric disturbances, hirsutism, centripetal obesity, indicated. If several hormones are over-secreted, ACCs are more likely.
purple striae, dorsocervical fat pad and supraclavicular fat pad
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History of a primary cancer outside of the adrenal gland raises the morphology, is lipid-poor, does not wash out on contrast-enhanced CT, is
question of metastatic disease to the adrenals. However, it is very larger than 4 cm, or is secreting more than one hormone. When malignant
important that pheochromocytoma is ruled out prior to considering hyperaldosteronism is suspected, an open adrenalectomy is
diagnostic biopsy of the adrenal mass. In these patients, an image-guided recommended, because these tumors are prone to rupture.324
needle biopsy can be considered only if clinical suspicion for
pheochromocytoma is low and plasma or urine fractionated Benign hyperaldosteronism is much more common and can be caused by
metanephrines are normal. False-negative biopsies are possible; a unilateral adrenal adenoma or bilateral adrenal hyperplasia. Adrenal vein
therefore, proceeding directly to surgery should be considered in some sampling for aldosterone and cortisol can be considered for distinguishing
cases. If the tumor is determined to be a metastasis from another site, these two causes of benign hyperaldosteronism and should be considered
treatment should be according to the appropriate NCCN disease-specific if the patient is a surgical candidate, because CT imaging cannot always
treatment guideline (to see the NCCN Guidelines Table of Contents, go to differentiate between an adenoma and hyperplasia. It may be reasonable,
www.NCCN.org). If biopsy reveals adrenal cortical tissue, then however, to exclude adrenal vein sampling in patients younger than 40
morphologic and functional evaluation should proceed as described here. years when imaging only shows one affected gland, because bilateral
hyperplasia is rare in this population. Minimally invasive adrenalectomy is
Evaluation and Treatment of Hyperaldosteronism recommended for adenoma, whereas medical management with
When hyperaldosteronism (also called primary aldosteronism) is spironolactone or eplerenone for hypertension and hypokalemia is
suspected, plasma aldosterone and plasma renin activity should be recommended for patients with bilateral adrenal hyperplasia and for
assessed. Patients with primary aldosteronism have elevated plasma nonsurgical candidates.
levels of aldosterone and low levels of renin activity. The plasma
aldosterone-to-renin ratio in patients with primary hyperaldosteronism is Evaluation and Treatment of Cushing Syndrome
usually greater than 30.322 Confirmatory testing is often recommended for Patients who present with symptoms of Cushing syndrome should be
equivocal results. Twenty-four-hour urine for aldosterone, following salt evaluated for evidence of hypercortisolemia with one of the following tests:
loading or a saline suppression test, as well as sodium and potassium 1) overnight 1-mg dexamethasone suppression test; 2) 2 to 3 midnight
levels should be considered for definitive diagnosis. Serum electrolytes salivary cortisol measurements; or 3) free cortisol in a 24-hour urine
should also be measured, because excessive aldosterone production sample.321,329 Elevated levels of cortisol are indicative of Cushing
causes both retention of sodium and excretion of potassium. The syndrome. Plasma ACTH should be checked to determine if it is ACTH
Endocrine Society has developed detailed guidelines for the detection, dependent or ACTH independent (ACTH <5 pg/mL). Adrenal masses that
diagnosis, and treatment of primary aldosteronism,322 and these guidelines secrete cortisol are not mediated by ACTH (ACTH independent), and
have been modified over time.327,328 ACTH dependent tumors can arise in the pituitary or ectopic NET sources.
If a clear pituitary adenoma is not visible by MRI, inferior petrosal sinus
Hyperaldosteronism is rarely associated with malignancy, but malignancy vein sampling can be considered to differentiate between pituitary and
should be suspected if the tumor has an irregular or inhomogeneous ectopic causes in ACTH-dependent Cushing syndrome. Endocrinology
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referral should be considered for the biochemical workup, localization of usually benign. A minimally invasive adrenalectomy is preferred for these
hypercortisolemia, and medical therapy for hypercortisolism until more tumors if resection is indicated due to tumor growth. If malignancy is
definitive therapy can be arranged. suspected and the disease is localized, locally resectable, or regionally
advanced, an open adrenalectomy is recommended.
Cushing syndrome can be associated with either benign adrenal tumors
(adrenal adenoma) or malignant adrenal tumors. Malignancy should be Evaluation of Adrenocortical Carcinoma
suspected if the tumor is larger than 4 cm or is inhomogeneous with ACC should be strongly suspected in tumors larger than 4 cm with
irregular margins and/or has local invasion and other malignant imaging irregular margins or that are internally heterogeneous and if they secrete
characteristics. Some centers may use 6 cm as a cutoff instead of 4 cm. multiple hormones.308 On CT scans with IV contrast, adjacent lymph nodes
FDG PET/CT scans, chest CT scans with or without contrast, and CT or or liver metastases may be present. On unenhanced CTs, the HU number
MRI scans with contrast of the abdomen and pelvis are recommended. is typically higher in carcinomas than in adenomas, and a threshold value
Benign adrenal tumors (ie, <4 cm, contralateral gland normal, of 10 HU has been proposed as a means of distinguishing benign from
circumscribed tumor, other benign imaging characteristics) should be malignant adrenal tumors.308 If the HU attenuation value is less than 10 on
resected. It is important that patients who have cortisol-secreting adrenal unenhanced CT, then the tumor is probably benign. If the HU attenuation
tumor receive perioperative glucocorticoids since the contralateral adrenal value is greater than 10 on unenhanced CT, then enhanced CT and
secretion will be transiently suppressed. For more details, please see the washout at 15 minutes is recommended. If the absolute washout value is
Endocrine Society's Clinical Practice Guidelines for the Treatment of greater than 60% at 15 minutes, the tumor is likely benign; if less than
Cushing Syndrome.330 60%, the tumor is possibly malignant.325,326 MRIs more clearly document
local invasion and involvement of the inferior vena cava than CT scans.308
Treatment of Nonfunctioning, Benign Adrenal Tumors Whether CT or MRI scans are performed, they should be performed using
Adrenal tumors that do not secrete hormones are often discovered an adrenal protocol to determine size, heterogeneity, lipid content (MRI),
incidentally during scans for unrelated reasons (incidentalomas). It is still contrast washout (CT), and margin characteristics.
important to evaluate for biochemical secretion of hormones for
hyperaldosteronism, Cushing syndrome, and pheochromocytoma and FDG PET/CT, chest CT scans with or without contrast, CT or MRI scans
paraganglioma as listed above to confirm they are non-secreting. Please with contrast of the abdomen and pelvis, and a biochemical workup are
refer to the American Association of Clinical Endocrinology and American also recommended for resectable, unresectable, or suspected metastatic
Association of Endocrine Surgeons (AACE/AAES) guidelines331 and the disease.
ESE guidelines324 for the management of adrenal incidentalomas. Most
nonfunctioning tumors are benign and can be left untreated. Masses One study found that 5.8% of adults with ACC tested positive for Li
showing radiographic features of myelolipoma are considered benign. In Fraumeni syndrome (TP53 gene) and genetic testing should be routinely
addition, tumors smaller than 4 cm that are homogenous, with smooth offered to all patients with ACC.332 Another analysis found that
margins, and that appear lipid-rich according to CT or MRI criteria are also approximately 3% of patients with ACC have Lynch syndrome, leading the
authors to recommend that patients with ACC also undergo genetic testing
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for Lynch syndrome.314 Patients with ACC may also consider MSI, MMR, mitotane therapy can also be considered after resection of ACC, although
and TMB (by an FDA-approved test) testing. Genetic counseling and its use in this setting is controversial (category 3). Mitotane blood levels
testing for inherited genetic syndromes is also recommended. should be monitored. Some institutions recommend target levels of 14 to
20 mcg/mL if tolerated. Steady-state levels may be reached several
Treatment and Surveillance of Non-metastatic Adrenocortical Carcinoma months after initiation of mitotane. Because of the adrenolytic effects of
Surgical resection of the tumor with removal of adjacent lymph nodes is mitotane, replacement doses of corticosteroids (hydrocortisone with or
recommended in patients with localized ACC, and may require removal of without fludrocortisone) should be prescribed to treat adrenal insufficiency
adjacent structures such as the liver, kidney, pancreas, spleen, and/or if it is used; corticosteroids may be required for the rest of the patient’s life.
diaphragm for complete resection. Open adrenalectomy is recommended Because of the potential risks and uncertain benefits of adjuvant mitotane,
in tumors with a high risk of being malignant because of increased risk for several NCCN Member Institutions do not advocate its use in the adjuvant
local recurrence and peritoneal spread when performed treatment of patients with resected ACCs.
laparoscopically.333 It is thus important to achieve negative margins and
avoid breaching the tumor capsule. A follow-up should be performed every 12 weeks to 12 months for up to 5
years, and then as clinically indicated. Recurrences after 5 years are
Because of the rarity of ACCs, no randomized, prospective trials of thought to be very rare. A chest CT scan, with or without contrast, and an
adjuvant therapy have been published. Most retrospective reports have abdominal CT or MRI scan with contrast and biomarkers (if the tumor is
examined the use of adjuvant mitotane, an oral adrenocorticolytic agent.334 initially functional) should be considered.
A recent systematic review and meta-analysis of the benefits of mitotane
after resection of ACC in patients without distant metastasis included five Management of Locoregional Unresectable or Metastatic Adrenocortical
retrospective studies reporting on 1249 patients.335 The meta-analysis Carcinoma
found benefit of adjuvant mitotane, with significantly longer recurrence-free Resection may be considered if greater than 90% of the tumor and
survival and OS, suggesting that adjuvant mitotane may be an effective metastases can be removed. In the case of bulky disease or if less than
postoperative strategy. The randomized phase III ADIUVO trial is currently 90% of the tumor is removable, surgery can be reconsidered following a
underway to assess the efficacy of adjuvant mitotane in patients with response to systemic therapy. Observation with chest CT scans with or
ACCs considered to be at low to intermediate risk for progression without contrast, abdominal/pelvic CT or MRI scans with contrast, and
(ClinicalTrials.gov identifier: NCT00777244). Disease-free survival is the relevant biomarkers (if the tumor is initially functional) every 12 weeks can
primary endpoint. also be considered for clinically indolent disease, with systemic treatment
initiated at tumor progression. For locoregional unresectable or metastatic
Based on the available data, adjuvant therapy can be considered if the disease, local therapy may be considered (ie, SBRT, thermal ablative
patient is at high risk for local recurrence based on positive margins, therapies, liver-directed therapies).
ruptured capsule, large size, and high grade. Adjuvant external beam RT
to the tumor bed can be considered in these cases, particularly if concern Systemic therapy should be considered, preferably in a clinical trial.
exists regarding tumor spillage or close margins after surgery. Adjuvant Choices of systemic therapy for advanced ACC are mitotane monotherapy
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or various combinations of cisplatin, carboplatin, etoposide, doxorubicin, Analysis of results from the international randomized controlled phase III
streptozocin, and mitotane. Mitotane monotherapy has been studied in the FIRM-ACT trial comparing treatment of metastatic ACC with etoposide,
setting of locally advanced or metastatic disease.336-338 Partial response doxorubicin, cisplatin, and mitotane versus treatment with streptozotocin
rates are thought to be 10% to 30% at most.339 Pembrolizumab can also and mitotane with a crossover design found no difference between the
be considered as a single agent or in combination with mitotane. These regimens in the primary endpoint of OS (14.8 vs. 12.0 months; HR, 0.79;
regimens were preference stratified. Preferred regimens include cisplatin 95% CI, 0.61–1.02; P = .07).345 However, response rates and PFS were
or carboplatin in combination with etoposide, with or without doxorubicin, improved with the 4-drug regimen and an OS benefit was seen in those
and with or without mitotane. Pembrolizumab, with or without mitotane, who did not cross over to the other combination (17.1 vs. 4.7 months).
and mitotane monotherapy are listed as “other recommended” regimens. Rates of serious adverse events were similar in the two arms.
Streptozocin, with or without mitotane, is listed as “useful in certain
circumstances.” However, the toxicity of concurrent chemotherapy plus mitotane should be
considered when making treatment decisions, and mitotane monotherapy
A small phase II study investigating the use of pembrolizumab in patients may still be appropriate in selected cases. The optimal doses and duration
with advanced ACCs found an ORR of 23% and a disease control rate of of mitotane treatment for metastatic disease have not yet been
52%.340 The median OS was 24.9 months. Another small study with 16 standardized, but some institutions recommend target levels of 14 to 20
patients with advanced ACC demonstrated an ORR of 14% (95% CI, 2%– mcg/mL, if tolerated. Higher doses may be difficult for patients to tolerate,
43%).341 One phase II study reported a 15% ORR and a 54% clinical whereas lower doses may be less effective.339 Steady-state levels may be
benefit rate.342 reached several months after initiation of mitotane. As noted above,
because of the adrenolytic effects of mitotane, replacement doses of
Several studies have evaluated the combination of mitotane with other corticosteroids (hydrocortisone with or without fludrocortisone) should be
cytotoxic agents, including cisplatin and etoposide. One of the larger prescribed to treat adrenal insufficiency. This replacement therapy may be
studies analyzed the combination of mitotane (4 g/day) with cisplatin, required for the remainder of the patient’s lifetime. A follow-up with chest
etoposide, and doxorubicin in 72 patients with unresectable adrenal CT scans, with or without contrast, and abdominal/pelvic CT or MRI scans,
carcinoma, yielding an ORR of 49% (according to WHO criteria) and a with contrast, or FDG-PET/CT scans should be performed every 12 weeks
complete hormonal response in 16 of 42 patients with functioning to 12 months, up to 5 years, and then as clinically indicated.
tumors.343 Another study examined the combination of mitotane with
streptozocin and reported an ORR of 36%.344 Of 12 patients in this study Pheochromocytomas/Paragangliomas
with advanced disease, 3 (25%) were converted to a resectable status Pheochromocytomas are neoplasms of the chromaffin cells of the adrenal
with this therapy and remained disease-free or with stable disease 3 to 18 medulla in 80% to 90% of cases. Ectopic/extra-adrenal
years after surgery; 1 (8%) had stable disease for 3 months, and the other pheochromocytomas that arise from sympathetic and para-aortic
8 (67%) showed no response. sympathetic ganglia are called paragangliomas.320 Pheochromocytomas
and paragangliomas occur in 0.05% to 0.1% of hypertensive patients, and
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their combined annual incidence in the United States is estimated to be careful, lifelong surveillance (see Surveillance of
between 500 and 1600 cases.346 Approximately 10% to 15% of Pheochromocytomas/Paragangliomas, below).
pheochromocytomas and paragangliomas are malignant, but it could be
Evaluation for Pheochromocytomas/Paragangliomas
up to 40%.323,347 Pheochromocytomas release catecholamines
(epinephrine and norepinephrine) and their metabolites metanephrine and A patient with possible pheochromocytoma should be evaluated with
normetanephrine, resulting in hypertension, arrhythmia, and/or fractionated metanephrines and normetanephrines in 24-hour urine or free
hyperglycemia. About 40% of paragangliomas secrete catecholamines. metanephrines in plasma. Elevated levels of metanephrines or
Head and neck paragangliomas only secrete catecholamines about 5% of normetanephrines are suggestive of pheochromocytoma or
the time and often it is dopamine. paraganglioma. In general, adrenal pheochromocytomas more commonly
secrete metanephrines and paragangliomas secrete normetanephrines,
The peak incidence of occurrence for pheochromocytomas is between the with a few exceptions.320 Concurrent medications should be reviewed
third and fifth decades of life, but they generally occur at a younger age before testing for those that interfere with plasma or blood
and are more likely to be bilateral in patients with familial disease. metanephrine/normetanephrine evaluation, including acetaminophen,
Paragangliomas are more likely to be malignant than pheochromocytomas certain beta- and alpha-adrenoreceptor blocking drugs, serotonin-reuptake
in the adrenal medulla (about 40% vs. 10%). Pheochromocytomas and inhibitors, and monoamine oxidase inhibitors.353 Elevations in
paragangliomas associated with a familial syndrome tend to be more metanephrine or normetanephrine levels that are three times above the
aggressive and more likely to metastasize than sporadic tumors.348 In fact, upper limit of normal are diagnostic. Urine or plasma catecholamines are
a study showed that 87.5% of patients presenting with these tumors prior no longer routinely recommended for the evaluation of pheochromocytoma
to age 20 harbored a germline mutation in one of several genes tested if as 15% to 20% of patients with pheochromocytoma have normal levels of
they also had metastatic disease.349 For those without metastases, the urine catecholamines due to intermittent secretion in some tumors and
rate of identification of these mutations was still high, at 64.7%. The OS of insignificant secretion by others.354 Measurement of serum and/or 24-hour
patients with pheochromocytomas and paragangliomas can be urine fractionated catecholamines can be considered since rare tumors
heterogeneous, but a systematic review and meta-analysis of seven preferentially secrete catecholamines, and cervical paragangliomas can
studies of 738 patients reported survival to be 63% at 5 years.350 secrete dopamine.
Predicting who will go on to develop metastasis is difficult, but some
studies have reported that almost half of patients have not progressed a Adrenal protocol CT scans (abdomen/pelvis) are recommended. Other
year after diagnosis.351 Delays at a median of 5.5 years with a range from imaging studies, including abdominal/pelvic multiphasic CT or MRI scans,
0.3 to 53.4 years between initial diagnosis and metastasis have been SSR-based imaging (PET/CT or PET/MRI), FDG-PET/CT scans (skull
reported in a retrospective study spanning 55 years of patients with base to mid-thigh), chest CT scans with or without contrast, and
pheochromocytomas or paragangliomas, and many such patients survive metaiodobenzylguanidine (MIBG) scans should be performed as
long term after treatment of metastatic disease.352 Thus, patients appropriate if metastatic or multifocal disease is suspected. CT scans are
presenting during childhood, adolescence, or young adulthood require most helpful for adrenal masses and paragangliomas. However, there are
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some instances where extra-adrenal paragangliomas are seen better with gene is affected and take into account known genotype-phenotype
MRI scans. relationships. MRI may be the preferable imaging modality for tumor
detection in these individuals in order to limit radiation exposure.
Genetic Counseling/Testing in Pheochromocytomas/Paragangliomas
While many pheochromocytomas and paragangliomas are thought to be Primary Treatment of Pheochromocytomas/Paragangliomas
sporadic, increasing evidence shows that a number of Surgical resection is the mainstay of treatment for both benign and
pheochromocytomas and paragangliomas are in fact associated with malignant pheochromocytomas and paragangliomas. Surgery or stress
inherited genetic syndromes.346,355 Pheochromocytomas occur in patients can cause a sudden release of large amounts of catecholamines, causing
with MEN2A, MEN2B, and other familial diseases such as very significant and sometimes life-threatening hypertension. Therefore,
neurofibromatosis and VHL syndrome (see Principles of Genetic Risk patients with pheochromocytomas or paragangliomas should receive
Assessment and Counseling in the algorithm). Paragangliomas are also preoperative alpha-adrenergic blockade with aggressive volume repletion
associated with polycythemia-paraganglioma-somatostatinoma syndrome and high-salt diet for 7 to 14 days or until stable. Alpha 1-selective
due to somatic mutations in the HIF2A gene.356,357 In addition to germline receptor blockers include terazosin, doxazosin, and prazosin, and non-
mutations associated with these syndromes (ie, RET, NF1, VHL), germline selective receptor blockers include phenoxybenzamine. If additional blood
mutations in SDHB, SDHA, SDHAF2, SDHD, SDHC, TMEM127, MAX, pressure control is needed after alpha blockade, the addition of
FH, and MDH2 have also been associated with an increased incidence of dihydropyridine calcium channel blockers can be considered. Calcium
pheochromocytomas and paragangliomas.347,355-361 SDHB gene mutations channel blockers are not recommended as monotherapy unless the
are associated with a 40% to 60% risk of developing metastatic disease.347 patient cannot tolerate alpha blockade. Metyrosine can be used in addition
Patients younger than 45 years of age or those with multifocal, bilateral, or to alpha blockade to control blood pressure. Beta blockade (B1-selective
recurrent lesions are more likely to have a heritable mutation, although blockers or non-selective beta-blockers) can also be added to alpha
many individuals with a hereditary syndrome present with solitary disease blockade to control tachycardia. Generally, alpha- and beta-blockers
and no family history.361 Because a significant proportion of patients with a should be administered independently, and use of combination beta-
pheochromocytoma or paraganglioma have a heritable mutation,355 /alpha-blockers is not recommended. Non-selective alpha blockade
genetic counseling is recommended in patients with such a diagnosis and phentolamine (IV) can be used intraoperatively for additional blood
in those with a family history of these tumors, with genetic testing when pressure control.
appropriate. The Endocrine Society has published guidelines that include
a genetic testing decision algorithm.320 Resection is the recommended treatment for patients with resectable
tumors. A minimally invasive approach, when safe and feasible, is the
Individuals with known germline mutations associated with preferred treatment for adrenal medullary tumors, including
pheochromocytomas and paragangliomas should undergo lifelong pheochromocytomas.362-364
biochemical and clinical surveillance, beginning around ages 6 to 8
years.361 The type and timing of the surveillance should be based on which For locally unresectable tumors, observation is recommended, if
asymptomatic. RT is recommended with cytoreductive resection, when
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possible. Alternatively, if tumors are positive on MIBG scan,365,366 with inoperable or metastatic pheochromocytomas or paragangliomas
treatment with high-specific-activity (HSA) iobenguane I-131 or other determined that treatment with PRRT led to an ORR of 25% (95% CI,
iodine-131-MIBG therapy is recommended. If tumors are SSR-positive 19%–32%) and a disease control rate of 84% (95% CI, 77%–89%).371
upon imaging, PRRT with 177Lu-dotatate or treatment with octreotide or Clinical responses were reported in 61% of patients.
lanreotide (if symptomatic) may be considered. The panel advises
diligence to ensure that the maximum cumulative radiation dose is not An ENETS Centre study with 22 patients with progressive or metastatic
reached for these patients. In addition, medical therapy as described pheochromocytomas or paragangliomas treated patients with PRRT with
above should be continued for unresectable secreting tumors. either 90Y-dotatate or 177Lu-dotatate, and 131I-MIBG.372 Patients treated
with PRRT had increased PFS and treatment response compared to 131I-
The results of a phase 2, open-label, multicenter study investigating HSA MIBG treatment, but no significant differences were seen in OS. Other
iobenguane I-131 to treat patients with malignant, recurrent, and/or case studies have been presented at conferences373-375 or published376,377
unresectable pheochromocytoma or paraganglioma367,368 revealed that the that have also shown improvements in patients with high SSR expressing
primary endpoint, which was a reduction in antihypertension medication by pheochromocytoma or paraganglioma treated with 177Lu-dotatate.
at least half, was met by 25% of all patients who received at least one
therapeutic dose (n = 68) and 32% of patients who received two When distant metastases are present, observation is recommended if
therapeutic doses (n = 50)369. The objective tumor response was asymptomatic. Medical therapy with octreotide or lanreotide should be
evaluated as a secondary endpoint. Overall 23% of patients had partial continued for secreting tumors. For the latter, cytoreductive resection is
response, which went up to 30% in patients who received two therapeutic recommended when possible. Other options for treating unresectable,
doses, and 68% of patients had stable disease. The median OS was 37 metastatic disease include: 1) clinical trial; 2) systemic chemotherapy (eg,
months. The most commonly reported side effects in patients who cyclophosphamide/vincristine/dacarbazine [CVD] or temozolomide)255,378-
received any dose of HSA iobenguane I-131 were nausea,
381
; 3) HSA iobenguane 131I or other iodine-131-MIBG therapy after
myelosuppression, and fatigue. In 2018, HSA iobenguane I-131 became positive MIBG scan365,366,369; 4) if SSR-positive PET imaging, consider
an FDA-approved option for patients who have an MIBG positive scan; PRRT with 177Lu-dotatate; or 5) palliative RT for symptomatic
have unresectable, locally advanced, or metastatic pheochromocytoma or metastases.
paraganglioma; and require systemic anticancer therapy.
A retrospective review of 52 evaluable patients treated with various
A study of 20 patients with high SSR expressing pheochromocytoma or systemic chemotherapy regimens for metastatic pheochromocytomas or
paraganglioma treated with 177Lu-dotatate measured the effectiveness of paragangliomas showed that patients with a response to chemotherapy
PRRT in controlling hypertension.370 Most patients receiving PRRT saw no (reduction in symptoms, antihypertensive medications, or tumor size) had
increase or reduction in medication to treat hypertension. The median PFS a median survival of 6.4 years and non-responders had a median survival
was 39 months and median OS was not reached with a median follow-up of 3.7 years.379 Approximately 33% of patients exhibited a tumor response.
time of 28 months. A systematic review and meta-analysis of 201 patients
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additional 20% to 55% of patients also have or will develop nonfunctioning hyperplasia, enteropancreatic NETs, pituitary tumors).388 For patients
pancreatic NETs.387 Approximately 2% of patients with MEN1 develop known or suspected to have MEN1, clinical evaluation includes
thymic or bronchopulmonary NETs.388 Thymic and duodenopancreatic biochemical evaluation of hormone levels and imaging to localize the site
neuroendocrine neoplasias are the leading cause of death in patients with of tumors. In particular, patients should be evaluated for pancreatic
MEN1.389 Approximately 30% of patients with MEN1 die from NETs.388 neuroendocrine, parathyroid, and pituitary tumors (see below). In addition,
genetic counseling and testing for inherited genetic syndromes should be
Examples of functional syndromes include hypercalcemia related to provided (see Genetic Counseling/Testing in MEN1, below).
parathyroid hyperplasia; galactorrhea or amenorrhea associated with a
prolactinoma; Zollinger-Ellison syndrome associated with gastrinoma and Evaluation for Parathyroid Tumors in MEN1
hypersecretion of gastrin; and Cushing’s syndrome or acromegaly related Primary hyperparathyroidism associated with parathyroid adenomas is the
to a pituitary tumor or solitary or bilateral adrenal tumors. Ectopic Cushing most common manifestation of MEN1. Measurement of serum calcium
syndrome may be caused by a neuroendocrine tumor of the pancreas, levels is recommended if hyperparathyroidism is suspected. If calcium
thymus, or bronchus, or by an MTC. In addition, although rare, patients levels are elevated, parathyroid hormone (PTH) and 25-OH vitamin D
may develop symptoms as a result of an excess of several hormones from levels should be checked.
more than one gland, such as hyperparathyroidism and a simultaneous
gastrinoma, insulinoma, or a functioning pituitary tumor. However, in most Imaging of parathyroid glands is less helpful in MEN1 because of the
patients, a single hormonal syndrome dominates the clinical picture. multiple gland hyperplasia.388 Imaging of the parathyroid glands using
neck ultrasound, 4-D CT, and/or sestamibi scanning with single photon
About 80% of patients with MEN1 and hypoglycemia related to insulinoma emission CT (SPECT) is optional but may aid in identifying ectopically
have multiple islet cell neoplasms. Patients with MEN1 and Zollinger- situated parathyroid glands. Preference of scan will depend on institutional
Ellison syndrome also frequently have more than one tumor. Of these practice/protocol.
tumors, 70% are gastrin-secreting NETs in the duodenum and/or
periduodenal lymph nodes. Nonfunctioning pancreatic NETs are usually The technetium 99m (Tc 99m) sestamibi and ultrasound scanning are
larger when clinically detected, and are more likely to be associated with about 80% and 70% sensitive, respectively, for identifying solitary
metastases at the time of presentation. The development of metastatic parathyroid adenomas found in most patients with sporadic
NETs of the pancreas or thymus are the most common causes of death hyperparathyroidism. However, these scans are only about 35% accurate
associated with MEN1. The clinical characteristics of pancreatic endocrine in patients with familial hyperparathyroidism and 4-gland hyperplasia.
tumors are summarized under Neuroendocrine Tumors of the Pancreas, Neither scan can distinguish between adenomatous and hyperplastic
above. parathyroid glands. Because most patients with familial
hyperparathyroidism have multiple abnormal parathyroid glands,
Evaluation of MEN1 Syndromes preoperative localization studies are less accurate and abnormal
A clinical diagnosis for MEN1 can be made when an individual patient has parathyroid glands are best identified during surgery.390,391 Tc 99m
two or more MEN1-associated tumors (ie, multi-gland parathyroid
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sestamibi with SPECT can improve sensitivity and specificity compared to Additional biochemical evaluation that can be considered includes
planar scan.392 measurement of thyroid-stimulating hormone (TSH [free T4]), produced by
some adenomas, and luteinizing hormone (LH) and follicle-stimulating
4D-CT is a method of multiphase CT imaging that uses a fourth dimension hormone (FSH). Screening for Cushing syndrome may also be
of changes in contrast attenuation over time and is increasingly used for considered.
preoperative imaging.393 It has 60% to 87% sensitivity and allows for more
robust diagnostic accuracy than traditional sonography or nuclear Evaluation for Bronchial/Thymic Tumors in MEN1
scintigraphy techniques. Three- or four-phase CT scanning protocols Chest CT with contrast and abdominal/pelvic multiphasic CT or MRI are
consist of precontrast, arterial, early-delayed, and late-delayed phases. recommended to evaluate for bronchopulmonary or thymic tumors in
patients with MEN1. Other biochemical evaluation should be done as
Evaluation for Pancreatic Tumors in MEN1 clinically indicated.
Approximately 75% of patients with MEN1 and pancreatic NETs have
associated symptoms of hormone hypersecretion. The various Genetic Counseling/Testing in MEN1
characteristics of endocrine tumors of the pancreas (eg, gastrinoma, Genetic counseling and MEN1 genetic testing should be offered to
insulinoma, glucagonoma, VIPoma, somatostatinoma) are summarized individuals with a clinical diagnosis of MEN1 (see Evaluation of MEN1
under Neuroendocrine Tumors of the Pancreas, above. The workup for Syndromes, above) and to at-risk relatives of individuals with known
pancreatic NETs in the context of MEN1 is similar to that for sporadic germline MEN1 mutations.387,388 Genetic risk evaluation is also
pancreatic NETs. Abdominal, with or without pelvis, multiphasic CT or MRI recommended in a patient with clinical suspicion for MEN1 with two or
is recommended. Imaging with EUS and SSR-based imaging can be used more of the following, or one of the following and a family history of one or
as appropriate if there are equivocal CT findings. In particular, EUS is more of the following: primary hyperparathyroidism, duodenal/pancreatic
recommended if resection is being considered to preoperatively assess NET, pituitary adenoma, or foregut carcinoid (bronchial, thymic, or gastric).
and localize tumors. For details on the evaluation for pancreatic tumors, It should be noted that a germline MEN1 mutation is uncommon in
see Neuroendocrine Tumors of the Pancreas, above. individuals with a single MEN1-associated tumor and no family history.
Only 10% of patients with MEN1 have a de novo germline mutation in
Evaluation for Pituitary Tumors in MEN1 MEN1, and thus no family history of MEN1-associated tumors.
Pituitary or sella MRI with contrast is recommended when evaluating for
pituitary tumors. Various laboratory tests are also used to evaluate for For patients with a clinical diagnosis of MEN1 and a negative MEN1
suspected pituitary tumors. The panel lists serum prolactin and insulin-like genetic test result, physicians should consider having the patients and
growth factor 1 (IGF-1) levels among recommended tests (category 2B). their first-degree family members follow the related surveillance
Elevated prolactin levels are indicative of prolactinoma, and increased recommendations (See MEN1 Surveillance, below).
IGF-1 occurs in acromegaly.
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Primary Treatment of MEN1 Syndromes single functioning tumor, although a reasonable approach for sporadic
Primary therapy of locoregional disease in patients with MEN1 focuses on tumors, may miss additional tumors in the setting of MEN1. MEN1-
treatment of the specific hormonal syndrome and/or treatment of the associated metastatic pancreatic NETs are often slower growing than
underlying hyperplasia or tumor. When a patient presents with metastatic sporadic tumors. Observation can be considered for non-
hyperparathyroidism and pancreatic NETs, the hyperparathyroidism is functioning, indolent tumors. Surgical resection should be considered in
usually treated first. A consultation with an endocrinologist for all patients cases of: 1) symptomatic functional tumors refractory to medical
with MEN1 should be considered. management; 2) a tumor larger than 1 to 2 cm in size; or 3) a tumor with a
relatively rapid rate of growth over 6 to 12 months. The panel recommends
Primary Treatment of Parathyroid Tumors in MEN1 endoscopy with EUS prior to pancreatic surgery to preoperatively assess
Treatment options for parathyroid hyperplasia in patients with MEN1 and localize tumors.
include subtotal parathyroidectomy with or without thymectomy (the
bilateral upper thymus is a common site of ectopic parathyroid glands and For clinically significant progressive disease or symptomatic patients,
thymic NETs) with or without cryopreservation of parathyroid tissue. Total treatment options are as for metastatic disease in the sporadic setting (see
parathyroidectomy with autotransplantation of parathyroid tissue with or Management of Locoregional Advanced and/or Metastatic Neuroendocrine
without thymectomy, and with or without cryopreservation of parathyroid Tumors of the Pancreas, above).
glands, is another recommended option.394-396 A randomized, prospective
trial compared these surgical approaches in 32 patients with MEN1 and All patients who might require splenectomy should receive trivalent
hyperparathyroidism.397 No significant differences were observed in vaccine (ie, pneumococcus, haemophilus influenzae b, meningococcal
outcomes including recurrent hyperparathyroidism. Adverse outcomes group C) preoperatively. Furthermore, in patients undergoing abdominal
include persistent hyperparathyroidism (2%–5%) and hypocalcemia (1%) surgery in whom octreotide or lanreotide treatment is planned,
because of inadequate or excessive resection, respectively, even by prophylactic cholecystectomy can be considered due to a higher risk of
expert surgeons. Additionally, postoperative bleeding or hoarseness due cholelithiasis in patients receiving somatostatin analogs.115 Metastatic
to injury to the recurrent laryngeal nerve may occur in about 1% of disease in patients with MEN1 is treated as in patients with NETs arising
patients. sporadically, according to the appropriate tumor type.
Primary Treatment of Pancreatic Tumors in MEN1 Primary Treatment of Pituitary Tumors in MEN1
Treatment of pancreatic NETs associated with MEN1 is similar to sporadic The panel recommends consultation with endocrinology for the treatment
pancreatic NETs and focuses on surgical excision preceded by medical of patients with pituitary tumors associated with MEN1, including those
management if necessary (see relevant site-specific recommendations in with prolactinoma, Cushing syndrome, acromegaly, and nonfunctioning
Neuroendocrine Tumors of the Pancreas, above). However, in contrast to tumors.
patients with sporadic disease where a tumor is usually solitary, pancreatic
NETs associated with MEN1 are frequently multiple.398 Removal of a
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Primary Treatment of Bronchial/Thymic Tumors in MEN1 Surveillance for MEN-1–associated pancreatic NETs is accomplished by
The recommendations for the workup and treatment of bronchopulmonary following serum hormones as symptoms indicate or if they were previously
and thymic tumors are the same as for patients with sporadic disease (see elevated. Cross-sectional imaging with abdominal/pelvic CT or MRI with
Neuroendocrine Tumors of the Gastrointestinal Tract (Well-Differentiated contrast every 1 to 3 years or serial EUS can also be considered in
Grade 1/2), Lung, and Thymus in the algorithm). patients with MEN1.
MEN1 Surveillance Surveillance for pituitary tumors includes a pituitary or sella MRI with
All patients with MEN1 should be followed for the development or contrast of the pituitary every 3 to 5 years. Prolactin, IGF-1, and other
progression of MEN1-associated tumors, regardless of previous tumors or previously abnormal pituitary hormones should be followed every 3 to 5
treatments. In contrast to sporadic hyperparathyroidism, patients with years or as symptoms indicate.
familial hyperparathyroidism (including MEN1), isolated familial
hyperparathyroidism, or hyperparathyroidism associated with jaw tumor For surveillance of bronchial or thymic NETs, the panel suggests that
syndrome are more likely to develop recurrent disease.399 Consider cross-sectional chest CT or MRI with contrast be considered every 1 to 3
referral to an endocrinologist. The patients are also more likely to have or years. MRI over CT should be considered to minimize radiation risks.
develop new parathyroid carcinomas, pancreatic NETs, pituitary tumors,
All close family members of patients with MEN1 should receive genetic
and/or bronchial/thymic tumors. Carcinoid (neuroendocrine) tumors occur
counseling, and genetic testing should be considered as described above.
in approximately 3% of patients with MEN1.388 Bronchial NETs occur more
frequently in females, while thymic NETs occur more frequently in males. MEN2 and Familial MTC
In addition, smokers appear to be at increased risk for the development of
MEN2 can be further subdivided into MEN2A (Sipple syndrome) and
thymic NETs.388 In one prospective study, the authors compared the use
MEN2B based on the spectrum of accompanying endocrine tumors and
of lanreotide to active surveillance in patients with MEN1-associated
disorders. MTC is seen in nearly all patients with MEN2A and MEN2B and
pancreatic NETs less than 2 cm.400 The results revealed that lanreotide
is often the first manifestation of the syndrome.206 Patients with MEN2A
treatment significantly improves the median PFS (median not reached vs.
may also have or develop pheochromocytoma (usually bilateral, 50%) and
40 months).
hyperparathyroidism (about 25%).206 Some patients with MEN2A have
The panel recommends annual calcium and serum PTH levels to screen lichen planus amyloidosis or Hirschsprung disease. Most patients with
for parathyroid tumors. If calcium levels rise, 25-OH vitamin D should be MEN2B have mucosal neuromas or intestinal ganglioneuromas in addition
measured and imaging with neck ultrasound and/or parathyroid sestamibi to MTC; 50% of these patients have pheochromocytoma, but almost none
with SPECT scan (SPECT-CT preferred) or 4D-CT should be performed. have hyperparathyroidism (<1%).206 Nearly all patients with MEN2B have
Cross-sectional CT or MRI with contrast of the neck can also be Marfanoid habitus and/or poor dentition. Some patients also have ectopic
considered. MRI over CT should be considered to minimize radiation risks. lenses in the eye or very flexible joints.
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MTC is a calcitonin-secreting tumor of the parafollicular or C cells of the to cry tears.402,403 For patients known or suspected to have MEN2A or
thyroid, accounting for about 4% to 7% of thyroid cancers but about 15% MEN2B, a clinical evaluation includes: 1) biochemical tests evaluating
of all thyroid cancer deaths. About 75% of MTC cases are sporadic, hormone levels; 2) imaging tests to localize MEN2-associated tumors; and
whereas approximately 25% are considered familial or hereditary. Familial 3) genetic counseling and testing for inherited genetic syndromes.
MTC associated with MEN2 normally arises in the first to third decades of
life, but sporadic MTC is typically diagnosed in the fourth to fifth decades Before surgical resection of MTC in these patients, basal calcitonin and
of life. All types of familial MTC are typically multifocal and preceded by carcinoembryonic antigen (CEA) levels should be measured, because
C-cell hyperplasia; however, sporadic MTC is usually unifocal. Familial these test results help guide the extent of nodal dissection required,
MTC arising in the absence of other endocrine malignancies or disorders particularly in patients with occult disease detected by screening. Patients
is the least aggressive, whereas MTC associated with MEN2B is the most with low calcitonin and high CEA levels usually have more aggressive
aggressive. MEN2A, MEN2B, and familial MTC are all autosomal- tumors. Neck ultrasound of thyroid and cervical lymph nodes should also
dominant inherited diseases and are associated with germline mutations be performed to document intrathyroidal tumors and to possibly identify
of the proto-oncogene, RET.9,401 cervical lymph node metastases.
The initial symptoms associated with MEN2A and MEN2B include a mass Patients with MEN2 should be evaluated for a coexisting
in the thyroid gland (with or without adjacent central or lateral cervical pheochromocytoma (see Evaluation for Pheochromocytomas/
lymph node adenopathy) and, less frequently, symptoms of excess Paragangliomas, above) before administration of anesthetic or before any
hormone production related to MTC (such as diarrhea and facial flushing), invasive procedure. Because patients with pheochromocytoma have
pheochromocytoma (headaches, increased perspiration, and rapid heart persistent vasoconstriction, medical therapy (ie, alpha blockade with
rate), or hyperparathyroidism. volume repletion, high salt diet, additional therapy as needed) is required
preoperatively (see Primary Treatment of
For a full discussion of the management of MTC, consult the NCCN Pheochromocytomas/Paragangliomas, above).
Guidelines for Medullary Thyroid Cancer (available at www.NCCN.org).
The following discussion focuses on the presentation of MEN2 and on the For patients with MEN2 who have a parathyroid tumor, serum calcium
issues unique to MTC in this setting. level should be measured. If it is found to be elevated, PTH and 25-OH
vitamin D levels should be measured. A neck ultrasound, sestamibi scan
Evaluation of MEN2A, MEN2B, and Familial MTC with SPECT, or 4D-CT can also be performed as appropriate. Preference
A clinical diagnosis of MEN2A includes findings of two or more MEN2A- of scan will depend on institutional practice/protocol.
associated tumors (MTC, pheochromocytoma, or hyperparathyroidism) in
a single individual or in first-degree relatives.402,403 A clinical diagnosis of Genetic Counseling/Testing in MEN2
MEN2B includes the presence of MTC, pheochromocytoma, mucosal Genetic counseling and RET genetic testing should be offered to
neuromas of the lips and tongue, medullated corneal nerve fibers, individuals with MTC or primary C-cell hyperplasia or a clinical diagnosis
distinctive facies with enlarged lips, Marfanoid body habitus, or the inability of MEN2 (see Evaluation of MEN2A, MEN2B, and Familial MTC,
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above).402,403 Genetic counseling and testing should also be offered to at- Patients with MEN2 and familial MTC may be prone to hypoparathyroidism
risk relatives of an individual with a known germline RET mutation at a because the thyroid gland is often already removed prophylactically or for
very young age.402,403 Surveillance should start by age 11 for children in treatment of C-cell hyperplasia or MTC. The consensus of the panel is for
the American Thyroid Association high and highest risk categories and by parathyroidectomy of abnormal glands. Subtotal parathyroidectomy is
age 16 in children in the moderate risk category.404 Surveillance comprises recommended when all glands appear abnormal. Some surgeons
an annual measurement of plasma-free metanephrines or 24-hour urine recommend prophylactic parathyroidectomy of all normal parathyroid
for fractionated metanephrines and adrenal imaging in patients with glands with immediate autotransplantation in patients with MTC, while
positive biochemical results.404 All patients with MTC should be tested for others believe the risk of hypoparathyroidism with this approach (about
germline mutation of the RET oncogene even if the family history is not 6%) is too high to warrant the procedure. If a normal parathyroid gland is
suggestive of a hereditary syndrome, because about 50% of patients with not preserved in situ in patients with MEN2A, it can be autotransplanted to
presumed sporadic MTC have a de novo germline mutation.403 the forearm, since recurrent primary hyperparathyroidism occurs in almost
20% of these patients. If hyperparathyroidism recurs with a documented
For patients with a clinical diagnosis of MEN2 and a negative RET genetic elevated PTH level in the ipsilateral basilic vein, the tumor can be removed
test result, physicians should consider having the patients follow the or subtotally resected.
related surveillance recommendations. This also applies to at-risk relatives
even if the affected relative had a negative test result or no genetic Management of patients with pheochromocytoma and MEN2 is similar to
testing.402 See MEN2 Surveillance, below. that of pheochromocytoma in other settings. As patients with MEN2 have
an appreciable risk for bilateral tumors, a cortical-sparing adrenalectomy
Primary Treatment of MEN2A, MEN2B, and Familial MTC
may be considered. An interesting retrospective, population-based,
In patients with a positive RET oncogene test who are otherwise observational study of 563 patients with MEN2 and pheochromocytoma
asymptomatic, prophylactic thyroidectomy is performed during the first 5 from 30 centers across three continents found that adrenal-sparing
years of life depending on the aggressiveness of the inherited RET resections led to similar rates of recurrence with lower rates of adrenal
mutation or at diagnosis,402,405-407 as detailed in the NCCN Guidelines for insufficiency or steroid dependency (43% vs. 86%).408 More studies are
Medullary Thyroid Carcinoma (available at www.NCCN.org). needed, however, before this approach can be routinely recommended.
The treatment of MTC associated with MEN2 is similar to the management MEN2 Surveillance
of its sporadic counterpart (see the NCCN Guidelines for Medullary Follow-up surveillance is described in the NCCN Guidelines for Medullary
Thyroid Carcinoma, available at www.NCCN.org). However, patients with Thyroid Carcinoma (available at www.NCCN.org) for patients with RET
familial disease are much more likely to have bilateral thyroid carcinomas. mutations treated for MTC or for patients who have undergone
In addition, patients may have synchronous pheochromocytoma and MTC. parathyroidectomy. Follow-up for treatment of pheochromocytomas in
In these cases, resection of pheochromocytoma should take priority over these patients is similar to patients who have sporadic disease (see
thyroidectomy. Surveillance of Pheochromocytomas/Paragangliomas above).
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