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Table 1.  

  Insulinoma VIPoma Gastrinoma Glucagonoma Carcinoid*
Symptoms Hypoglycemia Profuse, watery
of upper




Constipation and

Venous thrombosis





Valvular heart disease

Chromogranin A


Chromogranin A


peptide (fasting
for 8 h, on ice)
Chromogranin A

Gastrin (fasting
> 8 h and off
proton pump
inhibitor for 1 wk)
Blood glucose

Chromogranin A

5-HIAA (24-h urine)

Chromogranin A§
Imaging CT or MRI



CT or MR



Upper and lower
endoscopy +/- video

Symptoms and Evaluation of Neuroendocrine Tumors

Abbreviations: 5-HIAA, 5-hydroxyindoleacetic acid; VIPoma, vasoactive intestinal polypeptidoma.
*Workup varies based on location.
For most blood studies, a 1-hour fast is recommended.
Avoid avocados, bananas, cantaloupe, eggplant, pineapples, plums, tomatoes, hickory nuts, plantain, kiwi, dates, grapefruit, honeydew, walnuts, alcohol, coffee, tobacco, acetaminophen, ephedrine, diazepam, nicotine, glyceryl guaiacolate (in cough medicines), and phenobarbital 48 hours before urine collection, because these all affect results.
§Falsely elevated with proton pump inhibitor use.


Management of Neuroendocrine Tumors of Unknown Origin

  • Authors: Ariel Polish, MD; Maxwell T. Vergo, MD; Mark Agulnik, MD
  • CME Released: 12/9/2011
  • Valid for credit through: 12/9/2012, 11:59 PM EST
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Target Audience and Goal Statement

This activity is intended for primary care clinicians, internists, endocrinologists, neurologists, oncologists, and other healthcare professionals caring for patients with NETs of unknown origin.

The goal of this activity is to describe the evaluation and management of NETs of unknown origin.

Upon completion of this activity, participants will be able to:

  1. Describe the clinical and epidemiologic features of NETs and NETs of unknown origin on the basis of a review
  2. Describe the diagnostic workup of NETs of unknown origin on the basis of a review
  3. Describe the treatment of NETs of unknown origin on the basis of a review


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  • Ariel Polish, MD

    Division of Hematology/Oncology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois


    Disclosure: Ariel Polish, MD, has disclosed no relevant financial relationships.

  • Maxwell T. Vergo, MD

    Division of Hematology/Oncology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois


    Disclosure: Maxwell T. Vergo, MD, has disclosed no relevant financial relationships.

  • Mark Agulnik, MD

    Division of Hematology/Oncology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois


    Disclosure: Mark Agulnik, MD, has disclosed no relevant financial relationships.


  • Kerrin M. Green, MA

    Assistant Managing Editor, Journal of the National Comprehensive Cancer Network


    Disclosure: Kerrin M. Green, MA, has disclosed no relevant financial relationships.

CME Author(s)

  • Laurie Barclay, MD

    Freelance writer and reviewer, Medscape, LLC


    Disclosure: Laurie Barclay, MD, has disclosed no relevant financial relationships.

CME Reviewer(s)

  • Nafeez Zawahir, MD

    CME Clinical Director, Medscape, LLC


    Disclosure: Nafeez Zawahir, MD, has disclosed no relevant financial relationships.

  • Sarah Fleischman

    CME Program Manager, Medscape, LLC


    Disclosure: Sarah Fleischman has disclosed no relevant financial relationships.

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Management of Neuroendocrine Tumors of Unknown Origin

Authors: Ariel Polish, MD; Maxwell T. Vergo, MD; Mark Agulnik, MDFaculty and Disclosures

CME Released: 12/9/2011

Valid for credit through: 12/9/2012, 11:59 PM EST


Abstract and Introduction


Neuroendocrine tumors (NETs) of unknown origin account for more than 10% of all NETs. Most of these tumors are poorly differentiated and, thus, very aggressive. Establishing the location of the primary tumor can be challenging. Workup of these NETs of unknown origin includes a thorough family history, immunohistochemistry, imaging, and OctreoScan. If the location of the primary malignancy is not determined, treatment is often initiated based on the grade and level of differentiation of the tumor, with well- and moderately differentiated tumors treated as carcinoid tumors, whereas poorly differentiated tumors are treated similarly to small cell tumors. Therapy is chosen based on symptoms and with the goal of debulking tumor when feasible and safe. (JNCCN 2011;9:1397–1403)


Neuroendocrine tumors (NETs) are formed from cells of the nervous and endocrine systems. They frequently arise from the pancreas, parathyroid, adrenal gland, pituitary gland, thyroid (calcitonin-producing cells), lung, and argentaffin cells of the gut. NETs can be categorized as either functional or nonfunctional based on their ability to secrete hormones. Functionally active tumors are defined by the hormones they secrete and include insulinomas, gastrinomas, vasoactive intestinal polypeptidoma (VIPoma), glucagonomas, and carcinoid tumors. Regardless of the functional status of these tumors, NETs are malignant and have the potential to metastasize to lymph nodes, liver, bone, lung, brain, and other organs. The SEER database reports an age-adjusted incidence of 5.25 cases per 100,000 people in 2004, making NETs rare.[1]

NCCN divides NETs into the following categories[2]:

  • Carcinoid tumors (gastrointestinal tract)
  • Islet cell tumors (pancreatic endocrine tumors)
  • NETs of unknown primary
  • Adrenal gland tumors (including adrenal cortical tumors and incidentalomas)
  • Pheochromocytomas/paragangliomas
  • Poorly differentiated (high-grade or anaplastic or anaplastic/small cell tumors)
  • Multiple endocrine neoplasia type 1
  • Multiple endocrine neoplasia type 2

Functional NETs can cause symptoms from the release of hormones, whereas nonfunctional tumors are often clinically silent. However, these nonfunctional tumors may still present with symptoms from local or metastatic disease, such as right upper quadrant pain (liver metastases), back pain (bone metastases), or abdominal pain (bowel obstruction). Examples of functional syndromes from hormonal excess include hypoglycemia caused by an insulinoma; ulceration and diarrhea caused by gastrinoma; and rash, constipation, and hyperglycemia seen with glucagonomas ( Table 1 ). Symptoms associated with carcinoid tumors, the most common gastrointestinal NET, include flushing, diarrhea, abdominal cramps, and bronchospasm. In the proper clinical setting, these syndromes will often lead to the evaluation of hormone levels, which, if elevated, will prompt an investigation for a NET. Testing of various tumor markers in addition to chromogranin A, which is nonfunctioning but one of the most commonly elevated serum markers in NETs, should be based on the clinician’s suspicion of particular secretory syndromes. In addition, further diagnostic workup will be guided by the biochemical characterization of the tumor.

NETs are diagnosed histologically using light microscopy. Diagnosis is based on morphology using hematoxylin and eosin stains or immunohistochemistry to identify cytosolic proteins. These immunohistochemistry stains often include chromogranin A, a component of the dense core granules that are seen in NETs, and synaptophysin, a membrane protein of presynaptic vesicles.[3] Both of these markers have great specificity for neuroendocrine differentiation in tumors. In addition, aggressiveness of NETs is assessed pathologically through grading (well-differentiated, poorly differentiated, small cell features) and mitotic index, and through Ki-67 immunohistochemistry staining (> 20% considered as a more aggressive subtype regardless of histologic features). Because of the rarity of the diagnosis, an experienced pathologist is recommended to ensure appropriate diagnosis and grading.

Well-differentiated tumors progress slowly, and only 21% of patient cases in the SEER registry presented with distant metastases. This group includes typical carcinoid tumors, islet cell tumors, pheochromocytomas, paragangliomas, and medullary carcinomas. Poorly differentiated NETs comprise small cell carcinoma, large cell carcinoma, and occasionally carcinoids with poorly differentiated histology (atypical carcinoids). In marked contrast to well-differentiated NETs, patients with poorly differentiated tumors in the SEER registry had a poor prognosis, with a median survival of 10 months. Half of those patients had distant metastases at diagnosis.