Monday, September 25, 2023
| Insulinoma | VIPoma | Gastrinoma | Glucagonoma | Carcinoid* | |
|---|---|---|---|---|---|
| Symptoms | Hypoglycemia | Profuse, watery diarrhea |
Ulceration of upper gastrointestinal tract Diarrhea |
Rash Glossitis Cheilosis Constipation and ileus Venous thrombosis Hyperglycemia |
Flushing Diarrhea Cramps Bronchospasms Valvular heart disease |
| Tumor markers† |
C-peptide Chromogranin A Insulin/glucose ratio Proinsulin |
Chromogranin A Electrolytes Vasoactive intestinal 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 Glucagon |
5-HIAA (24-h urine)‡
Chromogranin A§ |
| Imaging | CT or MRI (pancreatic triphasic) Upper endoscopic ultrasound |
CT or MRI (pancreatic triphasic) OctreoScan |
CT or MRI OctreoScan |
CT or MR (pancreatic triphasic) OctreoScan |
CT or MRI OctreoScan Upper and lower endoscopy +/- video capsule |
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.
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.
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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]:
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.
