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 Table of Contents  
REVIEW ARTICLE
Year : 2018  |  Volume : 16  |  Issue : 4  |  Page : 143-147

Neuroendocrine tumors and role of nuclear medicine in diagnosis and management


Department of Nuclear Medicine, Christian Medical College, Vellore, Tamil Nadu, India

Date of Web Publication16-Apr-2019

Correspondence Address:
Junita Rachel John
Department of Nuclear Medicine, Christian Medical College, Vellore - 632 004, Tamil Nadu
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/cmi.cmi_49_18

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  Abstract 

Neuroendocrine tumours are a heterogenous group of tumours. They arise from the neuroendocrine cells and can occur in several organs including lung and GIT. This article aims to provide an overview of the nuclear medicine techniques that can be used for diagnosis and treatment of these tumours.

Keywords: Endocrine, nervous systems, neuroendocrine tumors, von Hippel-Lindau syndrome


How to cite this article:
John JR. Neuroendocrine tumors and role of nuclear medicine in diagnosis and management. Curr Med Issues 2018;16:143-7

How to cite this URL:
John JR. Neuroendocrine tumors and role of nuclear medicine in diagnosis and management. Curr Med Issues [serial online] 2018 [cited 2019 Sep 21];16:143-7. Available from: http://www.cmijournal.org/text.asp?2018/16/4/143/256317


  Introduction Top


Neuroendocrine tumors (NETs) are a heterogeneous group that originates from the cells of the endocrine and nervous systems. NETs account for about 0.5% of all newly diagnosed malignancies. Most frequent primary sites are the gastrointestinal (GI) tract (62%–67%) and the lung (22%–27%). Almost 12%–22% of patients are metastatic at presentation. Majority of NETs arise sporadically, but the association with the multiple endocrine neoplasia type 1 syndrome, Hippel-Lindau syndrome, neurofibromatosis type 1 and familial clustering is seen. Neuroendocrine cells have the capability to produce hormones, such as serotonin, as well as other proteins, for example, chromogranin A, which serve as biomarkers for NETs. They also express somatostatin receptors on their cell surfaces and so somatostatin analogs are used for diagnostic imaging and treatment.[1]


  Clinical Presentation Top


NETs may be found as an incidental finding or may be suspected from clinical symptoms [Table 1]. When NETs cause clinical symptoms from secreted hormones, they are termed “functioning.” Most NETs do not produce a biologically active hormone and are termed “nonfunctioning.”[2]
Table 1: Most common clinical presentations and symptoms associated with various neuroendocrine tumors

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There are two clinicopathologic features that drive the biological behavior of NETs: grade and stage.

Grade

Histologic grade reflects the biological aggressiveness of the neoplasm. There are two main features of grade: the Ki67 index, which measures the percentage of cancer cells that stain positive for Ki67, a marker of cell proliferation and the mitotic rate, which documents the number of mitoses per 10 high-power microscopic fields [Table 2].[3]
Table 2: Histological grades of neuroendocrine tumors of lung and gastroenteropancreatic neuroendocrine tumours

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Differentiation

Differentiation refers to how closely the neoplastic cells resemble their nonneoplastic counterparts in the tissue from which they arose. Well-differentiated cancer cells closely resemble nonneoplastic cells, whereas poorly differentiated cancer cells do not. In general, low-grade tumors (Grades 1 and 2) are well-differentiated, and high-grade tumors (Grade 3) are poorly differentiated.[3]

Gastroenteropancreatic NETs can be divided largely into two main categories:[4]

  • Well-differentiated NETs, conventionally referred to as carcinoid tumors (in the tubular GI tract) and pancreatic NETs (islet cell tumors), respectively. Although carcinoid tumors and pancreatic NETs may have similar characteristics on routine histologic evaluation, they have different pathogenesis and biology
  • Poorly differentiated neuroendocrine carcinomas (NECs) are high-grade carcinomas that resemble small cell or large-cell NEC of the lung. Poorly differentiated NECs are often associated with a rapid clinical course, while well-differentiated NETs generally have a much better prognosis, with overall 5-year survival of approximately 67%.



  Histology Top


On gross appearance, well-differentiated NETs of the tubular GI tract are often well-circumscribed round lesions in the submucosa or extending to the muscular layer, while those that arise in the pancreas may be well circumscribed, multinodular, or infiltrative. The cut surface appears red to tan, reflecting the abundant microvasculature, or sometimes yellow because of high lipid content. Morphologically, well-differentiated NETs have characteristic “organoid” arrangements of tumor cells, with solid/nesting, trabecular, gyriform, or sometimes, glandular patterns. The cells are relatively uniform, and they have round-to-oval nuclei, coarsely stippled (“salt and pepper”) chromatin, and finely granular cytoplasm.[2]

Poorly differentiated NECs less closely resemble nonneoplastic neuroendocrine cells and have a more sheet-like or diffuse architecture, irregular nuclei, and less cytoplasmic granularity. Immunohistochemical expression of neuroendocrine markers is generally more limited in extent and intensity.[2]


  Diagnosis Top


Diagnosis of NET requires a detailed history and thorough clinical examination [Table 3]. Characteristic history of flushing and intractable diarrhea warrants biochemical evaluation, which starts with measuring serum serotonin or the metabolite in the urine (5-hydroxy indole acid). Other NET markers, such as chromogranin A and neuron-specific enolase, are measured in serum. In general, these markers are elevated in carcinoid tumors.[1] In case gastrinoma is suspected (history of abdominal pain, diarrhea, and gastroesophageal reflux disease), the fasting gastrin level should be measured. If the diagnosis of insulinoma is suspected, elevated insulin levels are found in fasting condition, C-peptide and serum glucose levels are also measured. In case pheochromocytoma is suspected, metanephrines, catecholamines, and their metabolites should be measured in the blood and urine.[2]
Table 3: Most common clinical presentations and symptoms associated with various neuroendocrine tumors

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  Imaging Top


Chest X-ray should be performed specifically if a thoracic origin of the tumor is suspected. Conventional imaging modalities such as ultrasonography, computed tomography (CT) scan, magnetic resonance imaging (MRI), although useful for detecting the number of lesions and other anatomical details, do not give information on the functional status of the tumor, which is essential for defining the prognosis.[1] CT and MRI localize <10% of NETs smaller than 1 cm, 30%–40% of tumors 1–3 cm, and over 50% of NETs larger than 3 cm. Many carcinoids in the small intestinal are too small to be seen on CT or MRI.[2]

Majority of NETs produce an abundance (called overexpression) of a specific cell feature called somatostatin receptors. Molecular imaging technologies use this cell feature to detect cancerous cells throughout the body and as a target for the delivery of therapy [Table 4].[5]
Table 4: Somatostatin receptor distribution in normal tissues and associated tumors

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Somatostatin receptor scintigraphy (SRS) and other scanning methods: all 5 classes of somatostatin receptors can be detected in most NETs, particularly Class 2 (80%–100%) and 5 (50%–60%). Whereas endogenous somatostatin interacts with all 5 receptor subtypes with high affinity, the widely used synthetic somatostatin analogs, octreotide, and lanreotide, interact only with Class 2 and 5 with high affinity, with lower affinity for class 3. 111Indium-labeled octreotide or lanreotide have high sensitivity for localizing NETs. In patients with pancreatic NETs and GI-NETs (carcinoid), SRS localizes the primary tumor in 70%–80% of cases and hepatic metastases in over 90%. Sensitivity of SRS may vary somewhat with NET subtype and location. SRS also has high sensitivity for localizing nonhepatic metastases (e.g., bone) and has the advantage of allowing whole-body imaging, easily performed by most Nuclear Medicine Departments. SRS has a low sensitivity in detecting insulinomas because these tumors frequently have low densities of Class 2 and 5 somatostatin receptors. SRS has excellent specificity, although false-positive results can occur, particularly in granulomatous and inflammatory diseases, lymphoma, and thyroid diseases. Sensitivity of SRS can be increased using gallium-68 (68Ga)-radiolabeled somatostatin analogs. 68Ga somatostatin receptor imaging is currently the SRS method of choice.[5]

Insulinomas overexpress receptors for the glucagon-like peptide (GLP-1), and 1 study demonstrated that a radiolabeled GLP-1 analog can detect occult insulinomas not localized by other imaging modalities. 11C-and 18F-labeled levodopa have been used to visualize carcinoids using positron emission tomography (PET). 11C-5-hydroxy-L-tryptophan has also been used. PET using 18F-deoxyglucose may also be helpful in the subset of NETs with high proliferative rates and poor cell differentiation. Radiolabeled metaiodobenzylguanidine can be used to image GI-carcinoids, but it is less sensitive than SRS for detecting liver metastases and is not useful in detecting pancreatic NETs.[2]


  Treatment Top


Many patients with mild carcinoid syndrome remain active and well except for occasional episodes of flushing or diarrhea. Treatment of these patients involves avoiding stress and conditions or substances that precipitate flushing. Mild diarrhea may respond to antidiarrheal agents such as loperamide or diphenoxylate, wheezing may require an inhaled β-adrenergic agonist bronchodilator, and heart failure may require diuretics.[4]

If patients continue to have bothersome symptoms, somatostatin analogs are the drugs of choice. Use of somatostatin itself is limited by its short half-life (2.5–3 min). With the availability of synthetic longer-acting somatostatin analogs, octreotide and lanreotide, subcutaneous treatment can be given every 6–12 h. Sustained release formulations (octreotide LAR and lanreotide SR autogel) allow control of carcinoid symptoms in the majority of patients with once-monthly administration. Individual responses vary, and some patients require higher doses or more frequent dosing over time. Interferon-α is also effective in controlling the symptoms of the carcinoid syndrome.[4]

To prevent a carcinoid crisis, patients with carcinoid syndrome undergoing procedures should receive an additional somatostatin analog. A supplementary subcutaneous bolus dose of 250–500 μg octreotide should be given within 1–2 h before the procedure. For emergency surgery in therapy-naïve patients, current guidelines recommend a 500 to 1000 μg IV bolus of octreotide or 500 μg subcutaneously 1–2 h before the procedure, although some use higher doses, and others advise a continuous infusion of octreotide.[2]

Short-term adverse effects of somatostatin analogs are common, mild, and brief; most frequent are pain at the injection site, nausea, and diarrhea. Long-term side effects are usually mild and uncommonly lead to drug discontinutation, these include biliary sludge/stones, steatorrhea, and deterioration in glucose tolerance.[4]

Treatment of metastatic disease:

  1. Cytoreductive surgery: Removal of resectable metastatic tumor (cytoreductive surgery, debulking, metastasectomy) is often considered[4]
  2. Radiofrequency ablation: Locally ablative techniques, radiofrequency ablation (RFA), ethanol injection, and cryotherapy of hepatic metastases from NETs can be performed at the time of surgery or using interventional radiologic techniques. RFA is the most widely used, increasingly in combination with other techniques such as cytoreductive surgery. Relative contraindications to RFA include large lesions (>3.5–5.5 cm), numerous lesions (>5 to15), and metastases adjacent to vital structures[4]
  3. Chemotherapy: Cytotoxic chemotherapy is widely used in patients with advanced pNETs with modest success (response rates 10%–70%), but results have been disappointing in patients with GI-NETs (response rates <30%). The current chemotherapy regimen in patients with advanced well-differentiated pNETs is the combination of streptozotocin and doxorubicin, with or without 5-FU. The combination of the alkylating agent temozolomide with capecitabine (an oral 5-FU prodrug) has shown promise in the treatment of advanced pNETs[4]
  4. Biologicals: Everolimus-mammalian target of rapamycin (mTOR) is a serine-threonine kinase that plays an important role in cell growth, proliferation, and apoptosis. Activation of the mTOR cascade plays an important role in the growth of NETs, especially pNETs. mTOR inhibitors have been studied in patients with unresectable NETs[4]


  5. Sunitinib: TKRs mediate cell growth, angiogenesis, cell differentiation, and apoptosis. Several TKR inhibitors have antiproliferative activity in GI-NET cells, but only Sunitinib is approved for use in patients with advanced pNETs[4]

  6. Peptide Receptor Radionuclide Radiotherapy (PRRT): Somatostatin receptors are overexpressed or ectopically expressed in 60% to 100% of GI-NETs, PRRT allows targeted cytotoxic radiolabeled somatostatin receptor ligands to bind to the tumor. Two radioisotopes coupled to somatostatin analogs are available: 90Yttrium (90Y) and 177Lutetium. The most frequent somatostatin analogs used are octreotate or octreotide; common chelators are diethylenetriaminepentaacetic acid or DOTA. Highly targeted and effective form of mitochondrial replacement therapies with minimal side effects In PRRT, the patient receives an intravenous injection of a drug such as octreotide that is chemically bound to (or radiolabeled with) a radioactive material, mainly lutetium-177. The radioactive octreotide attaches to somatostatin receptors on tumor cells, which are destroyed by the radiation.[5]


Studies using 90Y-labeled analogs showed, a complete tumor response occurred in 0%–6% and a partial response in 7%–37% of patients; tumor stabilization was seen in 42%–86%. Using 177 Lu (DOTA0, Tyr3) octreotate, a complete response occurred in 2% of patients and a partial response in 28%; tumor stabilization was seen in 35%.[5]

Factors predicting reduced disease-specific survival were a lower Karnofsky performance score (≤70), lack of tumor response to PRRT, progressive disease, baseline weight loss, bone metastases, extensive liver involvement, and if the NET was a gastrinoma, insulinoma, or VIPoma.[2]

Most adverse effects associated with PRRT are mild and include abdominal pain and/or nausea/vomiting. More serious toxicities are hematologic (0.8% develop myelodysplasia), hepatic (0.6%), and renal, primarily in patients receiving 90Y-labeled analogs.[5]

Treatment of poorly differentiated NET: poorly differentiated tumors comprise <1% of all NETs, characterized by their histologic features of aggressive growth (Grade 3, with Ki67 index >20%, and usually 50%–90%), necrosis, nuclear atypia, rapid growth, and poor clinical prognosis. These tumors also contain few or no somatostatin receptors, and therefore, SRS may be negative and somatostatin analogs are not a therapy option. In contrast to well-differentiated tumors, poorly differentiated tumors do not express chromogranin A, although synaptophysin is expressed. Since most patients with poorly differentiated NETs present with regional or distant metastases, surgery is rarely curative, although it still should be considered in the occasional patient with only limited disease. In the typical patient with inoperable disease, chemotherapy with cisplatin and etoposide, alone or in combination with another agent (e.g., vincristine, paclitaxel), is recommended. These agents induce remission in 14%–80% of patients, with a mean duration of response of <12 months.[2]

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.
Biersack HJ. Freeman·LM, editors. Clinical Nuclear Medicine. Springer-Verlag Berlin Heidelberg. Berlin, Germany; 2007.  Back to cited text no. 1
    
2.
Feldman M, Tschumy WO, Friedman LS, Fried AR, Brandt LJ. Sleisenger and Fordtran's Gastrointestinal and Liver Disease. 10th ed. Saunders, US; 2016.  Back to cited text no. 2
    
3.
Klimstra DS, Modlin IR, Coppola D, Lloyd RV, Suster S. The pathologic classification of neuroendocrine tumors: A review of nomenclature, grading, and staging systems. Pancreas 2010;39:707-12.  Back to cited text no. 3
    
4.
Strosberg JR. Classification, epidemiology, clinical presentation, localization, and staging of pancreatic neuroendocrine neoplasms 2018. Available from: https://www.uptodate.com/contents/classification-epidemiology-clinical-presentation-localization-and-staging-of-pancreatic-neuroendocrine-neoplasms#H12145156. [Last updated on 2018 Oct 23 and Last accessed on 2019 Feb 28].  Back to cited text no. 4
    
5.
Jennifer CA, Kulke MH. Progress in the treatment of neuroendocrine tumors. Curr Oncol Rep 2009;11:193-9.  Back to cited text no. 5
    



 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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Abstract
Introduction
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Histology
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