Gastroenteropancreatic and Lung Neuroendocrine Tumors

Neuroendocrine tumors (NETs) are a diverse group of epithelial neoplasms that may occur in almost any organ but most commonly arise in the gastroenteropancreatic region (70%) and lung (20%). Well-differentiated neuroendocrine tumors in these regions were previously called carcinoids ( Fig. 13.1 ). Although they often produce specific clinical syndromes due to their unique secretory products (“carcinoid syndrome”), the majority of the tumors are nonfunctioning. Many NET tumors are well differentiated, and these patients have prolonged survival; however, some grow more aggressively and become metastatic. The initial clinical diagnosis can be difficult because of their nonspecific clinical manifestations, depending on the specific amines/peptides secreted, and their small size ( Table 13.1 ). Gastroenteropancreatic NETs are classified on the basis of the Ki-67 proliferation index or the mitotic count ( Table 13.2 ).

Primary sites of neuroendocrine tumors.

Redrawn from Oronsky B, Ma PC, Morgensztern D, et al: Nothing But NET: A Review of Neuroendocrine Tumors and Carcinomas. Neoplasia 19, Issue 12, 2017, pp. 991-1002. Source: An Elsevier journal.

Resection of NETs can potentially cure the patient of the malignancy and amine/peptide production; however, this is often not possible due to the extent of disease. Management guidelines emphasize that resection should be the first-line treatment for patients with advanced tumors if 90% of the disease burden is resectable. However, only 5% to 20% of patients meet this criterion. Liver-directed therapies (embolization, radiofrequency ablation, chemoembolization, and radioembolization) are used in appropriate cases. Chemotherapy has not been very effective, but somatostatin (Sandostatin), mTOR inhibitors (everolimus), and tyrosine kinase inhibitors (sunitinib) can extend survival. With metastatic disease, 5-year survival rates are less than 50%.

Computed tomography (CT), ultrasonography, and magnetic resonance imaging (MRI) are used for initial evaluation, but detection rates are not high due to the small size of the tumors and variable location. Because well-differentiated NETs express high levels of somatostatin receptors (SSTRs), SSTR-targeted radionuclide imaging (e.g., In-111 pentetreotide or Ga-68 dotatate) can detect and functionally characterize these tumors. The primary tumor and regional or distant metastases can also often be detected. Expression of SSTRs is associated with a good prognosis, whereas lack of expression of SSTRs and overexpression of GLUT (FDG uptake) is predictive of poor prognosis and survival.

The normal human hormone somatostatin is a 14-amino-acid peptide produced in the hypothalamus, pituitary gland, brainstem, gastrointestinal tract, and pancreas. Somatostatin receptors are found on many normal cells as well as tumors of neuroendocrine origin. In the central nervous system, somatostatin acts as a neurotransmitter. Outside of the brain, it inhibits the release of growth hormone, insulin, glucagon, gastrin, serotonin, and calcitonin. It also inhibits angiogenesis, is involved in the immune function of leukocytes, and has an antiproliferative effect on tumors.

Five different subtypes of human SSTRs have been identified, expressed to varying degrees on different tumors. Therapeutic drugs have been developed that readily bind to these receptors. Octreotide (Sandostatin) and lanreotide (Somatuline) are somatostatin analogs used clinically to inhibit growth in acromegaly and to control symptoms of carcinoid syndrome. Radiopharmaceuticals have also been developed that bind to SSTRs.

Diagnostic SSTR Radiopharmaceuticals

Indium-111 Pentetreotide (OctreoScan)

OctreoScan was approved by the U.S. Food and Drug Administration (FDA) in 1994 for imaging of NETs. This radiolabeled SSTR binding agent has high affinity for subtypes 2 and 5 ( Fig. 13.2 ). It has high-energy emissions (171, 245 keV), relatively slow pharmacokinetics, and thus unfavorable dosimetry (see Appendix 1 ), which limits the administered dose to 6 mCi (222 MBq) and adversely affects image quality.

Comparison of somatostatin analogs.

Normal Distribution

Splenic and renal uptake is quite high. Lesser uptake is seen in the liver. Low-level hepatobiliary excretion increases intestinal clearance over time ( Fig. 13.3 ). The kidneys rapidly excrete the radiopharmaceutical, with 85% of the dose cleared from the body by 24 hours after injection. Uptake may be seen in the pancreas in the region of the uncinate process; this must not be confused with tumor. Radiotracer uptake is also be seen with benign inflammatory conditions (e.g., thyroiditis, granulomatous disease, inflammatory bowel disease, postradiation therapy, and at sites of recent surgery) due to the SSTRs present on human immune cells (e.g., mononuclear leukocytes, peripheral blood lymphocytes, and macrophages).

Normal In-111 pentetreotide (OctreoScan) whole-body scans: 4 hours (A) and 24 hours (B). There is no intestinal activity at 4 hours, but it is present at 24 hours. Normal prominent renal and spleen uptake are both more intense than the liver uptake. Ant, Anterior; Post, posterior.

Methodology

An imaging protocol is described in Box 13.2 . Early planar imaging at 4 hours after injection permits visualization of tumor uptake before bowel excretion; however, 24-hour imaging has a higher tumor-to-background ratio and is more sensitive for tumor detection ( Fig. 13.4 ). Delayed imaging at 48 hours can further confirm tumor uptake versus bowel activity. With single-photon emission computed tomography with computed tomography (SPECT/CT), imaging only at 24 hours is routine, and it improves tumor identification and localization ( Fig. 13.5 ).

Box 13.2

Indium-111 Pentetreotide (OctreoScan): Protocol Summary

Patient Preparation

• 
  

  None

Radiopharmaceutical

• 
  

  Children: 0.14 mCi/kg (5 MBq/kg)

  
  
• 
  

  Adults: 6 mCi (222 MBq) In-111 octreotide, intravenously

Instrumentation

• 
  

  Gamma camera: Large field of view

  
  
• 
  

  Collimator: Medium energy

  
  
• 
  

  Windows: 20% centered at 173 keV and 247 keV

Acquisition

• 
  

  Imaging: Planar whole body and SPECT or SPECT/CT of abdomen and or other indicated site at 24 hours

  
  
  
  
  • 
    

    If only planar imaging: 4 and 24 hours; 48-hour images may occasionally be useful

  
  

Whole-Body Images

• 
  

  Dual-head camera 6 cm/min (approximately 40 minutes head to below hips)

  
  
• 
  

  1024 × 512 word matrix

SPECT

• 
  

  128 × 128 matrix, 3-degree angular sampling, 360-degree rotation, 35 sec/stop

  
  
• 
  

  Fusion to CT or SPECT/CT preferable

CT, Computed tomography; SPECT, single-photon emission computed tomography; SPECT/CT, single-photon emission computed tomography with computed tomography.

In-111 pentetreotide whole-body study in a patient with metastatic carcinoid, at 24 hours after injection. Metastases are seen in left supraclavicular region and liver, nodal disease in the abdomen and pelvis, and skull metastasis. Ant, Anterior; Post, posterior.

In-111 pentetreotide SPECT/CT. (A) Fused images localize a small focus of activity to a peripancreatic retroperitoneal lymph node, which was difficult to see on planar images (not shown), and (B) shows marked uptake in a precarinal nodal metastasis, which would likely be falsely called normal by computed tomography (CT) size criteria.

Accuracy

The sensitivity of In-111 pentetreotide for tumor detection is reported to be high for carcinoid tumors (85%–95%; Box 13.3 ). However, a lower sensitivity of approximately 75% occurs with pancreatic NETs (e.g., gastrinomas, glucagonomas, vasoactive intestinal polypeptide-secreting tumors [VIPomas], and nonfunctioning islet cell tumors). Because of high normal liver uptake, liver metastases are not always detected. Detection may be reduced in patients on octreotide therapy; thus, the study should be performed immediately before the patient’s monthly therapeutic injection.

Box 13.3

Sensitivity of Indium-111 Pentetreotide (OctreoScan) for Various Applications

High

• 
  

  Carcinoid (86–95%)

  
  
• 
  

  Islet cell tumors (75–100%)

  
  
  
  
  • 
    

    Gastrinoma, glucagonoma, VIPoma

  
  
  
  
• 
  

  Adrenal medullary tumors (>85%)

  
  
  
  
  • 
    

    Pheochromocytoma, neuroblastoma, paragangliomas

  
  
  
  
• 
  

  Small-cell lung cancer (80–100%)

Moderate

• 
  

  Medullary thyroid (50–75%)

  
  
• 
  

  Insulinoma (25–70%)

  
  
• 
  

  Medulloblastoma (61–93%)

  
  
• 
  

  Meningioma (50% and 100% reported)

Low

• 
  

  Pituitary adenoma

  
  
• 
  

  Astrocytoma grade IV (higher in grades I and II)

  
  
• 
  

  Breast cancer

  
  
• 
  

  Melanoma

  
  
• 
  

  Renal cell carcinoma

VIPoma, Vasoactive intestinal polypeptide-secreting tumor.

Gallium-68 (Ga-68) Dotatate (DOTA-0-Tyr3-Octreotate )

Several Ga-68-labeled somatostatin receptor positron emission tomography (PET) imaging agents have been investigated, including Ga-68 dotatoc, dotanoc, and dotatate (see Fig. 13.2 ). These short amino acid–chelator conjugates demonstrate superior affinity for somatostatin receptors compared with In-111 pentetreotide. The three dota agents are similar in imaging accuracy. Ga-68 dotatate (NetSpot) was approved by the FDA in 2016 for imaging of neuroendocrine tumors. The radionuclide, Ga-68, is produced in a Germanium 68/Ga-68 generator, similar to a Molybdenum-99/Tc-99m generator. The parent Ge-68 has a half-life of 271 days; thus, the generator can be used for at least a year. The Ga-68 daughter has a half-life of 68 minutes. In a high-volume clinic, a generator can make sense. Alternatively, some commercial radiopharmacies maintain a generator and distribute individual radiopharmaceutical doses on a regional basis. The recommended dose is 0.054 mCi/kg (2 MBq/kg) up to 5.4 mCi (200 MBq).

Normal Distribution

Ga-68 dotatate binds with high affinity to SSTR-2 receptors. Uptake is seen in the pituitary, thyroid, and salivary glands; spleen; adrenals; kidney; prostate; and liver ( Fig. 13.6 ). Normal uptake may also be seen in the uncinate process, similar to that seen with In-111 pentetreotide. There is no brain uptake, but focal activity in the nonenlarged pituitary is normal. Cardiac uptake is absent, and lung uptake is low. Twelve percent of the administered dose is excreted in the urine by 4 hours postinjection.

Ga-68 dotatate normal distribution. (Left) Maximum-intensity projection (MIP) image. (Right) Fused SPECT/CT coronal (left) and selected transverse images (right). Note normal uptake in pituitary and adrenals.

With permission, Kuyumcu S, Özkan ZG, Sanli Y, et al. Physiological and tumoral uptake of (68)Ga-DOTATATE: standardized uptake values and challenges in interpretation. Ann Nucl Med. 2013;27[6]:538–545.

Methodology

A Ga-68 dotatate PET/CT study requires considerably less patient time than SPECT/CT In-111 pentetreotide. PET/CT imaging begins approximately 1 hour after injection of the radiopharmaceutical. The total time from injection to the completion of imaging is about 2 hours, similar to routine F-18 FDG oncologic imaging. The radiation dose to the patient is less with Ga-68 dotatate compared with In-111 pentetreotide (see the Appendix).

Accuracy

In a large retrospective study of 728 patients with NETs, Ga-68 dotatate had a sensitivity of 94% and a specificity of 92%. The highest accuracy was for primary midgut tumors. In a comparison study of 131 patients with NETs and unknown primaries, Ga-68 dotatate PET/CT had a higher detection rate (95%) compared with In-111 pentetreotide SPECT/CT (31%) or CT or MRI (46%) ( Fig. 13.7 ). Additional clinical information is found in 70% to 80% of Ga-68 dotatate cases compared with pentetreotide (OctreoScan), and a change in clinical management is reported to occur in greater than 40% of patients ( Figs. 13.8 and 13.9 ). Patients with poorly differentiated tumors may not have uptake and may benefit from F-18 FDG PET, although these patients have a poorer prognosis. The use of intravenous contrast with SSTR PET/CT increases the detection rate for liver metastases and small bowel primaries. SSTR PET/MRI is also reported to provide improved detection of liver metastases.

Comparison of maximum-intensity projection (MIP) whole-body image of Ga-68 dotatate (left) and In-111 pentetreotide (OctreoScan) anterior and posterior whole-body scans in the same patient (right), illustrating the clear superiority of Ga-68 dotatate compared with the In-111 OctreoScan. Although a liver metastasis is seen on OctreoScan, many more are seen on the Ga-68 dotatate study, as well as multiple other intraabdominal nodal disease locations.

Courtesy of Corina Millo, MD.

Ga-68 dotatate positron emission tomography with computed tomography (PET/CT) scan in a 65-year-old male patient with abdominal pain. Ultrasonography showed liver lesions, and biopsy diagnosed well-differentiated neuroendocrine tumor (NET). The primary tumor was not detected. The Ga-dotatate PET/CT scan shows the primary lesion in the terminal ileum and additional metastases in the abdomen and liver.

Courtesy of Corina Millo, MD.

Bronchopulmonary carcinoid with Ga-67 dotatate positron emission tomography with computed tomography (PET/CT). Image shows radiotracer avid mass in the superior segment of the left lower lobe and extensive osseous metastases throughout the axial skeleton, worst in the thoracic spine.

Other Neuroendocrine Tumors

Because neuroendocrine cells are spread throughout the body, NETs can develop in many different places, including in endocrine glands. Other NETs include medullary carcinoma that starts in the C cells of the thyroid, parathyroid carcinoma or parathyroid adenoma, thymic neuroendocrine cancer, pheochromocytoma that starts in the chromaffin cells of the adrenal glands, paraganglioma, neuroblastoma, pituitary gland tumors, neuroendocrine tumors of the ovaries and testicles, Merkel cell carcinoma, a type of nonmelanoma skin cancer, and small-cell lung cancer.

Therapeutic Radionuclides Bound to SSTRs

High doses of In-111 pentetreotide have been investigated for peptide receptor radionuclide therapy (PRRT) of NETs, taking advantage of the radionuclide’s Auger and conversion electron emissions. Although showing effectiveness, more promising results were found using a pure beta emitter, Yttrium-90 (Y-90), bound to other SSTRs, dotatoc and dotatate. In spite of increased survival, bone marrow and renal toxicity were a significant problem.

Lutecium-177 (Lu-177) Dotatate (Lutathera) Therapy for Neuroendocrine Tumors

As an alternative to Y-90, Lu-177 labeled to dotatate, a beta and gamma emitter, was investigated. Retrospective studies had shown similar effectiveness without the side effects of Y-90. In 2017 a phase 3 multicenter randomized prospective controlled trial of Lu-177 dotatate ( Fig. 13.10 ) was published that studied therapeutic effectiveness in patients with advanced midgut (jejunum, ileum, proximal colon) NETs who had disease progression while on standard first-line octreotide therapy. The investigation reported that compared with octreotide therapy, Lu-177 dotatate resulted in longer progression-free survival (65% vs.11% at 20 months), a significantly higher response rate (18% vs. 3%), and a lower risk of progression, 79% lower than high-dose octreotide therapy. Clinically significant myelosuppression occurred in <10% of patients. Risk of death was 60% lower. Renal toxicity was not a problem with amino acid infusion. Lutathera was approved for clinical use by the FDA in early 2018.

Peptide receptor radionuclide therapy (PRRT). Primary pancreatic neuroendocrine tumor (NET) with extensive metastases. Serial Ga-68 dotatate maximum-intensity projection (MIP) images (above) and F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET; below ). Baseline study (a1, b1), after three cycles of chemotherapy (a2, b2), after one cycle of Y-90 dotatate and three cycles of Lu-177 dotatate (Lutathera; a3, b3 ). At this time point, complete response is seen on F-18 FDG and near-complete response on Ga-68 dotatate ( arrow shows small area of residual disease) and on similar images 6 months posttherapy (a4, b4).

With permission, Kong G, Callahan J, Hofman MS, et al. High clinical and morphological response using 90Y-DOTA-octreotate sequenced with 177Lu-DOTA-octreotate induction peptide receptor chemoradionuclide therapy [PRCRT] for bulky neuroendocrine tumors. Eur J Nucl Med Mol Imaging. 2017;44[3]:476–489.

Methodology

Lu-177 dotatate, 200 mCi (7.4 MBq), is infused intravenously over 30 minutes. Patients receive at least four infusions at 8-week intervals. The amino acid solution is infused simultaneously for renal protection. However, significant nausea accompanies the amino acid solution and requires simultaneous antinausea therapy. Reports suggest that the combination of lysine and arginine has far fewer side effects than the amino acid solution.

I-123 mIBG (AdreView)

I-123 mIBG (AdreView) was approved by the FDA in 2003 for the detection of primary or metastatic pheochromocytoma and neuroblastoma, as an adjunct to other diagnostic tests. As an analog of the drugs bretylium and guanethidine, mIBG shares structural features and biological behavior with the adrenergic neurotransmitter hormone norepinephrine. Both norepinephrine and mIBG are taken up in cells rich in sympathetic neurons by an active process mediated by the norepinephrine uptake-1 transporter. Once in the cytoplasm, it is actively transported into the presynaptic nerve terminal and catecholamine storage granules by the vesicular monoamine transporter ( Fig. 13.11 ).

Uptake mechanism of mIBG. It is actively taken up in the presynaptic nerve terminal and retained in catecholamine storage granules, similar to norepinephrine. In the nerve terminal, norepinephrine is converted from tyrosine to DOPA to dopamine and then to norepinephrine (noradrenaline) and then secreted in response to acetylcholine.

With permission, Scott LA, Kench PL. Schematic representation of the 123I-MIBG uptake mechanism. J Nucl Med Technol. 2004;32:66–71.

Uptake and Distribution

I-123 mIBG avidly localizes in organs with high adrenergic innervation, including the heart, salivary glands, kidneys, and liver. ( Fig. 13.12 ). Variable activity is seen in the lungs, gallbladder, salivary glands, and nasal mucosa. Mild to moderate adrenal uptake often occurs with planar I-123 mIBG imaging and is nearly always seen with SPECT. No uptake occurs in the normal skeleton. It is cleared through the colon and kidneys.

Pheochromocytoma. Planar I-123 mIBG whole-body scan. Patient with poorly controlled hypertension and very elevated serum and urinary catecholamines. Distribution is normal except for focal markedly increased uptake in the region of the left adrenal, best seen in posterior view (right), consistent with pheochromocytoma.

Methodology

Numerous drugs interfere with mIBG uptake. The most common include tricyclic antidepressants, reserpine, cocaine, and the alpha- and beta-blocker labetalol ( Table 13.3 ). A detailed imaging protocol is summarized ( Box 13.4 ). Pretreatment with saturated potassium iodide (SSKI) or Lugol’s solution is recommended in the package insert and in procedural guidelines to block thyroid uptake ( Table 13.4 ). Although the 159-keV photopeak can be imaged with a low-energy collimator, a fraction of the photons (<3%) are high energy (440–625 keV [2.4%] and 625–784 keV [0.15%]), reducing the image quality. Although a low-energy collimator is often used, a medium-energy collimator is preferable. Images are routinely acquired 24 hours after injection. Whole-body imaging is standard in order to detect an extraadrenal pheochromocytoma, malignant metastases, or primary and metastatic neuroblastoma. SPECT/CT is very useful for anatomical localization.

Table 13.3

Medications Recommended to Be Held Before I-123 mIBG Study

Drug	Related Drugs	Mechanism	Discontinue for:
Antihypertensive/cardiac agents	Bretylium, guanethidine, reserpine Calcium channel blockers (amlodipine, nifedipine, nicardipine) Labetalol	Deplete granules Deplete granules Deplete granules and inhibit uptake Beta-blocker	7 days 14 days 21 days
Antipsychotics	Butyrophenones (droperidol, haloperidol) Loxapine Phenothiazines (chlorpromazine, fluphenazine, promethazine)	Inhibit uptake Inhibit uptake Inhibit uptake	21 days
Cocaine/opioids		Inhibit uptake	7 days
Sympathomimetics	Amphetamine, dopamine, ephedrine, isoproterenol, fenoterol, phenylephrine, phenylpropanolamine, pseudoephedrine, salbutamol, terbutaline, xylometazoline	Deplete granules	7 days
Tramadol		Inhibits uptake	14 days
Tricyclic antidepressants	Amitriptyline (and derivatives), amoxapine, doxepin	Inhibit uptake	21 days

 

mIBG, Metaiodobenzylguanidine.

Box 13.4

Iodine-123 mIBG: Summary Protocol

Patient Preparation

• 
  

  Discontinue interfering medications ( Table 13.3 ).

  
  
• 
  

  Potassium iodide or Lugol’s solution to prevent thyroid uptake ( Table 13.4 )

Radiopharmaceutical

• 
  

  Intravenous injection over 30 seconds

  
  
• 
  

  I-123 MIBG

  
  
  
  
  • 
    

    Children: 0.14 mCi/kg (5.2 MBq/kg); minimum 1.0 mCi (20 MBq) and maximum 10 mCi (400 MBq)

    
    
  • 
    

    Adults: 10 mCi (400 MBq)

  
  

Instrumentation

• 
  

  Gamma camera: Large field of view for planar images

  
  
• 
  

  Planar imaging and SPECT/CT as indicated

  
  
• 
  

  Collimator: Medium energy, parallel hole; low energy can be used.

Acquisition

• 
  

  I-123: Image at 24 hours.

  
  
• 
  

  Whole-body planar images (8 cm/sec)

  
  
• 
  

  SPECT: 3-degree steps, 35 sec/step, 180 projections, 128 × 128 matrix

mIBG, Metaiodo-benzyl-guanidine; SPECT, single-photon emission computed tomography; SPECT/CT, single-photon emission computed tomography with computed tomography.

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