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Octreotide Scan
Introduction
An octreotide scan, also known as somatostatin receptor scintigraphy (SRS), is valuable for detecting carcinoid tumors and various neuroendocrine tumors (NETs). Neuroendocrine cells are found in multiple areas of the body, including the brain, thyroid, lungs, and gastrointestinal tract. The scan has a sensitivity ranging from 75% to 100% for detecting pancreatic NETs.[1] Octreotide is a synthetic analog of somatostatin, an endogenous peptide released by neuroendocrine cells, activated immune cells, and various types of inflammatory cells.[2]
Octreotide is radiolabeled with Indium-111 (111In) for imaging purposes. This radiolabeled tracer binds to tumor cells that express somatostatin receptors (SSTRs). Somatostatin is secreted in 2 forms in the body, consisting of 14 and 28 amino acids, which result from differential proteolytic processing of a single precursor. Both forms can activate SSTRs at nanomolar concentrations, as they both contain the peptide region critical for receptor interaction.[3]
Cortistatins are another class of endogenously secreted neuropeptides that bind to SSTRs with high affinity.[4][5] Somatostatin exerts its antiproliferative and antisecretory effects by binding to 1 of the 5 SSTR subtypes (SSTR1, SSTR2, SSTR3, SSTR4, and SSTR5), which are G-protein–coupled receptors (GPCRs). These receptors are widely distributed in the brain, pituitary gland, pancreas, thyroid, spleen, kidneys, gastrointestinal tract, blood vessels, peripheral nervous system, and immune cells.[6] SSTRs are most abundantly expressed in well-differentiated NETs, with SSTR2 showing the highest expression, followed by SSTR1, SSTR5, SSTR3, and SSTR4.[7] However, expression patterns can vary by tumor type.
Tumors such as pituitary adenomas, gastrointestinal tract NETs, lung NETs, pheochromocytomas, and paragangliomas typically show predominant expression of SSTR2. In contrast, adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas (SSTR5), insulinomas (SSTR1 and SSTR5), and medullary thyroid carcinomas predominantly express other SSTR subtypes. Both normal and tumor cells can exhibit varying patterns of SSTR subtype expression.[3]
The 2 types of imaging are based on these receptors. The first and most common is the octreotide scan, which uses 111In-DTPA (diethylenetriamine pentaacetate)-D-Phe-1-octreotide and primarily binds to SSTR2 and SSTR5. This scan provides a planar whole-body image, which, in modern medicine, is fused with single-photon emission computed tomography (SPECT) and computed tomography (CT). The specificity of the octreotide scan and the anatomic detail from SPECT/CT are thus combined.[8]
An octreotide scan has been shown to localize 86% of carcinoids, 89% of neuroblastomas, 86% of pheochromocytomas, 94% of paragangliomas, and 80% of primitive NETs. The effectiveness of the scan in detecting medullary thyroid carcinomas and pituitary tumors is comparatively lower. The second and more recent SSTR-based imaging technique uses the positron emitter gallium (Ga) to label somatostatin analogs such as Ga-DOTATOC (DOTA-Tyr3-octreotide), Ga-DOTANOC (1-Nal3-octreotide), and Ga-DOTATATE (DOTA-(Tyr)-octreotate). Uptake of these agents is measured by positron emission tomography (PET) imaging. Gamma cameras detect the gamma emissions from the radiolabeled tracer, enabling precise localization of SSTR-positive tumor sites.
Procedures
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Procedures
Typically, 3 visits to the Nuclear Medicine Department may be necessary. During the first visit, a radioactive tracer is injected into a vein. The recommended dosage for administering 111In-pentetreotide is 5 MBq/kg (0.14 mCi/kg) for children and 222 MBq (6 mCi) for adults, amounting to 11 to 20 µg of pentetreotide. 111In has a half-life of 2.8 days.[9]
Pentetreotide is rapidly cleared by the kidneys, with only one-third of the dose remaining in the bloodstream after 10 minutes. The primary route of elimination is through the kidneys, although its dialyzability status is unknown. During imaging, the patient is positioned on an imaging table beneath a gamma camera, which is a special, passive detector that does not emit radiation.
The gamma camera remains close to the area being imaged to capture accurate images. A CT scan may be used in some cases to provide better anatomical localization. Imaging typically occurs over a period of 4 to 48 hours following tracer injection, most commonly at 4, 24, and 48 hours.[10][11]
Indications
The octreotide scan is valuable for localizing primary NETs and assessing SSTR expression. This is critical in follow-up evaluations, posttreatment staging, and metastasis detection. NETs arise from at least 17 different neuroendocrine cell types distributed throughout the body, including those in the skin, lungs, hepatobiliary system, thyroid, and genitourinary and gastrointestinal tracts.[12] The most common primary sites include the lungs, rectum, and small intestine.[13]
Significant expression of SSTRs is present in adrenal medulla tumors (including pheochromocytoma, neuroblastoma, ganglioneuroma, and paraganglioma), gastroenteropancreatic NETs. These NETs were previously classified based on hormone secretion (eg, carcinoid, gastrinoma, glucagonoma, vasoactive intestinal polypeptide-secreting tumors, pancreatic polypeptide-secreting tumors, or nonfunctioning tumors), but the World Health Organization (WHO) now categorizes them by grade—low (G1), intermediate (G2), and high (G3).[11] While 111In-pentetreotide can aid in diagnosing pheochromocytoma, it is generally considered less sensitive than the meta-iodo-benzyl guanidine (MIBG) scan for detecting benign intra-adrenal pheochromocytomas.[14][15][16][17][18][19]
Harst E et al used preoperatively 123I-MIBG scintigraphy and radiolabeled somatostatin analogs to diagnose pheochromocytoma. They concluded that SSTR imaging may serve as a valuable supplement to MIBG scintigraphy, particularly in patients with pheochromocytoma or paraganglioma suspected of metastasis.[20] Newer somatostatin analogs, such as DOTATOC, have demonstrated promising results in imaging due to their high affinity for SSTRs. Moreover, these compounds are stable and easy to radiolabel, enhancing their clinical utility.[21] Although most existing somatostatin-based tracers primarily target SSTR2, this receptor subtype is not consistently expressed on pheochromocytoma and paraganglioma cells. Newer agents, such as DOTANOC, exhibit affinity for multiple SSTR subtypes, broadening their diagnostic potential in these tumors.[22][23]
DOTATOC and DOTANOC-labeled PET radiotracers ([Ga]) have shown great results in imaging SSTR-positive tumors compared to non-PET [In]-pentetreotide scintigraphy, highlighting the overall better performance of PET over scintigraphy.[22][24][25] 68Ga-DOTATOC has higher sensitivity (91% versus 86%) and specificity (90.6% versus 50%) than 111In-octreotide.[26] However, 68Ga PET has lower spatial resolution than 18F and 64Cu.[27]
68Ga-DOTATATE PET-CT has also shown better results than 111In-octreotide scintigraphy in evaluating NETs, demonstrating a better ability to accurately assess the extent of the disease. In a study, 68Ga PET identified additional findings that led to changes in treatment planning for approximately 12% of patients.[28] However, the expression of NET and SSTRs can be lost in dedifferentiated tumors, potentially leading to false-negative imaging results in metastatic disease.[20][29][17] In metastatic tumors associated with an SDHB mutation, [18F]-FDG PET has demonstrated superior diagnostic performance.[30] The integration of both visual and quantitative assessments is emerging as a valuable approach and may serve as a new predictive marker for SRS.[31]
A 111In-octreotide scan was used in a study to localize an intracardiac pheochromocytoma in a child aged 13. In this case, CT scans of the abdomen, pelvis, and chest, as well as a whole-body MIBG scan, failed to identify the lesion.[32] This case highlights the clinical value of octreotide scanning in detecting elusive tumors. Additionally, octreotide scans are effective in the diagnosis and follow-up of thymic carcinoid tumors, which are often associated with multiple endocrine neoplasia.[33] Somatostatin analogs, such as technetium depreotide and DTPA, are used to image pituitary tumors. While pituitary prolactinomas and ACTH-secreting adenomas may not be localized, clinically nonfunctioning pituitary adenomas can be identified in approximately 75% of cases using 111In-DTPA-octreotide.[34][35][36] Positive test results suggest that patients with growth hormone and thyroid-stimulating hormone–secreting pituitary tumors may benefit from the suppressive effects of octreotide on hormone release from these tumors.[34] Additional tumors that can be detected include Merkel cell tumor of the skin, small cell lung carcinoma, meningioma, astrocytoma, breast carcinoma, and lymphoma.
In a study, an octreotide scan successfully localized insulinomas in 4 out of 17 (24%) patients. This technique also detected ectopic and malignant insulinomas, with only the octreotide scan able to localize the ectopic insulinoma. Notably, pretreatment with octreotide did not affect tumor detectability in this series. While pretreatment with octreotide may saturate the SSTRs, administering it within a week before the scan can improve contrast and enhance tumor detectability.[37][38][39] Out of the 5 patients receiving octreotide treatment, 3 patients showed positive scintigraphy, compared to only 1 patient among the 12 who did not receive treatment. Octreotide scans may underestimate the number of insulinoma patients who respond to octreotide therapy. Notably, 6 out of 10 patients who responded to octreotide treatment showed no tracer uptake. Interestingly, all benign insulinomas detectable on the octreotide scan responded to octreotide treatment.
As previously mentioned, the octreotide scan followed by SPECT resulted in the localization of only 24% of insulinomas.[40] However, the sensitivity for detecting carcinoid tumors is over 90%.[41][42] Some carcinoids, though, have a limited number of SSTR sites, resulting in a low affinity for octreotide. This occurs in fewer than 10% of carcinoids and other NETs.[43] Liver metastases from carcinoids may exhibit tracer accumulation similar to the surrounding liver tissue, making it challenging to differentiate from normal hepatic tissue. In these cases, the subtraction technique using 99m-technetium colloid and SPECT can aid in diagnosis.[9] A case report highlighted the use of pre- and postoperative octreotide scans in a patient with an equivocal CT scan, where the feasibility of accurately excising an indistinct lesion was uncertain. The octreotide scan facilitated a more targeted, limited resection while preserving lung parenchyma. This case underscored the value of octreotide scanning in the effective management of carcinoid tumors.[44]
SSTRs are expressed in approximately 80% of gastrinomas. Pentetreotide scanning can successfully localize these neoplasms (whether primary or nodal metastases) in up to 78% to 86% of cases.[45][46][47] In a study involving 80 patients, Gibril et al reported that CT, magnetic resonance imaging (MRI), or angiography identified extrahepatic gastrinomas in 28% to 31% of cases, whereas ultrasound detected extrahepatic tumors in only 9% of patients.[48] A pentetreotide scan localizes primary lesions and is valuable in screening for metastases and monitoring therapeutic response.[48] Currently, the use of hybrid SSTR PET/MRI for evaluating head and neck tumors is also being explored.[49] Other applications include SRS for monitoring appendicular NETs post-surgery, particularly when recurrence or metastasis is suspected.[50] In cases of progressive prostate carcinoma, which may undergo neuroendocrine transformation, SRS can help localize targets with neuroendocrine differentiation.[51]
Certain autoimmune and granulomatous disorders, such as sarcoidosis, may occasionally show octreotide uptake due to overexpression of SSTRs. In sarcoidosis patients, octreotide scanning has been shown to correlate with the degree of dyspnea and provides a more accurate assessment of pulmonary involvement compared to radiological evaluation. Additionally, octreotide scans can aid in monitoring idiopathic interstitial pneumonias (IIPs), particularly in specific histological subtypes such as nonspecific interstitial pneumonia (NSIP) and desquamative interstitial pneumonia (DIP). In some cases, it may even serve as an alternative to high-resolution CT (HRCT) in evaluating usual interstitial pneumonia (UIP), given its high diagnostic accuracy.[52]
Other applications include identifying metastatic tumors eligible for peptide receptor radionuclide therapy (PRRT) and assessing treatment response. The Krenning score is commonly used to grade the uptake intensity of NETs on SSTR imaging modalities such as the octreotide scan.[1] This scoring system has since been adapted for use with SSTR PET imaging (modified Krenning score).[53] A score greater than 2 typically indicates suitability for PRRT, making the scan a critical tool in patient selection.[53] The grading criteria are as follows:
- Grade 0: No uptake
- Grade 1: Uptake is much less than normal liver function
- Grade 2: Uptake is equal to or slightly less than normal liver function
- Grade 3: Uptake is greater than normal liver function
- Grade 4: Uptake is greater than spleen or kidneys
The correlation between the traditional Krenning score and the modified Krenning score derived from SSTR PET is limited.[54] SSTR PET tends to yield higher scores due to its superior sensitivity compared to planar scintigraphy methods or SPECT. Additionally, SSTR PET imaging is typically performed earlier (around 1 hour post-injection), whereas scintigraphy is done at 24 hours. SSTR PET has become the preferred standard for selecting patients for PRRT, partly due to its lower associated radiation dose. For lesions larger than 2 cm, the modified Krenning score is more reliable. However, caution is warranted when considering PRRT in patients with lesions smaller than 2 cm that show a modified Krenning score of more than 2, as these cases may not meet eligibility criteria when imaged using traditional 111In-pentetreotide.
A patient is considered to have homogeneous disease if fewer than half of the target lesions exhibit heterogeneous SSTR expression. Patients with heterogeneous SSTR expression tend to have shorter overall survival (OS) and time to progression (TTP). Octreotide scans are often more effective at detecting liver metastases than primary tumors, with reported sensitivities ranging from 49% to 91%. In various studies evaluating NET metastases, octreotide scanning revealed new lesions in 47% and 4.6% of patients, respectively, that were missed by CT or MRI.[55][56][57][58][59] The use of cold somatostatin analogs may enhance tumor margin delineation by improving contrast between tumor and surrounding normal tissue.[60] SRS can also identify metastatic lymph node masses based on SSTR immunostaining, although its spatial resolution is relatively limited.[61]
Interfering Factors
Patients receiving octreotide or other somatostatin therapies should discontinue treatment before the scan. Short-acting somatostatin analogues should ideally be stopped 24 hours before the 111In-pentetreotide injection, or at least 12 hours prior. This requirement may be waived if the patient's clinical condition necessitates continued therapy.
Long-acting octreotide should be discontinued 4 to 6 weeks before the scan. Alternatively, patients may be temporarily transitioned to short-acting analogues, which can be continued up to 24 hours before the scheduled study. Another option is to administer the long-acting drug just before its next scheduled dose administration. However, pharmacologically relevant drug levels may still persist, potentially interfering with the results, such as lower radiotracer activity in the spleen.[11][62] Dosage adjustments may be necessary in cases of renal impairment.
Several factors can contribute to false-positive and false-negative results in this test. False positives may be seen in the following situations:
- Respiratory tract or other infections.
- Pulmonary or pleural collections after radiotherapy.
- Recent surgery or colostomy.
- Physiological tracer accumulation in normal structures such as the pituitary, thyroid, liver, spleen, kidneys, intestines, gallbladder, ureters, bladder, and occasionally stimulated adrenal glands.
A false-negative test may occur under the following conditions:
- Presence of unlabeled somatostatin due to octreotide therapy or tumor production.
- Variable affinities of different SSTRs for radioligands, especially in insulinomas and medullary thyroid cancers.
- Hepatic metastases from NETs may appear isointense, requiring correlation with subtraction scintigraphy, sulfur colloid imaging, or anatomical imaging (CT/MRI) for accurate assessment.
Complications
The octreotide scan is generally a safe procedure, although it may result in minor adverse effects related to radioactivity, similar to other imaging modalities.
Patient Safety and Education
Octreotide scans are not recommended for pregnant women due to the radiation exposure. Breastfeeding women should temporarily stop breastfeeding and avoid close contact with infants for a period of time. The effective half-life of 4.1 days is longer than the physical half-life of indium (2.83 days). This discrepancy is likely due to the continued release of indium from internal compartments over time, leading to radioactivity accumulation in breast milk.
Clinical Significance
Octreotide scintigraphy is crucial in detecting and staging NETs, assessing metastatic burden, and guiding treatment decisions, particularly for SSTR-positive malignancies. The applications of this technique are expanding beyond oncology, with emerging uses in immunology and chronic inflammatory conditions.
Contemporary oncological practice increasingly depends on octreotide scintigraphy for staging and detecting occult primary neuroendocrine neoplasms. This method is also relatively safe, as it avoids the adverse effects of using contrast in contrast-enhanced CT (CECT) and offers significantly lower radiation exposure. Newer studies highlight its potential in immunology, although further research is necessary to explore its broader applicability across various medical fields.
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