Introduction

Octreotide scan is also known as somatostatin receptor scintigraphy. This scintigraphy is useful in the detection of carcinoid tumors and various neuroendocrine tumors. Neuroendocrine cells appear in many areas, including the brain, thyroid, lungs, and GIT. For the detection of pancreatic neuroendocrine tumors, an octreotide scan has a sensitivity of 75 to 100%.[1] Octreotide is a synthetic analog of somatostatin, which is an endogenous peptide released by neuroendocrine cells, activated immune cells, and various inflammatory cells.[2] 

Octreotide radiolabeling is with indium-111. This radiolabelled tracer then attaches to the tumor cells having the receptor for somatostatin. Somatostatin exerts its anti-proliferative and anti-secretory function after attaching with one of the five types of somatostatin receptors (SSTR1- SSTR5), which are G-protein coupled receptors (GPCRs). These receptors show their presence in the brain, pituitary, pancreas, thyroid, spleen, kidney, GIT, blood vessels, peripheral nervous system, and immune cells.[3] SSTRs maximally express on well-differentiated neuroendocrine tumors (NETs). SSTR-2 shows maximum expression, followed by SSTR 1,5,3 and 4.[4] 

There are two types of imaging based on these receptors; the first and commonest is an octreotide scan utilizing 111 In-DTPA (diethylenetriamine pentaacetate)-D-Phe-1-octreotide and binding mainly to SSTR 2 and 5. This scan provides a planar whole-body image, which in modern medicine fuses with single-photon emission computed tomography (SPECT) and CT. Octreotide scan specificity and the anatomic details of SPECT/CT are thereby combined.[5] The second and newest somatostatin receptor-based imaging uses positron emitter gallium (Ga) to mark somatostatin analogs, including Ga-DOTATOC (DOTA-Tyr3-octreotide), Ga-DOTANOC (1-Nal3-octreotide) and Ga-DOTATATE (DOTA-(Tyr)-octreotate), whose uptake is measured by PET. Gamma cameras work to detect the radioactive octreotide tracer, and that tells the location of the tumor cells. An octreotide scan has shown to localize 86% carcinoids, 89% neuroblastomas, 86% pheochromocytomas, 94% paragangliomas, and 80% primitive neuroectodermal tumors (PNETs). Its utility in detecting medullary thyroid carcinomas and pituitary tumors is comparatively less.

Procedures

Typically, three visits to the Nuclear Medicine Department might be necessary. In the first visit, a radioactive tracer is injected into the vein. Recommendation for the administration of 111-In pentetreotide is 5 mega Becquerel/kilogram (0.14 milliCurie/kilogram) for children and 222 mega Becquerel (6 milliCurie) for adults, amounting to 11 to 20 mg pentetreotide. 111 Indium has a half-life of 2.8 days.[6]

Pentetreotide gets cleared rapidly by kidneys with just 1/3rd dose remaining in blood after 10 minutes. Elimination is principally by kidneys, but dialysability status is not known. The patient will be on an imaging table under a special detector, namely a gamma camera. The camera itself is non-radiation producing. It stays near the body part, which is under focus for imaging. CT scans may also be an option for better anatomical localization. Imaging may take place over periods of  4 to 48 hours (usually at 4,24 and 48 hours) after injection.[7][8]

Indications

The scan is useful in the localization of primary neuroendocrine tumors (NET), showing somatostatin receptors. It is also used in follow-up, staging after treatment, and detection of metastasis. NETs arise from about 17 different cell types, which are present in the skin, lung, hepatobiliary system, genito-urinary tract, thyroid, and gastrointestinal tract [9]. Commonest primary sites are lung, rectum, and small intestines.[10] Significant expression of somatostatin receptors presents in adrenal medulla tumors (pheochromocytoma, neuroblastoma, ganglioneuroma, and paraganglioma), gastroenteropancreatic neuroendocrine tumors [formerly classified into carcinoid, gastrinoma, glucagonoma, vasoactive intestinal polypeptide (VIP), pancreatic polypeptide(PP) secreting tumor or non-functioning tumors] which is recently classified by WHO as low, intermediate and high grade (G1, G2, G3, respectively).[8] [In]-pentetreotide can be useful to diagnose pheochromocytoma. However, it is considered inferior to MIBG in benign intra-adrenal pheochromocytoma.[11][12][13][14][15][16] 

Van der Harst et al. used preoperatively [I]-MIBG scintigraphy and radio-labeled somatostatin analog for diagnosis of pheochromocytoma and concluded that somatostatin receptor imaging might be considered a supplement to MIBG scintigraphy in pheochromocytoma and paraganglioma patients with suspected metastasis.[17] New somatostatin analogs like DOTA-Tyr3-octreotide (DOTATOC) are showing good results in imaging with a high affinity for somatostatin receptors. Moreover, they are stable and easy to label.[18] Even though existing somatostatin based tracers mostly have affinities for somatostatin receptor subtype 2, that subtype is not always present on pheochromocytoma and paraganglioma cells. The new substrates like DOTANOC have an affinity for other somatostatin receptor subtypes also.[19][20] DOTATOC and DOTANOC labeled with PET radiotracer [Ga] have shown great results for imaging the somatostatin receptor-positive tumors in comparison with non PET  [In]-pentetreotide scintigraphy; this again exemplifies better performance of PET over scintigraphy in general.[19][21][22] Expression of NET and somatostatin receptors can be lost in dedifferentiated tumors, which may result in false-negative image reporting in metastatic disease.[17][23][14] In metastatic tumors associated with an SDHB mutation, [F]-FDG PET shows superiority.[24] 

111-In octreotide scan was used in localizing the presence of an intracardiac pheochromocytoma in a 13-year old boy. In that case, even a CT scan of the abdomen, pelvis, chest and whole body meta-iodo-benzyl guanidine (MIBG) scan could not localize the lesion.[25] This case shows the importance of octreotide scanning. Octreotide scan is beneficial in the diagnosis and follow-up of cases of thymic carcinoid tumors also which are associated with multiple endocrine neoplasias (MEN).[26] Somatostatin analogs (technetium depreotide, DTPA) are used in imaging of pituitary tumors. Pituitary prolactinoma and adrenocorticotrophic hormone (ACTH) secreting adenomas can't be localized, but clinically non-functioning pituitary adenomas may be visible in 75% of cases with 111In-DTPA-octreotide.[27][28][29] Positive test results mean patients with growth hormone (GH) and thyroid-stimulating hormone (TSH) secreting pituitary tumors may have a good suppressive effect of octreotide on hormone release by these tumors.[27] Other tumors which can be detected include:

• Merkel cell tumor of the skin
• Small-cell lung carcinoma
• Meningioma
• Astrocytoma
• Breast carcinoma
• Lymphoma

In a study, an octreotide scan helped to localize insulinomas among 4 out of 17 (24%) patients. This technique also detected ectopic insulinoma and malignant insulinoma. Only an octreotide scan could help in the localization of the ectopic insulinoma. Importantly, treatment with octreotide before the octreotide scan did not appear to alter tumor detectability in this series. Pre-treatment with octreotide may saturate the somatostatin receptors, but this treatment within a week before the scan can improve contrast and tumor detectability.[30][31][32] Out of five patients on treatment with octreotide, three showed positive scintigraphy, which is in contrast to only one patient showing positivity amongst the twelve who did not get any treatment. Octreotide scan may underestimate patients with insulinoma that respond to octreotide treatment. Six out of ten patients that responded to octreotide had no uptake of tracer. Surprisingly, all benign insulinomas detectable with an octreotide scan responded to octreotide treatment. As mentioned before, the octreotide scan followed up by SPECT could result in the localization of only 24% insulinomas.[33] In the detection of carcinoid tumors, there is a high sensitivity of over 90%.[34][35] Still, some carcinoids have a limited number of somatostatin receptor sites with resulting in low affinity for octreotide; this occurs in less than 10% of carcinoids and other neuroendocrine tumors.[36] 

Liver metastases from carcinoids can demonstrate similar tracer accumulation like that of the surrounding liver; hence it may not be easy to distinguish it from normal hepatic tissue. Here subtraction technique using 99m-technetium colloid and SPECT is useful to arrive at a diagnosis.[6] A case report shows the use of a pre and post-operative octreotide scan in a patient in whom the CT scan was equivocal, and the ideal surgical excision of the indistinct lesion was doubtful. Octreotide scan allowed for a limited resection with preservation of the lung parenchyma. It showed that octreotide scanning is beneficial in the management of carcinoids.[37] 

Somatostatin receptors are present in 80% of gastrinomas. Pentetreotide scan successfully localizes these neoplasms (primary or nodal metastases) in up to 78 to 86% cases.[38][39][40]  Gibril et al., in a study of 80 patients, found that CT, MRI, or angiography resulted in the identification of extrahepatic gastrinomas in 28  to 31%  patients, whereas ultrasound led to the detection of extrahepatic tumors in 9% of patients.[41] Pentetreotide scan not just localizes the primary lesions, but also can be useful in screening for metastases and monitoring therapeutic response.[41] 

Certain autoimmune/granulomatous disorders (like sarcoidosis) can occasionally demonstrate octreotide takeup via overexpression of somatostatin receptors. Octreotide scanning correlates with the degree of dyspnea in sarcoidosis patients and more accurately quantifies the degree of pulmonary involvement compared with the radiological assessment. Octreotide scan can be useful in monitoring idiopathic interstitial pneumonia (IIP) in specific histological types [non-specific interstitial pneumonia (NSIP) and desquamative interstitial pneumonia (DIP)]. It may even substitute HRCT in the assessment of usual interstitial pneumonia (UIP) for its excellent accuracy.[42] Apart from these, other uses include recognizing metastatic tumors for peptide receptor radionuclide therapy (PRRT) and recognizing its effect. Krenning score is used in grading the uptake intensity of neuroendocrine tumors on somatostatin receptor imaging modalities like octreotide scan.[1] Typically PRRT is taken into consideration if this score is >2. The grading is as follows:

• Grade 1: uptake < normal liver
• Grade 2: uptake = normal liver
• Grade 3: uptake > normal liver
• Grade 4: uptake > spleen or kidneys

Octreotide scan performs even better to detect liver metastases than it does in primary tumor detection with sensitivity ranging from 49-91%. In different studies to identify NET metastases, Octreotide scanning was able to identify new lesions in 47% and 4.6% patients, respectively, whose lesions were missed by CT or MRI.[43][44][45][46][47] 

Interfering Factors

Patients on octreotide therapy or somatostatin therapy must stop treatment. Long-acting octreotide should be stopped 4 to 6 months before the scan. These medications may affect the test results, although conflicting results may occur as previously described. Dose alteration may be necessary in cases of renal impairment. This test has a lot of factors contributing to false positive and negative results. A false-positive test may occur in:

• Respiratory tract infections/ other infections
• Pulmonary/pleural collections after radiotherapy
• Recent surgical/colostomy site
• Tracer accumulation in normal sites(pituitary, thyroid, liver, spleen, kidney, intestines, gall bladder, ureter, bladder, stimulated adrenals)

A false-negative test may occur in:

• Unlabeled somatostatin present as a result of octreotide therapy/ production by tumor
• Different somatostatin receptors demonstrate variable affinities for radioligands, particularly insulinomas and medullary thyroid cancers.
• Hepatic metastases of neuroendocrine tumors can look isointense; can correlate along with subtraction scintigraphy along with sulfur colloid or anatomical imaging (CTscan/MRI) 

Complications

Octreotide scan is a safe procedure but may lead to minor side effects of radioactivity, as seen with other modalities.

Patient Safety and Education

Octreotide scan is not suitable for pregnant women because of the radiation dose. Breastfeeding females may stop breastfeeding and avoid close contact with young-ones for some time. Effective half-life (4.1 days) is greater than the physical half-life of In (2.83 days). This fact might be because of continued radioactivity accumulation within breast milk as Indium gets released from internal compartments over time.

Clinical Significance

As mentioned above, octreotide scanning has a significant role in recognition of various neuroendocrine tumors, assessing their progress and recognition of metastasis, along with a greater scope of recognizing all malignancies with somatostatin receptor positivity and even autoimmune disorders also. Modern oncologic practices call for greater use of octreotide scanning.

It is quite useful in staging as well as recognition of many occult primary tumors also. It is also relatively safe as it avoids the side effects associated with the use of contrast as in CECT. Moreover, radiation exposure is also quite less. Newer studies are demonstrating the role of octreotide scans in different fields like immunology also. More studies are necessary for further utilization of this technique in various other sub-divisions.