Somatostatin Receptor Imaging

Gabriel Soudry, M.D.

Kevin J Donohoe, M.D.

May 30, 1995

Case Presentation:

A 62 year-year-old man presented with severe diarrhea, weight loss and increased flatulence. On exam he was icteric and had a palpable gallbladder.

Abdominal CT (50k bytes) revealed a mass (arrow, 54k bytes) in the head of the pancreas measuring 4 X 4.5 X 3 cm. No abnormalities were demonstrated in the liver, adrenals or spleen.
The total bilirubin was 5.2.
An exploratory laparotomy showed liver metastasis.
A cholecystojejunostomy was performed.
The tumor cells showed no staining for insulin, glucagon, somatostatin or gastrin.
The final pathologic diagnosis was metastatic neuroendocrine carcinoma.

One month after the surgery, an Indium-111-Pentetreotide (Octreoscan(R)) study was obtained. Three weeks later, a repeat abdominal CT was performed.

Findings:

An Indium-111-Pentetreotide scintigram was obtained 4 hours (54k bytes) and 24 hours (51k bytes) after injection. There was intense increased tracer localization in the pancreatic mass (arrow head, 59k bytes) and multiple abnormal foci of uptake throughout the liver (arrow) consistent with diffuse liver metastases.

Three weeks later, a repeat abdominal CT (54k bytes) with oral and IV contrast injection showed the pancreatic mass to have increased in size (arrow, 54k bytes) measuring now 4 X 6 X 3 cm and the presence of three small peripheral liver metastases (one (50k bytes) is well seen on this slice, arrow, 64k bytes).

Discussion:

Introduction:

Somatostatin is a naturally occurring neuropeptide with a wide range of pharmacologic actions including inhibition of growth hormone release and suppression of insulin and glucagon secretion. A high concentration of somatostatin receptors has been demonstated on neuroendocrine tumors by binding tumor cell membranes with radioiodine labeled somatostatin or its long acting analog, octreotide. Indium-111-Pentetreotide, a radiolabelled form of the somatostatin analog octreotide, binds at the same binding sites as naturally occurring somatostatin, making it a sensitive indicator for somatostatin receptor-bearing neuroendocrine tumors. Since the concentration of receptors on tumors is variable, the sensitivity of Indium-111-Pentetreotide may vary among tumor types.

Somatostatin and Key Analogs:

Endogenous somatostatin has a half-life of 2-3 minutes. Octreotide (Sandostatin(R)), the first commercially available peptide analog that possesses the same pharmacologic properties as somatostatin. Octreotide clear much more slowly from the circulation, and it suppress hormonal hypersecretion from endocrine secreting tumors.

In 1987, octreotide was labeled with I-123 which permitted imaging of somatostatin receptors on neuroendocrine tumors in vivo. This compound was not ideal because of difficult labeling chemistry, limited availability of the isotope, and in vivo clearance patterns that made abdominal imaging difficult. The radiolabelled analog, Indium-111 DTPA-octreotide (Octreoscan(R)) is cleared primarily via the renal system and allows for clear visualization of abdominal tumor sites containing somatostatin receptors.

Normal Tissue Accumulation of Indium-111-Pentetreotide in Humans:

Accumulation of radioactivity after intravenous injection of Indium-111-Pentetreotide is observed in the:

pituitary gland,
thyroid gland,
spleen,
liver,
kidneys,
urinary bladder, and

occasionally in the:

gallbladder and
colon.

To avoid false positive readings:

Transient accumulation in the nasal region and lung hili has been observed, which is attributed to the common cold virus or influenza.
Radiation therapy of the lung can cause local pulmonary accumulation of tracer.
Bleomycine can likewise cause local pulmonary accumulation.
Tracer may accumulate at sites of recent operation.

Incidence of Somatostatin Receptors in Neuroendocrine Tumors:

Somatostatin receptors have been demonstrated in most neuroendocrine tumors using both in vivo scintigraphy and in vitro receptor status.

                                    In vivo      In vitro
GH-producing pituitary tumour      7/10  70%    45/46  98%
TSH-producing pituitary tumour     2/2  100%      -     -
Non-functioning pituitary tumour  12/16  75%    12/22  55%
Gastrinoma                        12/12 100%     6/6  100%
Insulinoma                        14/23  61%     8/11  72%
Glucagonoma                        3/3  100%     2/2  100%
Unclassified APUDoma              16/18  89%     4/4  100%
Paraganglioma                     33/33 100%    11/12  92%
Medullary thyroid carcinoma       20/28  71%    10/26  38%
Neuroblastoma                      8/9   89%    15/23  65%
Pheochromocytoma                  12/14  86%    38/52  73%
Carcinoid                         69/72  96%    54/62  88%
Small cell lung cancer            34/34 100%     4/7   57%

Failure to visualize some insulinomas may be due to the existence of somatostatin receptors subclasses that show high affinity binding sites for native somatostatin but not for octreotide.

Normal tracer uptake in surrounding tissues may be responsible for eight false negative studies of medullary thryroid cancer metastatic to the liver in seven patients as well as one lesion in the thyroid.

GH-producing pituitary adenomas, clinically nonfunctioning pituitary adenomas and also TSH-secreting pituitary adenomas have been visualized. In addition, other intra or para-sellar tumors may be positive which limits the specificity of octreotide scintigraphy.

Prevalence of Somatostatin Receptors in Non-neuroendocrine Tumors:

A number of non-neuroendocrine tumors have been visualized using somatostatin receptor scintigraphy and using in vitro receptor status.

                                 In vivo       In vitro
Non-small cell lung cancer     36/36 100%     0/17   0%
Meningiomas                    14/14 100%    54/55  98%
Breast cancer                  37/50  74%    33/72  46%
Exocrine pancreatic tumours     0/24   0%     0/12   0%
Astrocytoma                     4/6   67%    14/17  82%

Somatostatin receptors on immune cells surrounding non-small cell lung cancer may be responsible for the high sensitivity of Indium-111-Pentetreotide scintrigraphy with this tumor. Somatostatin receptors are absent on most non-small cell lung cancers. Meningiomas and astrocytomas have high numbers of somatostatin receptors. These tumors can be seen only with the break down of the blood brain barrier. The high somatostatin receptor content of the normal brain cannot be visualized by scintigraphy because the normal blood brain barrier is not penetrated by somatostatin and octreotide.

The role of octreotide scintigraphy in imaging breast cancer is unknown. It may be of value in selecting patients for clinical trials with somatostatin analogs.

Prevalence of Somatostatin Receptors in Granulomatous and Auto-immune Diseases:

Somatostatin receptors have also been detected on a variety of white blood cells using both in vivo scintigraphy and in vitro receptor status.

                              In vivo       In vitro
Non-Hodgkin's lymphoma      59/74  80%    26/30  87%
Hodgkin's disease           23/24  96%     2/2  100%
Sarcoidosis                 23/23 100%     3/3  100%
Wegener's granulomatosis     4/4  100%      -
Tuberculosis                 6/6  100%     2/2  100%
Graves' disease: thyroid       9             1
Graves' ophthalmopathy         25            -

Both Hodgkin's and non-Hodgkin's lymphoma can be detected using somatostatin receptor scintigraphy. However, it is not clear how this technique compares to traditional gallium imaging. Infections or inflammatory lesions, such as sarcoidosis, tuberculosis and Wegener s granulomatosis investigated, can show tracer uptake as they would with gallium scans. In addition, lesions located adjacent to the liver and spleen may be missed because of the adjacent normal uptake.

In Graves' hyperthyroidism, accumulation in the thyroid gland is markedly increased which may be related to the presence of activated lymphocytes. In clinically active Graves' ophthalmopathy, the orbits may show accumulation of radiotracer.

Conclusions:

Indium-111-Pentetreotide is a new radiopharmaceutical with high sensitivity for various neuroendocrine tumors and their metastases. An understanding of normal tracer distribution and knowledge of lesions expected to accumulate the tracer are essential for accurate interpretation of the images.

References:

Somatostatin receptor imaging for neuroendocrine tumors. Product monograph. Mallinkrodt Medical inc.
Krenning EP, Kwekkeboom DJ, Bakker WH et al. Somatostatin receptor scintigraphy with [111In-DTPA-D-Phe1]- and [123I-Tyr3]-octreotide: the Rotterdam experience with more than 1000 patients. Eur J Nucl Med 1993; 20:716-731.
Weinel RJ, Neuhaus C, Strapp J et al. Preoperative localization of gastrointestinal endocrine tumors using somatostatin-receptor scintigraphy. Ann Surg 1993; 218(5):640-645.
Reubi JC, Kvols E, Krenning E, Lamberts SWJ. Distribution of somatostatin receptors in normal and tumor tissue. Metabolism 1990; 9(2):78-81.

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J. Anthony Parker, MD PhD, Tony_Parker@bih.harvard.edu