Somatostatin Analogs for Diagnosis and Staging of Tumors

Laurent Dinh M.D.

Milos Janicek M.D., Ph.D.

March 8, 1994

Case Presentation:

A 49 years old female patient was diagnosed with non-Hodgkin's lymphoma (nodular poorly differentiated) stage IIIA in 1983. She underwent chemotherapy and successfully obtained remission. However, in October 1990, a recurrence was detected as an abdominal mass and mediastinal mass were seen on the gallium scan-67. She underwent several regimens of chemotherapy with marginal success. On February 1994, the mass in the abdomen was still present, but the chest mass disappeared.

Findings:

A 111-In-octreotide was obtained in February 1994 as part of an investigational study for staging lymphoma. The 111-In-octreotide done 24 hours post tracer injection did not demonstrate any abnormalities. The 48 hour delayed images and SPECT images were also normal.

A gallium-67 scintigraphy obtained for comparison showed a large gallium-avid mass in the mid abdomen (outline) that correlates with the lymphadenopathy seen on the CT (arrow). The scintigraphic appearance of this mass was essentially unchanged or slightly improved as compared with the previous study of October 1992, suggesting an indolent tumor. The remainder of the gallium-67 study was unremarkable; no other abnormality was demonstrated.

Discussion:

What is somatostatin ?

Somatostatin is a peptide hormone consisting of 14 amino acids. It is present in the hypothalamus, the cerebral cortex, the brain stem, the GI tract, and the pancreas. In the CNS, it acts as a neurotransmitter; its hormonal activities include inhibition of the release of growth hormone, insulin, glucagon, gastrin, TSH, ACTH, secretin, pancreozymin, cholecystokinin, pepsin, and renin. In addition it inhibits the effects of pentagastrin and histamine on the gastric mucosa. It appears to possess anti-proliferative action on some cell lines.

Somatostatin receptors in tumors:

Most human tumors originating from the somatostatin target tissue have conserved their somatostatin receptors. It was first described in growth hormone producing adenomas and TSH-producing adenomas. Only half of endocrine inactive adenomas display somatostatin receptors.

While brain tumors contain somatostatin receptors, the receptor content varies with the tumor type. Medulloblastomas, oligodendrogliomas, and differentiated astrocytomas display somatostatin receptors. High grade glioblastomas lack somatostatin receptors. Meningiomas that arise from the meninges, which does not express somatostatin receptors, do exhibit these receptors.

The third group of tumors harboring somatostatin receptors originates from the gastroenteropancreatic tissues. Both islet cell carcinoma and carcinoids contain a high density of homogeneously distributed somatostatin receptors.

A miscellaneous group of tumors exhibiting somatostatin receptors comprises breast and lung carcinoma. Fifteen percent of breast cancer have showed somatostatin receptors on their surface. Only the small cell lung cancer appears to contain somatostatin receptors. The lymphopoietic system may be a target for somatostatin. Somatostatin has been shown to inhibit lymphocyte proliferation as well as IgA synthesis. Specific receptors have been identified in peripheral lymphocytes. Subsequently these receptors were also found on both B and T cells isolated from the spleen and Peyer's patches, although these receptors have a low affinity with somatostatin.

Somatostatin analogs:

Octreotide is an octapeptide that possesses the same pharmacological properties as somatostatin, except that it is cleared from the circulation at a much slower rate. The time to half-max. is 117 minutes as compared to approximately a minute for somatostatin, making it more suitable for therapeutic and imaging purposes.

For imaging, octreotide is labeled with 111-In by complexing it with DTPA. This tracer is mainly excreted by the kidneys and shows only minimal accumulation in the liver and biliary tree.

Reubi et al evaluated the somatostatin receptor's status in a variety of malignant lymphoma using in vitro autoradiography with 125-I-Tyr-3-Octreotide. Eleven of 12 low grade lymponomas were positive for somatostatin receptors, as were 8 of 8 for intermediate grade and 7 of 10 for high grade tumors. Low to moderate density of receptors was observed in all the samples, but the high grade lymphomas expressed a higher density of receptors. These receptors were preferentially located on the follicular cells.

Lymphoma                        SS-R in vitro
---------------------------------------------
Low grade                       11/12  (92%)
Intermediate grade              8/8    (100%)
High grade                      7/10   (70%)

References:

J.C. Reubi, B. Waser, M. Van Hagen, S.W.J.Lamberts and coll., In vitro and in vivo detection of somatostatin receptors in human malignant lymphomas. Int. J. Cancer: 50, 895-900, 1992.

W.H. bakker, E.P. Krenning, W.A. Breenan and coll., In vivo use of a radioiodinated somatostatin analogue: dynamics, metabolism and binding somatostatin receptor-positive tumors in man. JNM 32: 1184-1189 June 1991.

S.W. Lamberts, E.P. Krenning, J.C. Reubi, The Role of somatostatin and its analogs in the diagnosis and treatment of tumors. Endocrine Reviews 12 (4): 450-482, 1991.

E.P. Krenning, W.H. Bakker, P.P.M. Kooil and coll. Somatostatin receptor scintigraphy with indium-111-DTPA-D-Phe-1-Octreotide in man: metabolism, dosimetry and comparison with iodine-123-Tyr-3-Octreotide. JNM 33: 652-658, 1992.

W.H. Bakker, E.P. Krenning, J.C. Reubi and coll. In vivo application if 111-In-DTPA-D-Phe-Octreotide for detection fo somatostatin receptors-positive tumors in rats. Life Sciences 49: 1593-1601, 1991.

P. Marbach, U. Briner, M. Lemaire and coll. From somatostatin to Sandostatin: pharmacodynamics and pharmacokinetics. Metabolism 41 (9), suppl 2: 7-10, 1992.

J.C. Reubi, R. Maurer, K. vonWerder and coll. Somatostatin receptors in human endocrine tumors. Cancer Research 47: 551-558, 1987.

J.C. Reubi, L.Kvols, E. Krenning and coll. Distribution of somatostatin receptors in normal and tumor tissue. Metabolism 39 (9) suppl 2: 78-81, 1990.

E.P. Krenning, D.J.Kwekkeboom, J.C.Reubi and coll. 111-In-Octreotide scintigraphy in oncology. Metabolism 41 (9) suppl 2: 83-86, 1992.

S. Larson. Editorial: Receptors on tumors studied with radionuclide scintigraphy. JNM 32: 1189-1191 June1991.

________________________________________________________

J. Anthony Parker, MD PhD, jap@nucmed.bih.harvard.edu