Liver, Pancreas and Biliary TractImmunohistochemical expression of somatostatin receptors in digestive endocrine tumours
Introduction
Gastro-entero-pancreatic endocrine tumours (GEP-ETs) are relatively rare neoplasms occurring at a rate of two cases per 100,000 persons a year [1]. They are heterogeneous tumours, in terms of both clinical and biological features that present both diagnostic and therapeutic challenges.
These tumours typically produce and secrete biologically active peptides and amines which can cause distinct clinical syndromes or else be functionally inactive.
Peptide hormone-receptors, like other cell surface receptors, have acquired increasing clinical importance because of their overexpression in selected tumour types, allowing in vivo tumour targeting for diagnostic and therapeutic purposes with peptide hormone analogs [2], [3].
Somatostatin (SST) has attracted much attention since it plays a functional inhibitory role in the regulation of a wide variety of physiological functions such as the inhibition of both endocrine and exocrine secretion, cell proliferation and angiogenesis [4], [5]. The biological effects of somatostatin are mediated by high affinity interactions with a family of G protein-coupled-receptors. Five somatostatin receptors (SSTR1–5) have been cloned and characterized [6], [7], [8]. These receptors have high affinity for the natural somatostatin peptides; however, they differ in their affinity for synthetic somatostatin analogs. They are widely distributed in many systems and organs, such as the central nervous system, the pancreas and intestine, and also in the pituitary gland, kidney, thyroid, lungs and immune cells [5], [6], [7], [8], [9], [10], [11]. Tumours arising from somatostatin-target tissues frequently express a high density of SSTR [10], [11], [12], [13], [14]. GEP endocrine tumours express more than one subtype, being SSTR2a the most frequently expressed subtype (about 80%) [13], [14], [15], [16], [17]. The frequency and pattern of expression are heterogeneous, and may vary not only in different tumour types but also in each patient.
Binding of SSTR by SST analogs results in the inhibition of hormone hypersecretion and cell proliferation of these tumours. Long acting somatostatin analogs are today routinely used to reduce hormonal hypersecretion and accompanying symptoms. Radiolabeled somatostatin analogs may be used to locate neuroendocrine tumours by scintigraphy with high specificity and sensitivity [18]. Moreover, current studies show that SST-targeted radiotherapy with radiolabeled somatostatin analogs is useful to treat these tumours [19].
The aim of this study is to determine the protein expression profile of SSTR subtypes 1–5 in a series of 100 GEP-NET using an immunohistochemical technique.
Section snippets
Methods
From a prospectively built database of patients with GEP-NETs referred from three institutions (Gastroenterology Hospital, Fleming Institute and Breast Clinic) assembled by the Argentum Working Group, patients with complete clinical and pathological data were selected.
The GEP-NETs included were gastrointestinal neuroendocrine neoplasms, pancreatic endocrine neoplasms and liver metastasis of unknown origin.
Investigated specimens were surgical biopsies, percutaneous needle biopsies, endoscopic
Results
Our study included one hundred patients with complete data. Fifty-three patients were female, median age was 54 years (IQR 43.3 to 64). Tumours were more frequently located in the small bowel and pancreas. Seventy-three specimens were classified as WHO class WDEC, 17 as WDET and 10 as PDEC. Thirty-one patients had functioning tumours, and carcinoid syndrome was the most frequent (n = 23). More than 75% of specimens were obtained through surgical biopsies (Table 1).
Ninety-four tumours expressed
Discussion
The immunohistochemical location of SSTR has been investigated in normal brains and spinal cords of rats [21], neurons of the myenteric and submucosal plexuses, interstitial cells of Cajal of the intestine and enterochromaffin-like cells of the stomach of rats [22], pancreas of rats [23], and some human tissues [24], [25], [26]. However, to our knowledge, few immunohistochemical studies about SSTR subtypes 1–5 have been performed in large series of gastrointestinal and pancreatic neuroendocrine
Conflict of interest statement
None declared.
Acknowledgments
We thank Mrs Estela Carbone (Department of Pathology, Hospital of Gastroenterology) for her expert technical assistance, Dr. Javier Mariani for statistical calculations and Mrs Claudia Tarassona for english translation assistance.
This work was supported by grants from Novartis Argentina.
References (35)
Somatostatin and its receptor family
Front Neuroendocrinol
(1999)- et al.
Somatostatin receptors as tools for diagnosis and therapy: molecular aspects
Best Pract Res Gastroenterol
(2005) - et al.
Somatostatin receptors in human cancer: incidence, characteristics, functional correlates and clinicals implications
J Steroid Biochem Mol Biol
(1992) - et al.
In vitro detection of somatostatin receptors in human tumors
Metabolism
(1992) - et al.
Somatostatin receptors and their subtypes in human tumors and in peritumoral vessels
Metabolism
(1996) - et al.
Peptide receptors in gut endocrine tumours
Baillieres Clin Gastroenterol
(1996) - et al.
Epidemiology of neuroendocrine tumors
Neuroendocrinology
(2004) Peptide receptors as molecular targets for cancer diagnosis and therapy
Endocr Rev
(2003)- et al.
The role of somatostatin and its analogs in the diagnosis and treatment of tumors
Endocr Rev
(1991) - et al.
Somatostatin receptors, an expanding gene family: cloning and functional characterization of human SSTR3, a protein coupled to Adenyl ciclase
Mol Endocrinol
(1992 b)