Liver, Pancreas and Biliary Tract
Immunohistochemical expression of somatostatin receptors in digestive endocrine tumours

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Abstract

Introduction

Somatostatin receptors are expressed in a large number of human tumours. The somatostatin receptors types 1–5 expression in a series including 100 gastro-entero-pancreatic endocrine tumours were analysed.

Methods

From a prospectively built database of patients with gastro-entero-pancreatic endocrine tumours referred from three institutions, 100 cases with clinical and pathological data were selected. Somatostatin receptors expression by immunohistochemistry with somatostatin receptor types 1–5 antibodies in tissue paraffin sections were studied and correlated with the histological diagnosis according to the WHO classification, location and functional status.

Results

Of the 100 cases, 67 were gastrointestinal tumours, 25 pancreatic and 8 liver metastasis of unknown origin. Thirty-one of them were functioning tumours: 2 insulinomas, 5 gastrinomas, 1 glucagonoma and 23 carcinoids.

Somatostatin receptors expression was observed in 94 tumours. The six negative cases were all non-functioning tumours. Somatostatin receptors 2a and 5 were highly expressed (86 and 62%, respectively), and surprisingly found even in poorly differentiated endocrine carcinomas. Somatostatin receptors expression was less frequent in pancreatic than in gastrointestinal tumours. Well-differentiated neoplasms had a higher density of somatostatin receptors. Only SSTR2a showed membrane staining.

Conclusions

Immunohistochemistry revealed that somatostatin receptors were highly expressed in both primary and metastatic gastro-entero-pancreatic endocrine tumours with heterogeneous staining distribution. It proved to be a reliable technique even in small tumour samples.

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.

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