Molecular imaging in neuroendocrine tumors: Molecular uptake mechanisms and clinical results☆
Introduction
Neuroendocrine tumors are unique and rare tumors originating from neuroendocrine cells. These neuroendocrine cells are postulated to arise from common precursor cells of the embryologic neural crest and are dispersed throughout the human body. Characteristic is a common phenotype consisting of the simultaneous expression of general protein markers of neuroendocrine cells and hormonal products specific to each cell type [1]. The main function of neuroendocrine cells is to regulate a large variety of body functions through paracrine action with dedicated amines and peptides, of which the “biogenic amines”, such as serotonin and catecholamines, are most prominent. In order to be able to synthesize these amines, neuroendocrine cells have the ability to take up and decarboxylate amine precursors (APUD; amine precursor uptake and decarboxylation). Other biogenic amines, substances such as adrenocorticotropic hormone, growth hormone, neuropeptide K, substance P, bradykinin, kallikrein and prostaglandins can also be secreted [2], [3]. Neuroendocrine tumors arise in nearly every organ but primary sites in gastrointestinal (56%) and bronchopulmonary (12%) tracts are most frequent [4].
Due to the slow growth of most neuroendocrine tumors and the long time span between the onset of symptoms, many patients present with metastases (Fig. 1). Even with advanced disease, patients may survive for many years. However, there are also subtypes, which behave more aggressively. The diagnosis is based on histology and can be considered when specific symptoms induced by tumor products are present, such as diarrhea or flushing. Apart from clinical symptoms, determination of tumor secretory products using biochemical assays can assist in obtaining a diagnosis.
A division based on the embryological origin of the organs in which neuroendocrine tumors arise has been made in the past. This division classifies these tumors as foregut, midgut and hindgut tumors. However, the recent World Health Organization (WHO) classification of the different subtypes of neuroendocrine tumors of gastro-intestinal and pancreatic origin is based on histopathologic characteristics consisting of cellular grading, primary tumor size, primary tumor localization, proliferation markers, degree of invasiveness and the production of biologically active substances. The main categories defined by this classification are the well differentiated endocrine tumors with a low grade of malignancy, well differentiated, more aggressive carcinomas, poorly differentiated endocrine carcinomas with a high grade of malignancy and a poor prognosis and finally mixed exocrine–endocrine tumors. In this WHO classification the term carcinoid is abandoned and replaced by neuroendocrine tumor [5].
Currently, there is a broad variety of treatment options for patients with neuroendocrine tumors. Surgery is the only curative option. When cure is not possible, palliative treatment aims to control symptoms, maintain local tumor control and prolong life. Palliative procedures include surgical debulking, correction of bowel obstruction, chemo-embolizations, or systemic treatment using interferon-α or somatostatin analogues [2]. Other treatment options are chemotherapy and radionuclide therapy. New targeted therapies such as anti-angiogenic therapies are currently being explored [4], [6], [7].
Accurate localization of tumor lesions can guide treatment decisions. In general, radiological techniques such as CT, ultrasound or MRI are applied in staging and restaging, but also nuclear medicine techniques, such as somatostatin receptor scintigraphy (SRS), have proven to be of great value. The presence of somatostatin receptors on many neuroendocrine tumors was the driving force that enabled the development of SRS. Besides receptors, the remarkable metabolic activity of specific biochemical pathways used in substance synthesis provides possibilities for molecular nuclear medicine imaging.
The unique characteristics of neuroendocrine tumors have led to the development of interesting new diagnostic methods for these tumors over the last years, both in receptor imaging and metabolic imaging. Especially the increase in positron emission tomography (PET) facilities allows developments of tracers for new molecular targets with a high-resolution method for imaging. In addition new insights in the genetic, biochemical and metabolic aspects of subtypes of the neuroendocrine tumor family have arisen over the last years. It is therefore important to understand the receptor and metabolic targets for neuroendocrine tumors, as the molecular mechanisms that drive tracer uptake, translate into images and determine the final clinical applicability.
The unique characteristics of neuroendocrine tumors are increasingly exploited to successfully enhance our imaging and therapeutical options for these tumors. Three directions can be seen in the development of new tracers for imaging use. The first uses tumor receptor expression, the second uses the metabolic properties and the last method uses antibodies.
Therefore, the purpose of this review is to describe the receptor and metabolic imaging methods of neuroendocrine tumors and translate the molecular uptake mechanisms into clinical parameters such as sensitivity and specificity. For this purpose, a review of current literature is presented, both for imaging methods and for tumor types.
Section snippets
Search strategy and selection criteria
For this non-systematic review, a Medline and PubMed search was performed. Due to the many subtypes of neuroendocrine tumor and imaging methods a multitude of different search terms was necessary. A detailed list is available on request. Only papers with an English abstract published over the last 10 years (1995) were included. Material from review articles also referring to older studies was evaluated and was used if relevant. Reference lists of individual papers were also analyzed for study
Nuclear imaging methods
The methods for nuclear imaging of neuroendocrine tumors can be divided in three main categories, namely tracers based on (a) the selective expression of different receptors, (b) metabolic properties of tumors and (c) tracers which exploit antigens expressed by the tumors. For each category, currently available tracers will be described and their clinical impact. A schematic overview of the uptake mechanisms of these tracers can be found in Fig. 2.
A general principle in nuclear medicine is that
Conclusion
Most receptor-based tracers have been developed for scintigraphic use, and changing to positron emitting labels (i.e. 18F, 64Cu, 68Ga) could make these tracers suitable for PET imaging. For SRS, different somatostatin analogues are investigated which are more stable and bind more receptor subtypes with a higher affinity.
Most neuroendocrine tumors share common metabolic pathways, such as the catecholamine and serotonin pathways. Different strategies in the development of tracers suitable to
Conflict of interest statement
There are no conflicts of interest.
Prof. Elisabeth GE de Vries, M.D., Ph.D., Medical Oncologist UMCG. She is Professor in Medical Oncology and head of the Department of Medical Oncology and coordinator of the “Northern Netherlands Oncology Center”. She was research fellow (1982–1983) at the Department of Medical Oncology, City of Hope National Medical Center, Duarte, CA, USA. She is involved in patient care, teaching and research. Her research lines are aiming at increasing sensitivity of tumors for anticancer drugs and she uses
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Prof. Elisabeth GE de Vries, M.D., Ph.D., Medical Oncologist UMCG. She is Professor in Medical Oncology and head of the Department of Medical Oncology and coordinator of the “Northern Netherlands Oncology Center”. She was research fellow (1982–1983) at the Department of Medical Oncology, City of Hope National Medical Center, Duarte, CA, USA. She is involved in patient care, teaching and research. Her research lines are aiming at increasing sensitivity of tumors for anticancer drugs and she uses imaging techniques to support neuroendocrine tumors and breast cancer research. Apart from laboratory studies she performs and coordinates clinical studies. She served as member of the Scientific Board of the Dutch Cancer Society, KWF Kankerbestrijding, 1993–2000, the last 2 years as chairperson. Currently she is vice-chair of the board of Dutch Cancer Society. In 2002 she was appointed as member of the Royal Dutch Academy of Arts and Sciences (KNAW). She serves as member of the Health Council of the Netherlands, and is as of 2008 the chairperson of the Medical Sciences committee of the KNAW.
Klaas P. Koopmans, M.D., Ph.D. He received his M.D. in 2000. In 2003 he started his Ph.D. project in collaboration with Oliver C. Neels (Radiochemist, Ph.D.). This project ‘Metabolic characterization and localization of neuroendocrine tumors and their metastases using positron emission tomography’ was funded by the Dutch Cancer Society. Oliver Neels is currently fellow at the Peter MacCallum Cancer Centre, East Melbourne, Australia. Klaas Pieter Koopmans started his residency nuclear medicine in 2006 and is still involved in research projects concerning neuroendocrine tumors.
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This work was supported by project grant 2003-2936 from the Dutch Cancer Society.