Functional Anatomical Image Fusion in Neuroendocrine Tumors

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1 CANCER BIOTHERAPY & RADIOPHARMACEUTICALS Volume 19, Number 1, 2004 Mary Ann Liebert, Inc. Functional Anatomical Image Fusion in Neuroendocrine Tumors Orazio Schillaci Department of Diagnostic Imaging, University Tor Vergata, Rome, Italy ABSTRACT Nuclear medicine provides physiologic and functional data for normal and pathologic organs but often the clear definition of the sites of radiotracers uptake are difficult. Radiological methods are able to identify structural changes in a detailed way, but do not give precise information on function of organs or pathologic lesions. The registration and fusion of nuclear medicine studies with structural information obtained by radiological exams allows the precise correlation of functional and anatomical data. Software-based fusion of independently performed nuclear medicine and morphologic studies is uncertain of success and the alignment procedures are labor intensive. Recently, a new imaging device combining a dual-head, variable angle gamma camera with a low-dose x-ray tube has been introduced; the acquired single-photon emission computed tomography (SPECT) and x-ray computed tomography (CT) images are coregistered by means of the hardware in the same session. This new technology can be particularly useful when applied to scintigraphic procedures in neuroendocrine tumors. In-111 pentetreotide and radiolabeled MIBG play an important role in the study of patients with these tumors; the addition of anatomical maps provides a precise localization of SPECT findings and allows the exclusion of disease in sites of physiologic tracer uptake. SPECT/CT fused images are able to provide additional information that improves the accuracy of SPECT interpretation and leads to changes in therapeutic options, so enhancing the clinical role of nuclear medicine in evaluating patients with neuroendocrine tumors. Key words: image fusion, hybrid imaging, neuroendocrine tumors, In-111 pentetreotide, MIBG INTRODUCTION Medical imaging technology has shown remarkable developments in the last decades, so medical images have become increasingly used in health care and in biomedical research and a very wide range of imaging modalities are now available. It is common for patients to be imaged multiple times today, either repeated imaging with a single modality or with different modalities. The ever-increasing amount of image data acquired Address reprint requests to: Orazio Schillaci; Department of Diagnostic Imaging; University Tor Vergata ; Viale Mazzini 121, Rome, Italy; Tel.: ; Fax: oschil@tiscali.it makes necessary to relate one image to another to assist the physicians in extracting the relevant clinical information. Image registration can help in this task; it is the process of aligning images so that corresponding features can easily be related. 1 FUSION OF FUNCTIONAL AND ANATOMICAL IMAGES Functional images using single-photon emission computed tomography (SPECT) and positron emission tomography (PET) are extremely valuable in the diagnosis of various disorders. Uncertainty in the anatomical definition on SPECT 129

2 and PET images, however, often limits their usefulness. Other drawbacks of nuclear medicine imaging studies are limited spatial resolution, poor signal to noise ratio, and sometimes poor uptake of the radiotracer in the diseased condition. Registration with a structural or anatomical image can be useful in addressing a number of these issues. 2 In fact, nuclear medicine imaging demonstrates function rather than anatomy; conversely, detailed cross-sectional anatomical images are obtained with either x-ray computed tomography (CT) or magnetic resonance imaging (MRI); they identify structural changes in a precise manner, but do not provide detailed information on function of organs and pathologic lesions. The combination of structural images (CT or MRI) with functional SPECT or PET images of the same sections of the body can provide complementary anatomical and physiological information that is of great importance to diagnosis and treatment. 4 Moreover, structural and functional images are now increasingly understood as complementary rather than competing imaging methods and their combination can often lead to additional clinical information not apparent in the separate images. 5,6 Image datasets obtained from different techniques can be registered and presented as fused images, allowing the interpretation of two modalities to be correlated. 7 The goal of image fusion is to impose a structural anatomical framework on functional images because often in a functional image there is not enough anatomical detail to determine, for example, the position of a tumor or other lesion. Moreover, the registration of PET and SPECT data with anatomical atlases provide an important means to correlate radiotracers uptake properties with anatomy. 8 METHODS OF IMAGE FUSION IN NUCLEAR MEDICINE To fuse two images, the data from the different modalities must be matched as accurately as possible. In many clinical scenarios, images from several modalities are compared by visual analysis, with the observer mentally integrating the data before rendering an interpretation; this approach is adequate only for a crude comparison of large lesions. 9 A more accurate comparison can be achieved by combining the images with the aid of a computer to extract and manipulate the desired information. 10 Image registration aligns the images and so establishes correspondence between different features seen on different imaging modalities. Registration methods can simply be divided into image-based and non-image based. 7 Imagebased registration includes extrinsic methods, based on foreign objects introduced into the imaged space, and intrinsic methods, based on the image information as generated by the patients. 7 Extrinsic methods involve the use of some form of external fiducial markers attached to the body surface. 7 The objects attached to the patient are designed to be accurately detectable in all the different imaging modalities. Based on the assumption that the distance between markers is the same in the different images, the registration of the acquired images is easy and fast, and can usually be automated without the need of complex optimization algorithms. Nevertheless, extrinsic methods are not suitable for retrospective registration tasks and are not practical for routine clinical use, especially if patient studies are on different days. 8 Intrinsic registration methods rely on patientgenerated image content only; they are based on a set of identified points (landmarks), on the alignment of segmented binary structures (segmentation based), or directly onto measures computed from the image gray values (voxel property based). 7 Landmarks can be anatomical (points 11 identified by the operator) or geometric (corners or other geometric features 12 localized in an automatic fashion). Segmentation based methods can be rigid model based, where anatomically the same structures are extracted from both images to be registered and are used as the only input for the alignment procedure, and deformable model based, where an extracted structure from one image is elastically deformed in the second one. 7 Voxel property methods are based on intensity values in the different images to be aligned. The main drawback of these techniques is that the registration performance is limited in low-resolution nuclear medicine images. A non image-based registration is possible if the imaging coordinate systems of the two scanners involved are calibrated to each other. This usually needs the scanners to be brought in the same physical location, with the assumption that the patient remains motionless between both acquisitions. 7 This method forms the basis for the development of multi-modality devices combining structural and functional measurements. 130

3 DUAL-MODALITY IMAGING DEVICES Figure 1. Hybrid single-photon emission computed tomography/positron emission tomography device with the x-ray tube (single arrow) and detectors (double arrow). These new devices include scanners capable of PET or SPECT with CT ; they are able to acquire data at the same time, or at least in the same session, and therefore limit the problems of the other methods of image registration that demonstrated to be not very accurate in the fusion between PET or SPECT and anatomical modalities outside of the brain. The acquisition of SPECT or PET and CT in a single session circumvents potential sources of error caused by the positioning and movement of patients. Moreover, a combined functional/anatomical scanner facilitates the production of fused images, without the need of fiducial markers and complicated mathematical algorithms. In fact, the work involved in retrospective image fusion should not be underestimated and even if there is a prospective optimization of each modality s scan acquisition to facilitate subsequent fusion, it can be a laborintensive and time-consuming procedure. 18 In particular, a hybrid imaging device combining a dual-head, variable angle gamma camera with a low-dose x-ray tube has been recently developed (Fig. 1). This is gamma camera/ct scanner that is able to provide, in addition to scintigraphic data, cross-sectional x-ray transmission images that facilitate anatomical localization of radiotracer uptakes; the acquired SPECT and CT images are coregistered by means of the hardware in the same session. 14 The system has also coincidence acquisition capabilities and so it can provide relatively rapid low-noise transmission PET images. 19,20 Moreover, the structural data from the CT scan can be also used for attenuation and scatter correction of the emission data. 16 SPECT/CT FUSION IN NEUROENDOCRINE TUMORS Neuroendocrine tumors are rare neoplasms that are derived from neuroendocrine cells interspersed throughout the body. They are wellknown for producing various hormonal syndromes and for their indolent clinical course in most patients, although some of these tumors do not produce hormones of clinical significance. Patients may have symptoms for many years before the diagnosis is suspected and confirmed; symptoms are caused by hormonal excess, local tumor growth, or metastatic spread. 21 Nuclear medicine procedures play an important role in the evaluation of patients with neuroendocrine tumors. Scintigraphic exams with radiolabeled somatostatin analogues 22 and metaiodobenzylguanidine (MIBG) 23 give important information on receptor expression, functional status, metabolism, and tissue viability of these neoplasms. A large variety of clinical studies have clearly demonstrated that In-111 pentetreotide is effective in the diagnosis and staging of somatostatin receptor-positive tumors, especially gastroenteropancreatic neuroendocrine ones The acquisition of SPECT imaging proved very useful, especially when tumors are small, located in the abdomen, and not visualized on planar scans, as an overprojection by other tissues and/or organs (liver, spleen, kidneys, and intestines), which show some variable individual accumulation of the radiopharmaceutical. 28 However, in the interpretation of SPECT studies, it can be difficult to localize the precise anatomical sites of localization of the radiotracers. 29 Moreover, although SPECT is able to enhance the possibility to localize a focus of abnormal accumulation in crosssection, normal activity containing structures may be more difficult to identify. Combining the anatomical localizing capability of CT with 131

4 SPECT data through image fusion, a more accurate identification of disease sites can be made. Radiolabeled MIBG with I-123 or I-131 plays its major role in patients with pheochromocytoma and neuroblastoma. 23 SPECT was found to improve lesion detectability and location, but it is controversial whether tomographic images can detect more lesion than planar scans. 30,31 The fusion with CT may be of value in providing a better localization of tumor sites, especially in the vicinity of normal organs with high MIBG uptake (i.e., liver and myocardium), and in characterizing areas of normal MIBG biodistribution or excretion, so alleviating the need for delayed images. Moreover, SPECT/CT may also improve the quantification of radiation burden in patients treated with I-123 MIBG therapy. Forster et al. 32 studied ten patients with known liver metastases from neuroendocrine tumors with In-111 pentetreotide imaging and CT. Just before the CT scan, the patients were positioned in a large vacuum cushion on which nine markers suitable for imaging with CT and SPECT were fixed. Immediately after the CT study, a SPECT of the abdomen was acquired without changing the patients positions; a second SPECT was performed the following day after repositioning the patients in the vacuum cushion. Dataset were then fused by means of the external markers or internal markers (liver metastases or margin of abdominal organs). All the 28 lesions detected by SPECT appeared superpositioned on the respective CT morphology by visual inspection; the method of external markers for fusion demonstrated faster and easier when compared with the use of internal landmarks. Perault et al. 33 investigated the feasibility of SPECT and CT superimposition in the thoracoabdominal region without the use of external markers in five patients with medullary thyroid carcinoma and in three with carcinoid tumor. A dual-isotope tomoscintigraphy was performed, with Tc-99m hydroxymethylene diphosphonate for bone scan and In-111 pentetreotide (seven patients) or I-123 MIBG (only in one case of carcinoid) for tumor scintigraphy. A CT scan was performed in all patients 1 month after the SPECT study. For image registration, internal anatomical structures seen on both CT and bone scintigraphy were used to determine the geometric transformation that, when applied to tumor scintigraphy images, made them coincide with the CT images. SPECT-CT superimposed images enabled the localization of abnormal tumor scintigraphy foci; however, the accuracy of this retrospective technique for fusing images was limited primarily by variable relative displacements of the thoraco-abdominal organs between the SPECT and CT studies. Tang et al. 34 used a combined CT-scintillation camera prototype imaging system for the absolute in-vivo measurement of I-131 MIBG uptake in three neuroblastoma patients. After the CT scan, the patients remained on the imaging table without moving and were translated into the scintillation camera gantry. Markers containing Tc-99m and K 2 HPO 4 were placed on patients to aid in registration in case of movement during imaging acquisition. Activity were quantified from the patients having a total of six lesions; anatomic information available from coregistered CT images was useful to improve localization and measurement of I-131 MIBG uptake in tumors. The clinical value of the new technology of combined emission and transmission tomography using the above described hybrid device was firstly assessed by Even-Sapir et al. 15 in 13 patients with neuroendocrine tumors. In-111 pentetreotide was used in 10 cases and I-123 MIBG in the remaining three ones. Fused images added value in SPECT interpretation in six patients and provided information of clinical value in four, assisting in better planning of surgery in two patients and changing the treatment approach in the other two. The same hybrid imaging system was used with In-111 pentetreotide scintigraphy to evaluate 73 patients with neuroendocrine tumors. 35 Additional data provided by fused images as compared with SPECT alone for image interpretation were recorded. In 40% of the patients with abnormal scintigraphic findings, SPECT/CT improved the accuracy of nuclear medicine studies by providing better localization of SPECT-detected lesions; in particular, in 21 patients, it precisely defined the organ involved and the relationship of lesions to adjacent structures, in four cases, it showed unsuspected bone involvement and in four patients, it differentiated physiologic from tumor uptake. Fifty-four (54) patients with known or suspected neuroendocrine tumors were prospectively studied by Pfannenberg et al. 36 with In-111 pentetreotide (n 5 43) or I-123 MIBG (n 5 13) using the above described SPECT/CT device. The accuracy of SPECT/CT in classifying neuroendocrine tumours lesions was higher than that of SPECT alone and the results of imaged fusion 132

5 caused a change in treatment approach in a substantial proportion (28%) of patients. Our experience with the everyday clinical use of this imaging system suggests that functional/anatomical imaging is easy to perform: After reconstruction of raw data, the slices of the different modalities are automatically aligned in a short time; moreover, it demonstrated a valuable method for a more precise interpretation of scintigraphic studies in several cases because fused images are able to improve the diagnostic accuracy of SPECT in various clinical situations. 37 When applied to somatostatin receptor scintigraphy for neuroendocrine gastroenteropancreatic (GEP) tumors imaging, our preliminary findings in 19 patients indicate that SPECT/CT is able to improve image interpretation and accuracy in a significant percentage of cases (47%), so enhancing the clinical role of In- 111 pentetreotide SPECT in evaluating these patients. In particular, in our study, anatomical functional images revealed unsuspected bone metastases in two patients, and provided a correct localization of SPECT findings in six cases and the exclusion of disease in sites of physiologic radiopharmaceutical uptake in one patient. Further studies in larger series are needed to better evaluate in which types of clinical indications there will be the most significant benefit of the SPECT/CT technology in In-111 pentetreotide and radiolabeled MIBG studies. The applications and use of fused images for patients management in the near future will include the determination of disease resectability, the planning of surgery and/or chemotherapy, and the establishment of the correct prognosis; moreover, the possible role in dosimetric estimations for target radionuclide therapy and in interventional procedures such as CT-guided biopsy must be investigated. CONCLUSION Diagnostic imaging plays a major role in the management of patients with neuroendocrine tumors. Anatomical images such as CT and MRI and functional scintigraphic methods are complementary, and, if combined, a very high diagnostic accuracy is yielded. However, their precise alignment can be difficult when functional and structural images are separately acquired and the registration is based on extrinsic or intrinsic body markers. The recent development of a combined functional/morphologic device demonstrated able to provide a simple and accurate anatomical framework of CT for the assessment of early physiologic information detected by nuclear medicine, adding structure to function and providing the solution to a variety of clinical questions in patients with neuroendocrine tumors, as suggested by the first applications of this new technology with In-111 pentetreotide and radiolabeled MIBG. REFERENCES 1. Weber DA, Ivanovic M. Correlative image registration. Semin Nucl Med 1994;24: Maisey MN, Hawkes DJ, Lukswiecki-Vydelingum AM. Synergistic imaging. Eur J Nucl Med 1992;19: Wagner HN. Images of the future. J Nucl Med 1978;19: Cook JR, Ott RJ. Dual-modality imaging. Eur Radiol 2001;11: Israel O, Keidar Z, Iosilevsky G, et al. The fusion of anatomic and physiologic imaging in the management of patients with cancer. Semin Nucl Med 2001;24: Shreve PD. Adding structure to function. J Nucl Med 2000;41: Maintz JB, Viergever MA. A survey of medical imaging registration. Med Image Anal 1998;2:1. 8. Hutton BF, Braun M, Thurfjell L, Lau DYH. Image registration: An essential tool for nuclear medicine. Eur J Nucl Med Mol Imaging 2002;29: Treves ST, Mitchell KD, Habboush IH. Three-dimensional image alignment, registration and fusion. J Nucl Med 1998;42: van den Elsen PA, Pol EJD, Viergever MA. Medical imaging matching a review with classification. IEEE Eng Med Biol 1993;12: Hill DLG, Hawkes DJ, Crossman JE, et al. Registration of MR and CT images for skull base surgery using pointlike anatomical features. Br J Radiol 1991;64: Thirion J. New feature points based on geometric invariants for 3D image registration. Int J Comp Vision 1996;18: Townsend DW, Cherry SR. Combining anatomy with function: The path to true image fusion. Eur Radiol 2001;11: Bocher M, Balan A, Krausz Y, et al. Gamma cameramounted anatomical x-ray tomography: Technology, system characteristics and first images. Eur J Nucl Med 2000;27: Even-Sapir E, Keidar Z, Sachs J, et al. The new technology of combined transmission and emission tomography in evaluation of endocrine neoplasms. J Nucl Med 2001;42: Patton JA, Delbeke D, Sandler MP. Image fusion using an integrated-dual-head coincidence camera with x-ray tube-based attenuation maps. J Nucl Med 2000;41:

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