Review Article
Advances in Oncologic Imaging Alexander J. Towbin1
Andrew T. Trout1
Derek J. Roebuck2
1 Department of Radiology, Cincinnati Children’s, Cincinnati, Ohio,
United States 2 Department of Radiology, Great Ormond Street Hospital for Children, London, United Kingdom
Address for correspondence Alexander J. Towbin, MD, Department of Radiology, Cincinnati Children’s, 3333 Burnet Avenue ML5031, Cincinnati, OH 45229, United States (e-mail: [email protected]).
Eur J Pediatr Surg 2014;24:474–481.
Abstract
Keywords
► ► ► ► ►
oncology radiology functional imaging PET/CT MRI
Over the past two decades, there has been an increased reliance on radiologic imaging to diagnose and stage malignancies. This increased reliance on imaging has occurred because the quality of imaging has improved markedly. Currently, modalities such as MRI and CT allow the radiologist to obtain highly detailed images of the human body with a resolution of less than 1mm. More recently, researchers have shifted their focus from anatomic imaging to functional imaging. This burgeoning field of radiology strives to provide quantitative information regarding the behavior of tumors (or other pathology) to deliver patients and clinicians with prognostic information regarding the disease process. The purpose of this article is to describe the recent advances in pediatric oncologic imaging.
Introduction Over the past two decades, there have been considerable advances in medical imaging. These advances have helped to revolutionize the practice of medicine, enabling clinicians to not only diagnose disorders rapidly and accurately but also effectively monitor and tailor therapy in patients with acute or chronic illnesses. As imaging has advanced, its role has expanded beyond providing a detailed evaluation of anatomy, morphology, and macrostructure to providing functional and microstructural information about disease processes. The expansion into functional imaging is already underway in pediatric oncology. The purpose of this article is to review the current status and current frontiers in functional imaging of pediatric malignancy.
Quantitative Imaging with PET/CT F-18-fluorodeoxyglucose (18F-FDG) positron-emission tomography (PET) is well established as a functional imaging modality in pediatric patients with malignancy. FDG-PET uses a radiolabeled analog of glucose (18F-FDG) as a marker of cellular metabolic activity. Because many malignant
received October 30, 2014 accepted November 4, 2014 published online December 5, 2014
processes represent increases in cellularity and increased metabolic activity by malignant cells, 18F-FDG disproportionately accumulates in tumor deposits. The accumulation of 18 F-FDG at sites of disease can be qualitatively or semiquantitatively assessed at diagnosis and throughout therapy to monitor treatment response. Semiquantitative assessment is most simply achieved through measurement of a standardized uptake value (SUV), which takes into account patient size, the amount of 18F-FDG administered, and decay of the radiolabel. In pediatric patients, prediction of response based on semiquantitative FDG-PET data has been most extensively explored for sarcoma. For both osteosarcoma and Ewing sarcoma, the percent of tumor necrosis following neoadjuvant chemotherapy is an important prognostic factor.1 In general, a good histologic response to therapy is defined as tumor necrosis of more than 90%.2 Because the percent necrosis can only be determined after resection, researchers have attempted to identify a reliable imaging indicator that might be used to monitor tumor response to neoadjuvant therapy. For both osteosarcoma and Ewing sarcoma, initial studies have identified maximum SUV (SUVmax) following chemotherapy as a most useful metric to predict the degree of
© 2014 Georg Thieme Verlag KG Stuttgart · New York
DOI http://dx.doi.org/ 10.1055/s-0034-1396423. ISSN 0939-7248.
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Fig. 1 A 14-year-old male with left distal femoral osteosarcoma. Coronal images from 18 F-FDG PET scans show that at diagnosis (A), the distal femoral mass is markedly FDG avid with a SUV max of 23.8. (B) Following 3 months of neoadjuvant chemotherapy, and immediately prior to limb salvage, FDG-avidity of the tumor had substantially decreased (SUV max 2.3). At pathology, following limb salvage, there was 98% tumor necrosis.
histologic necrosis, though the defined cut-offs have varied between studies and tumor types (►Fig. 1).1,3–8 For osteosarcoma, other studies have combined semiquantitative variables with the aim of better predicting outcomes.5,9 Bajpai et al found that a combination of initial tumor volume and the postchemotherapy:prechemotherapy SUVmax ratio could be used to predict the histologic response5 and Cheon et al showed that a combination of SUVmax after chemotherapy and metabolic volume change ratio (% change in volume postchemotherapy:prechemotherapy % change in SUVmax postchemotherapy:prechemotherapy) could predict the response.9 While the greatest body of research exists for sarcomas, the role of FDG-PET in semiquantitative tumor assessment is expanding beyond these tumors. There are few studies describing the utility of FDG-PET/CT in providing prognostic information for patients with neuroblastoma. One study showed that maximum tumor SUV > 5.3 is a predictor of poor prognosis.10 This study and others have also shown that when 18F-FDG uptake is more extensive than MIBG uptake, the patients have more aggressive disease and worse outcomes, likely reflecting dedifferentiation of the tumor.10,11 There are additionally some limited data for Wilms tumor suggesting that high-risk disease may have higher maximum SUV values though further study of this tumor type is needed.12 While FDG is the main 18F tracer used for PET, different 18 F-based radiopharmaceuticals can be used to evaluate certain other biological processes. For example, 18F-dopa can be used to detect and stage neuroendocrine and neuroblastic tumors, and may outperform conventional imaging with 123I-metaiodobenzylguanidine (MIBG).13,14 In addition, other positron-emitting radionuclides may also be useful in the evaluation and staging of pediatric solid tumors.
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Octreotide has high affinity for somatostatin receptors, which are highly expressed in neuroblastoma, as well as other embryonal neoplasms of childhood.15 Dotatate, a derivative of DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) and octreotate (an octreotide analog) can be used to chelate gallium-68 for PET imaging (►Fig. 2), or lutetium-177 for radionuclide therapy.16 Most other positron-emitting radionuclides with potential clinical applications in pediatrics have short half-lives, which limits their use to centers with a nearby cyclotron. These isotopes include carbon-11 (20 minutes) and rubidium-82 (75 seconds). Iodine-124, however, has a half-life of 4.2 days,17 and is consequently usable in centers remote from a cyclotron. 124I-MIBG PET may find a role in the staging of neuroblastoma. Currently, the majority of PET imaging involves the coregistration of data from two different imaging modalities, usually with the aim of registering functional imaging, which has relatively poor spatial resolution (such as certain nuclear medicine studies), with high-resolution anatomical imaging (such as MRI or CT).18 One practical application of image fusion is the precise localization of tumor tissue18 to facilitate biopsy (►Fig. 3). It may also be helpful in planning surgery (►Fig. 4).
Quantitative Imaging with PET/MR One of the barriers to the widespread application of PET in pediatric patients is concern about radiation exposure. This is being addressed through efforts to standardize the dose of 18 F-FDG that is administered as well as through technologic advances aimed at improving detection of the radioisotope and reducing the dose associated with the CT performed for attenuation correction and localization.19 PET/MRI is being heavily marketed for use in pediatric patients with dose reduction, achieved through attenuation correction, being touted as one of its major advantages. While experience with the technology in pediatric patients is growing, current studies are small in size and have been aimed at
Fig. 2 Gallium-68-dotatate PET-CT in a 10-year-old girl with stage M neuroblastoma. There is intense tracer uptake in the primary tumor (large arrow) and a vertebral body metastasis (small arrow). Normal activity is present in the liver and kidneys. European Journal of Pediatric Surgery
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Fig. 3 Determination of best site for biopsy in a child with neuroblastoma. Conventional MRI fat-suppressed, contrast-enhanced T1-weighted transverse image shows a large right suprarenal mass with probable central necrosis (A). Apparent diffusion coefficient (ADC) map shows restricted diffusion (compatible with increased cellularity 18) in the periphery of the tumor (B). Fused SPECT(single photon emission computed tomography)-CT image using 123I-metaiodobenzylguanidine (MIBG) identifies the ideal site for biopsy (C, arrow).
demonstrating diagnostic equivalence to PET/CT.20 In addition to the potential for dose reduction and increased acceptance of PET imaging in children, PET/MRI has the potential to be a valuable functional imaging tool in pediatric oncology patients through combination and synthesis of functional information derived from both the PET and MR components of the examination.21 These benefits and applications are currently being explored.
Hepatocyte-Specific Contrast Agents There are several different liver tumors that affect pediatric patients.22,23 Over the past 5 years, MRI has become the preferred modality to image these tumors due to the advent of hepatocyte-specific contrast agents. These contrast agents differ from traditional MRI contrast agents in that they are taken up by functioning hepatocytes and are partially excreted via the biliary system. Hepatocyte-specific contrast agents allow the radiologist to image the liver during multiple phases of contrast enhancement without the potentially harmful effects of ionizing radiation. In addition to the standard hepatic arterial and portal venous phases that can be obtained with traditional MR or CT contrast agents, hepatocyte-specific contrast agents allow additional imaging to be obtained in hepatocyte phase. This phase of imaging typically is performed 20 minutes after the administration of
contrast and provides the radiologist with additional data so that he or she can further characterize the liver tumor.24 In adults, hepatocyte-specific contrast agents have been shown to improve detection of liver lesions, reliably distinguish hepatocellular adenomas from focal nodular hyperplasia (FNH), improve the detection of liver metastases, and increase overall diagnostic confidence in characterizing and diagnosing specific liver tumors.25–32 There are few papers describing its efficacy in children; however, a recent study by Kolbe et al showed that the addition of a hepatocyte-specific contrast agent helps to improve lesion detection and improve diagnostic confidence for all liver tumors.33 Nowhere is the improved diagnostic confidence more apparent than in the diagnosis of FNH.25,28,29,33 This is of particular importance in patients who are long-term survivors of a pediatric malignancy; these children, adolescents, and young adults are at increased risk of developing FNH.34 Typically, FNH is more much common in females and represents an incidental lesion on imaging. In these otherwise normal patients, the lesions tend to be larger, solitary, and have a central stellate scar.35 This appearance differs from what is seen in long-term cancer survivors where the lesions occur in both males and females and tend to be smaller, multiple, and lack a visible central scar35 (►Fig. 5). Given the patient’s history of malignancy, there is often concern that these multiple enhancing hepatic lesions represent
Fig. 4 Transverse short-tau inversion recovery (STIR) MRI shows renal expansion due to bilateral Wilms tumor (A). Coronal SPECT-CT using 99m Tc-dimercaptosuccinic acid (DMSA) shows tracer uptake in residual functioning renal tissue (B). European Journal of Pediatric Surgery
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Fig. 5 A 26-year-old female with history of spinal myxopapillary ependymoma diagnosed as a child now with multiple focal nodular hyperplasia (FNH) identified on surveillance imaging. Axial T2-weighted (A), arterial phase postcontrast (B), portal venous phase postcontrast (C), and hepatocyte phase postcontrast (D) images show a lesion in the left hepatic lobe that has typical imaging features for a focal nodular hyperplasia including T2 hyperintensity, arterial hyper-enhancement, and retention of contrast in the portal venous and hepatocyte phases. Note also, the T2-hyperintense scar that does not enhance. (E) Coronal hepatocyte phase image in the same patient shows a second lesion with similar imaging characteristics.
metastases. Hepatocyte-specific contrast agents are able to distinguish between the two entities reliably and confidently.33 On the hepatocyte phase of imaging, metastases are hypointense, while FNH lesions are isointense to hyperintense compared with the background enhancing liver. The strikingly different imaging appearance of the two lesions allows the radiologist to be confident in diagnosing a specific entity and can obviate the need for biopsy.
lymphoproliferative disease.36 Potentially, CEUS could also be used to improve the detection of tumors or tumor margins, lymphadenopathy,37 or to make lesions transiently more conspicuous to facilitate ultrasound-guided biopsy.38 CEUS has also shown some promise as a measure of response to therapy in clinical trials, especially of antiangiogenic agents.39
Contrast-Enhanced Ultrasound of the Liver
Diffusion weighted imaging (DWI) is an MRI technique that measures the diffusion of extracellular water molecules in the body. There are several entities such as stroke, abscesses, and highly cellular tumors, which restrict the diffusion of water and appear bright on DWIs. The apparent diffusion coefficient (ADC) is a means to quantify the degree of diffusion restriction, which, in the setting of oncologic imaging, might be used to characterize a tumor and monitor its response to therapy.40 In the past, DWI was limited to neuroimaging because of a low signal-to-noise ratio outside of the brain, poor spatial resolution, and the propensity for patient motion (including
In oncologic imaging, contrast-enhanced ultrasound (CEUS) relies on the intravenous injection of highly echogenic gasfilled microbubbles, which are detected with ultrasound equipment using a low mechanical index technique. The contrast agents that have been used in children include sulfur hexafluoride and octafluoropropane. Most of the clinical experience of CEUS in children has been in evaluating small liver nodules—for example, in children previously treated for cancer (►Fig. 6), or at risk of
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Fig. 6 Contrast-enhanced ultrasound evaluation and biopsy of a small liver nodule in a girl previously treated for neuroblastoma. Images shown were obtained 10 seconds (A) and 2 minutes (B) after intravenous injection of 2.4 ml of sulfur hexafluoride microbubbles. The lesion is barely identifiable with conventional ultrasound (A, left-hand panel, arrows), but shows early intense enhancement compared with the normal liver parenchyma (A, right-hand panel). The delayed images (B) show that the lesion is approximately isoechoic with normal liver. Relatively decreased echogenicity at this time (“washout”) would have suggested malignancy. Needle biopsy confirmed that this was a benign nodule.
respiratory motion, cardiac motion, and bowel peristalsis) to cause significant artifact.41 In 2004, Takahara et al introduced DWI with background body suppression (DWIBS).42 This freebreathing technique suppresses the signal from normal soft tissue structures and fat, highlighting the areas with restricted diffusion.43 The biggest disadvantage of DWIBS is that it is a qualitative method for assessing diffusion and quantitative data (e.g., ADC values) are not generated.43 There have been multiple studies in adult cancer patients showing the benefit of both targeted DWI and whole body DWIBS.43–57 While several of these studies have included pediatric patients, there are few studies evaluating the role of DWI or DWIBS specifically in pediatric patients.41,43,44,46,52 A study by Gawande et al evaluated the ability of DWI to differentiate between benign and malignant pediatric abdominal tumors.41 They analyzed the DWI scans in 68 patients with a variety of abdominal tumors and found that by using an ADC cut-off value of 1.29 10 3, they were able to differentiate benign and malignant lesions with a sensitivity of 77% and a specificity of 82%. While these performance statistics show the test to be only moderately useful, the images were reviewed in isolation. It is thought that if the DWI images were evaluated along with anatomic imaging, the overall performance would be much higher. The same group recently has tested this hypothesis, comparing PET/CT with whole-body MRI European Journal of Pediatric Surgery
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fused with DWI in children and young adults with lymphomas and sarcomas.58 They found that there was no significant difference in the performance of the two modalities with whole-body MRI with DWI having an overall sensitivity of 90.8%, a specificity of 99.5%, and a diagnostic accuracy of 98.3%.58 While early data on use of DWI and DWIBS are promising both in terms of demonstrating the value of qualitative assessments of diffusion restriction as well as in terms of some value of quantitation of diffusion restriction, enthusiasm for this technique must be tempered as several limitations remain. In terms of the significance/clinical importance of the presence of qualitative diffusion restriction, Muller et al have shown that there is baseline normal diffusion restriction in the pelvis and lumbar spine of children that may limit the detectability of disease.43 Moreover, normal lymph nodes show restricted diffusion in the absence of tumor involvement. In terms of quantifying diffusion through ADC measurement, this technique is currently limited as ADC values are dependent on scanner and technique and thereby limiting the widespread application of ADC cut-offs. In its current state, it is unlikely that DWI or DWIBS in isolation will be able to fully replace other types of functional imaging. More likely, DWI or DWIBS will be used in conjunction with other anatomic or functional imaging, providing an additional imaging biomarker.
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Fig. 7 A 22-year-old female with Li-Fraumeni syndrome undergoing surveillance with whole body MRI. Typical sequences acquired include T1-weighted (A), fluid-sensitive inversion recovery (STIR) images (B) and DWIBS images (C). Images are acquired in segments and can then be stitched together for whole-body assessment. This patient remains disease free.
WB MRI in Cancer Predisposition There is increasing interest in identifying ways to noninvasively screen for malignancy in patients with cancer predisposition syndromes. The expectation is that such patients will be screened at multiple time points throughout their life and will often need whole body imaging. FDG-PET/CT can, and has been, effectively used for screening of these patients. Pediatric patients with cancer predisposition syndromes are somewhat of a unique population. In addition to some of these predisposition syndromes carrying increased susceptibility to radiation-induced malignancy, pediatric patients are, as a group, believed to be more susceptible to radiation-induced malignancies and have a greater life span in which screening complications may occur. As such, there is increasing interest in developing low or no-radiation screening methods.58 Recent advances in MRI scanner design have made it feasible to perform whole-body imaging. This allows radiologists to obtain large field-of-view images similar to what is obtained in PET/CT without using ionizing radiation. Whole-body MRI can be combined with DWI or DWIBS to highlight areas of high cellularity that might be reflective of malignancy. Li-Fraumeni syndrome is one example of a syndrome in which screening with whole-body MRI has been employed (►Fig. 7). Li-Fraumeni syndrome is an autosomal dominant cancer predisposition syndrome caused by a mutation in TP53 tumor suppressor gene.59 Patients with Li-Fraumeni syndrome are at an elevated risk of developing multiple different malignancies including soft tissue sarcomas, osteosarcomas, breast cancer, brain tumors, adrenocortical carcinoma, and leukemia.59 A study by Villani et al incorporated whole-body MRI as part of the screening strategy for patients with Li-Fraumeni syndrome. In this study, 18 patients underwent surveillance and 10 asymptomatic tumors were detected in 7
patients.59 The 3-year overall survival was significantly improved in patients enrolled in the surveillance program compared with those who were not in the program (100 vs. 21%).59 Whole-body MRI has also been described as a method to assess tumor burden in patients with neurofibromatosis, type 1. Determining the whole body tumor burden is important in these patients to assess tumor growth and monitor response to therapy.60 Because patients can have extensive tumors spanning multiple body parts, it is difficult to image them effectively and efficiently. Recently, Cai et al described a computerized method for assessing tumor volume. They evaluated 398 nerve sheath tumors in 29 patients finding that whole-body MRI coupled with the computerized method for lesion volume assessment was an accurate method for determining tumor volume.60
Conflict of Interest None.
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Advances in Oncologic Imaging
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Advances in Oncologic Imaging Alexander J. Towbin1
Andrew T. Trout1
Derek J. Roebuck2
1 Department of Radiology, Cincinnati Children’s, Cincinnati, Ohio,
United States 2 Department of Radiology, Great Ormond Street Hospital for Children, London, United Kingdom
Address for correspondence Alexander J. Towbin, MD, Department of Radiology, Cincinnati Children’s, 3333 Burnet Avenue ML5031, Cincinnati, OH 45229, United States (e-mail: [email protected]).
Eur J Pediatr Surg 2014;24:474–481.
Abstract
Keywords
► ► ► ► ►
oncology radiology functional imaging PET/CT MRI
Over the past two decades, there has been an increased reliance on radiologic imaging to diagnose and stage malignancies. This increased reliance on imaging has occurred because the quality of imaging has improved markedly. Currently, modalities such as MRI and CT allow the radiologist to obtain highly detailed images of the human body with a resolution of less than 1mm. More recently, researchers have shifted their focus from anatomic imaging to functional imaging. This burgeoning field of radiology strives to provide quantitative information regarding the behavior of tumors (or other pathology) to deliver patients and clinicians with prognostic information regarding the disease process. The purpose of this article is to describe the recent advances in pediatric oncologic imaging.
Introduction Over the past two decades, there have been considerable advances in medical imaging. These advances have helped to revolutionize the practice of medicine, enabling clinicians to not only diagnose disorders rapidly and accurately but also effectively monitor and tailor therapy in patients with acute or chronic illnesses. As imaging has advanced, its role has expanded beyond providing a detailed evaluation of anatomy, morphology, and macrostructure to providing functional and microstructural information about disease processes. The expansion into functional imaging is already underway in pediatric oncology. The purpose of this article is to review the current status and current frontiers in functional imaging of pediatric malignancy.
Quantitative Imaging with PET/CT F-18-fluorodeoxyglucose (18F-FDG) positron-emission tomography (PET) is well established as a functional imaging modality in pediatric patients with malignancy. FDG-PET uses a radiolabeled analog of glucose (18F-FDG) as a marker of cellular metabolic activity. Because many malignant
received October 30, 2014 accepted November 4, 2014 published online December 5, 2014
processes represent increases in cellularity and increased metabolic activity by malignant cells, 18F-FDG disproportionately accumulates in tumor deposits. The accumulation of 18 F-FDG at sites of disease can be qualitatively or semiquantitatively assessed at diagnosis and throughout therapy to monitor treatment response. Semiquantitative assessment is most simply achieved through measurement of a standardized uptake value (SUV), which takes into account patient size, the amount of 18F-FDG administered, and decay of the radiolabel. In pediatric patients, prediction of response based on semiquantitative FDG-PET data has been most extensively explored for sarcoma. For both osteosarcoma and Ewing sarcoma, the percent of tumor necrosis following neoadjuvant chemotherapy is an important prognostic factor.1 In general, a good histologic response to therapy is defined as tumor necrosis of more than 90%.2 Because the percent necrosis can only be determined after resection, researchers have attempted to identify a reliable imaging indicator that might be used to monitor tumor response to neoadjuvant therapy. For both osteosarcoma and Ewing sarcoma, initial studies have identified maximum SUV (SUVmax) following chemotherapy as a most useful metric to predict the degree of
© 2014 Georg Thieme Verlag KG Stuttgart · New York
DOI http://dx.doi.org/ 10.1055/s-0034-1396423. ISSN 0939-7248.
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Fig. 1 A 14-year-old male with left distal femoral osteosarcoma. Coronal images from 18 F-FDG PET scans show that at diagnosis (A), the distal femoral mass is markedly FDG avid with a SUV max of 23.8. (B) Following 3 months of neoadjuvant chemotherapy, and immediately prior to limb salvage, FDG-avidity of the tumor had substantially decreased (SUV max 2.3). At pathology, following limb salvage, there was 98% tumor necrosis.
histologic necrosis, though the defined cut-offs have varied between studies and tumor types (►Fig. 1).1,3–8 For osteosarcoma, other studies have combined semiquantitative variables with the aim of better predicting outcomes.5,9 Bajpai et al found that a combination of initial tumor volume and the postchemotherapy:prechemotherapy SUVmax ratio could be used to predict the histologic response5 and Cheon et al showed that a combination of SUVmax after chemotherapy and metabolic volume change ratio (% change in volume postchemotherapy:prechemotherapy % change in SUVmax postchemotherapy:prechemotherapy) could predict the response.9 While the greatest body of research exists for sarcomas, the role of FDG-PET in semiquantitative tumor assessment is expanding beyond these tumors. There are few studies describing the utility of FDG-PET/CT in providing prognostic information for patients with neuroblastoma. One study showed that maximum tumor SUV > 5.3 is a predictor of poor prognosis.10 This study and others have also shown that when 18F-FDG uptake is more extensive than MIBG uptake, the patients have more aggressive disease and worse outcomes, likely reflecting dedifferentiation of the tumor.10,11 There are additionally some limited data for Wilms tumor suggesting that high-risk disease may have higher maximum SUV values though further study of this tumor type is needed.12 While FDG is the main 18F tracer used for PET, different 18 F-based radiopharmaceuticals can be used to evaluate certain other biological processes. For example, 18F-dopa can be used to detect and stage neuroendocrine and neuroblastic tumors, and may outperform conventional imaging with 123I-metaiodobenzylguanidine (MIBG).13,14 In addition, other positron-emitting radionuclides may also be useful in the evaluation and staging of pediatric solid tumors.
Towbin et al.
Octreotide has high affinity for somatostatin receptors, which are highly expressed in neuroblastoma, as well as other embryonal neoplasms of childhood.15 Dotatate, a derivative of DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) and octreotate (an octreotide analog) can be used to chelate gallium-68 for PET imaging (►Fig. 2), or lutetium-177 for radionuclide therapy.16 Most other positron-emitting radionuclides with potential clinical applications in pediatrics have short half-lives, which limits their use to centers with a nearby cyclotron. These isotopes include carbon-11 (20 minutes) and rubidium-82 (75 seconds). Iodine-124, however, has a half-life of 4.2 days,17 and is consequently usable in centers remote from a cyclotron. 124I-MIBG PET may find a role in the staging of neuroblastoma. Currently, the majority of PET imaging involves the coregistration of data from two different imaging modalities, usually with the aim of registering functional imaging, which has relatively poor spatial resolution (such as certain nuclear medicine studies), with high-resolution anatomical imaging (such as MRI or CT).18 One practical application of image fusion is the precise localization of tumor tissue18 to facilitate biopsy (►Fig. 3). It may also be helpful in planning surgery (►Fig. 4).
Quantitative Imaging with PET/MR One of the barriers to the widespread application of PET in pediatric patients is concern about radiation exposure. This is being addressed through efforts to standardize the dose of 18 F-FDG that is administered as well as through technologic advances aimed at improving detection of the radioisotope and reducing the dose associated with the CT performed for attenuation correction and localization.19 PET/MRI is being heavily marketed for use in pediatric patients with dose reduction, achieved through attenuation correction, being touted as one of its major advantages. While experience with the technology in pediatric patients is growing, current studies are small in size and have been aimed at
Fig. 2 Gallium-68-dotatate PET-CT in a 10-year-old girl with stage M neuroblastoma. There is intense tracer uptake in the primary tumor (large arrow) and a vertebral body metastasis (small arrow). Normal activity is present in the liver and kidneys. European Journal of Pediatric Surgery
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Fig. 3 Determination of best site for biopsy in a child with neuroblastoma. Conventional MRI fat-suppressed, contrast-enhanced T1-weighted transverse image shows a large right suprarenal mass with probable central necrosis (A). Apparent diffusion coefficient (ADC) map shows restricted diffusion (compatible with increased cellularity 18) in the periphery of the tumor (B). Fused SPECT(single photon emission computed tomography)-CT image using 123I-metaiodobenzylguanidine (MIBG) identifies the ideal site for biopsy (C, arrow).
demonstrating diagnostic equivalence to PET/CT.20 In addition to the potential for dose reduction and increased acceptance of PET imaging in children, PET/MRI has the potential to be a valuable functional imaging tool in pediatric oncology patients through combination and synthesis of functional information derived from both the PET and MR components of the examination.21 These benefits and applications are currently being explored.
Hepatocyte-Specific Contrast Agents There are several different liver tumors that affect pediatric patients.22,23 Over the past 5 years, MRI has become the preferred modality to image these tumors due to the advent of hepatocyte-specific contrast agents. These contrast agents differ from traditional MRI contrast agents in that they are taken up by functioning hepatocytes and are partially excreted via the biliary system. Hepatocyte-specific contrast agents allow the radiologist to image the liver during multiple phases of contrast enhancement without the potentially harmful effects of ionizing radiation. In addition to the standard hepatic arterial and portal venous phases that can be obtained with traditional MR or CT contrast agents, hepatocyte-specific contrast agents allow additional imaging to be obtained in hepatocyte phase. This phase of imaging typically is performed 20 minutes after the administration of
contrast and provides the radiologist with additional data so that he or she can further characterize the liver tumor.24 In adults, hepatocyte-specific contrast agents have been shown to improve detection of liver lesions, reliably distinguish hepatocellular adenomas from focal nodular hyperplasia (FNH), improve the detection of liver metastases, and increase overall diagnostic confidence in characterizing and diagnosing specific liver tumors.25–32 There are few papers describing its efficacy in children; however, a recent study by Kolbe et al showed that the addition of a hepatocyte-specific contrast agent helps to improve lesion detection and improve diagnostic confidence for all liver tumors.33 Nowhere is the improved diagnostic confidence more apparent than in the diagnosis of FNH.25,28,29,33 This is of particular importance in patients who are long-term survivors of a pediatric malignancy; these children, adolescents, and young adults are at increased risk of developing FNH.34 Typically, FNH is more much common in females and represents an incidental lesion on imaging. In these otherwise normal patients, the lesions tend to be larger, solitary, and have a central stellate scar.35 This appearance differs from what is seen in long-term cancer survivors where the lesions occur in both males and females and tend to be smaller, multiple, and lack a visible central scar35 (►Fig. 5). Given the patient’s history of malignancy, there is often concern that these multiple enhancing hepatic lesions represent
Fig. 4 Transverse short-tau inversion recovery (STIR) MRI shows renal expansion due to bilateral Wilms tumor (A). Coronal SPECT-CT using 99m Tc-dimercaptosuccinic acid (DMSA) shows tracer uptake in residual functioning renal tissue (B). European Journal of Pediatric Surgery
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Fig. 5 A 26-year-old female with history of spinal myxopapillary ependymoma diagnosed as a child now with multiple focal nodular hyperplasia (FNH) identified on surveillance imaging. Axial T2-weighted (A), arterial phase postcontrast (B), portal venous phase postcontrast (C), and hepatocyte phase postcontrast (D) images show a lesion in the left hepatic lobe that has typical imaging features for a focal nodular hyperplasia including T2 hyperintensity, arterial hyper-enhancement, and retention of contrast in the portal venous and hepatocyte phases. Note also, the T2-hyperintense scar that does not enhance. (E) Coronal hepatocyte phase image in the same patient shows a second lesion with similar imaging characteristics.
metastases. Hepatocyte-specific contrast agents are able to distinguish between the two entities reliably and confidently.33 On the hepatocyte phase of imaging, metastases are hypointense, while FNH lesions are isointense to hyperintense compared with the background enhancing liver. The strikingly different imaging appearance of the two lesions allows the radiologist to be confident in diagnosing a specific entity and can obviate the need for biopsy.
lymphoproliferative disease.36 Potentially, CEUS could also be used to improve the detection of tumors or tumor margins, lymphadenopathy,37 or to make lesions transiently more conspicuous to facilitate ultrasound-guided biopsy.38 CEUS has also shown some promise as a measure of response to therapy in clinical trials, especially of antiangiogenic agents.39
Contrast-Enhanced Ultrasound of the Liver
Diffusion weighted imaging (DWI) is an MRI technique that measures the diffusion of extracellular water molecules in the body. There are several entities such as stroke, abscesses, and highly cellular tumors, which restrict the diffusion of water and appear bright on DWIs. The apparent diffusion coefficient (ADC) is a means to quantify the degree of diffusion restriction, which, in the setting of oncologic imaging, might be used to characterize a tumor and monitor its response to therapy.40 In the past, DWI was limited to neuroimaging because of a low signal-to-noise ratio outside of the brain, poor spatial resolution, and the propensity for patient motion (including
In oncologic imaging, contrast-enhanced ultrasound (CEUS) relies on the intravenous injection of highly echogenic gasfilled microbubbles, which are detected with ultrasound equipment using a low mechanical index technique. The contrast agents that have been used in children include sulfur hexafluoride and octafluoropropane. Most of the clinical experience of CEUS in children has been in evaluating small liver nodules—for example, in children previously treated for cancer (►Fig. 6), or at risk of
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Fig. 6 Contrast-enhanced ultrasound evaluation and biopsy of a small liver nodule in a girl previously treated for neuroblastoma. Images shown were obtained 10 seconds (A) and 2 minutes (B) after intravenous injection of 2.4 ml of sulfur hexafluoride microbubbles. The lesion is barely identifiable with conventional ultrasound (A, left-hand panel, arrows), but shows early intense enhancement compared with the normal liver parenchyma (A, right-hand panel). The delayed images (B) show that the lesion is approximately isoechoic with normal liver. Relatively decreased echogenicity at this time (“washout”) would have suggested malignancy. Needle biopsy confirmed that this was a benign nodule.
respiratory motion, cardiac motion, and bowel peristalsis) to cause significant artifact.41 In 2004, Takahara et al introduced DWI with background body suppression (DWIBS).42 This freebreathing technique suppresses the signal from normal soft tissue structures and fat, highlighting the areas with restricted diffusion.43 The biggest disadvantage of DWIBS is that it is a qualitative method for assessing diffusion and quantitative data (e.g., ADC values) are not generated.43 There have been multiple studies in adult cancer patients showing the benefit of both targeted DWI and whole body DWIBS.43–57 While several of these studies have included pediatric patients, there are few studies evaluating the role of DWI or DWIBS specifically in pediatric patients.41,43,44,46,52 A study by Gawande et al evaluated the ability of DWI to differentiate between benign and malignant pediatric abdominal tumors.41 They analyzed the DWI scans in 68 patients with a variety of abdominal tumors and found that by using an ADC cut-off value of 1.29 10 3, they were able to differentiate benign and malignant lesions with a sensitivity of 77% and a specificity of 82%. While these performance statistics show the test to be only moderately useful, the images were reviewed in isolation. It is thought that if the DWI images were evaluated along with anatomic imaging, the overall performance would be much higher. The same group recently has tested this hypothesis, comparing PET/CT with whole-body MRI European Journal of Pediatric Surgery
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fused with DWI in children and young adults with lymphomas and sarcomas.58 They found that there was no significant difference in the performance of the two modalities with whole-body MRI with DWI having an overall sensitivity of 90.8%, a specificity of 99.5%, and a diagnostic accuracy of 98.3%.58 While early data on use of DWI and DWIBS are promising both in terms of demonstrating the value of qualitative assessments of diffusion restriction as well as in terms of some value of quantitation of diffusion restriction, enthusiasm for this technique must be tempered as several limitations remain. In terms of the significance/clinical importance of the presence of qualitative diffusion restriction, Muller et al have shown that there is baseline normal diffusion restriction in the pelvis and lumbar spine of children that may limit the detectability of disease.43 Moreover, normal lymph nodes show restricted diffusion in the absence of tumor involvement. In terms of quantifying diffusion through ADC measurement, this technique is currently limited as ADC values are dependent on scanner and technique and thereby limiting the widespread application of ADC cut-offs. In its current state, it is unlikely that DWI or DWIBS in isolation will be able to fully replace other types of functional imaging. More likely, DWI or DWIBS will be used in conjunction with other anatomic or functional imaging, providing an additional imaging biomarker.
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Fig. 7 A 22-year-old female with Li-Fraumeni syndrome undergoing surveillance with whole body MRI. Typical sequences acquired include T1-weighted (A), fluid-sensitive inversion recovery (STIR) images (B) and DWIBS images (C). Images are acquired in segments and can then be stitched together for whole-body assessment. This patient remains disease free.
WB MRI in Cancer Predisposition There is increasing interest in identifying ways to noninvasively screen for malignancy in patients with cancer predisposition syndromes. The expectation is that such patients will be screened at multiple time points throughout their life and will often need whole body imaging. FDG-PET/CT can, and has been, effectively used for screening of these patients. Pediatric patients with cancer predisposition syndromes are somewhat of a unique population. In addition to some of these predisposition syndromes carrying increased susceptibility to radiation-induced malignancy, pediatric patients are, as a group, believed to be more susceptible to radiation-induced malignancies and have a greater life span in which screening complications may occur. As such, there is increasing interest in developing low or no-radiation screening methods.58 Recent advances in MRI scanner design have made it feasible to perform whole-body imaging. This allows radiologists to obtain large field-of-view images similar to what is obtained in PET/CT without using ionizing radiation. Whole-body MRI can be combined with DWI or DWIBS to highlight areas of high cellularity that might be reflective of malignancy. Li-Fraumeni syndrome is one example of a syndrome in which screening with whole-body MRI has been employed (►Fig. 7). Li-Fraumeni syndrome is an autosomal dominant cancer predisposition syndrome caused by a mutation in TP53 tumor suppressor gene.59 Patients with Li-Fraumeni syndrome are at an elevated risk of developing multiple different malignancies including soft tissue sarcomas, osteosarcomas, breast cancer, brain tumors, adrenocortical carcinoma, and leukemia.59 A study by Villani et al incorporated whole-body MRI as part of the screening strategy for patients with Li-Fraumeni syndrome. In this study, 18 patients underwent surveillance and 10 asymptomatic tumors were detected in 7
patients.59 The 3-year overall survival was significantly improved in patients enrolled in the surveillance program compared with those who were not in the program (100 vs. 21%).59 Whole-body MRI has also been described as a method to assess tumor burden in patients with neurofibromatosis, type 1. Determining the whole body tumor burden is important in these patients to assess tumor growth and monitor response to therapy.60 Because patients can have extensive tumors spanning multiple body parts, it is difficult to image them effectively and efficiently. Recently, Cai et al described a computerized method for assessing tumor volume. They evaluated 398 nerve sheath tumors in 29 patients finding that whole-body MRI coupled with the computerized method for lesion volume assessment was an accurate method for determining tumor volume.60
Conflict of Interest None.
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European Journal of Pediatric Surgery
Vol. 24
No. 6/2014
481
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Advances in Oncologic Imaging
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