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© 2001 American Society for Clinical Oncology Extending Positron Emission Tomography Scan Utility to High-Risk Neuroblastoma: Fluorine-18 Fluorodeoxyglucose Positron Emission Tomography as Sole Imaging Modality in Follow-Up of PatientsByFrom the Departments of Medical Imaging and Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, NY., Submitted January 2, 2001; accepted April 4, 2001. Address reprint requests to Brian H. Kushner, MD, Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021; email: kushnerb{at}mskcc.org
PURPOSE: Although positron emission tomography (PET) with fluorine-18 fluorodeoxyglucose (18F-FDG) has a major impact on the treatment of adult cancer, the reported experience with extracranial tumors of childhood is limited. We describe a role for PET in patients with neuroblastoma (NB). PATIENTS AND METHODS: In 51 patients with high-risk NB, 92 PET scans were part of a staging evaluation that included iodine-123 or iodine-131 metaiodobenzylguanidine (MIBG) scan, bone scan, computed tomography (and/or magnetic resonance imaging), urine catecholamine measurements, and bone marrow (BM) examinations. The minimum number of tests sufficient to detect NB was determined. RESULTS: Of 40 patients who were not in complete remission, only 1 (2.5%) had NB that would have been missed had a staging evaluation been limited to PET and BM studies, and 13 (32.5%) had NB detected by PET but not by BM and urine tests. PET was equal or superior to MIBG scans for identifying NB in soft tissue and extracranial skeletal structures, for revealing small lesions, and for delineating the extent and localizing sites of disease. In 36 evaluations of 22 patients with NB in soft tissue, PET failed to identify only two long-standing MIBG-negative abdominal masses. PET and MIBG scans showed more skeletal lesions than bone scans, but the normally high physiologic brain uptake of FDG blocked PET visualization of cranial vault lesions. Similar to MIBG, FDG skeletal uptake was diffusely increased with extensive or progressing BM disease but faint or absent with minimal or nonprogressing BM disease. CONCLUSION: In the absence or after resolution of cranial vault lesions, and once the primary tumor is resected, PET and BM tests suffice for monitoring NB patients at high risk for progressive disease in soft tissue and bone/BM.
WITH NEUROBLASTOMA (NB), which is among the most common and most lethal of pediatric extracranial solid tumors,1 primary tumors can arise anywhere from the pelvis to the neck. More than 90% of cases are associated with high urinary levels of the catecholamines vanillylmandelic acid (VMA) and/or homovanillic acid (HVA). This embryonal neoplasm has a strong propensity to metastasize to bone, bone marrow (BM), lymph nodes, and liver. These clinical characteristics make optimally accurate assessment of disease status in patients with NB dependent on a multitude of studies. Thus, at diagnosis, and often at follow-up, these patients need to undergo computed tomography (CT) (or magnetic resonance imaging [MRI]), bone scan, metaiodobenzylguanidine (MIBG) scan, and BM testing, and urine must be collected for measurement of VMA and HVA.2 Carrying out this complex battery of tests in the young children who make up the majority of NB patients is a daunting ordeal for medical staff, family members, and patients. Reducing the number of staging studies in this patient population, without compromising patient care, would be most welcome, but no single imaging modality suffices for defining the extent of disease because each of the standard imaging modalities has drawbacks and pitfalls. Positron emission tomography (PET) with fluorine-18 fluorodeoxyglucose (18F-FDG) exploits the increased aerobic glycolysis of malignant as compared with most normal cells, plus the retention within cells of the phosphorylated form of FDG. FDG uptake is, therefore, directly proportional to tumor burden and to tumor-cell proliferation. The capacity to characterize tumors both anatomically and metabolically sets PET apart from standard imaging modalities.3-5 Studies in adult cancer patients have shown that PET has superior sensitivity, specificity, and accuracy relative to CT, MRI, and the older scintigraphic imaging methods in a number of difficult clinical settings. As a consequence, PET is increasingly used in adults to delineate primary tumors, to detect regional and distant metastases, to monitor tumor response to treatment, to identify early recurrence, and to distinguish between benign and malignant lesions, particularly in lungs, mediastinum, and lymph nodes.5 Although PET is proving to be of considerable practical importance—with a major impact on the management of adults with common cancers such as those of colon, breast, and lung as well as melanoma—few reports assess its use with extracranial solid tumors of childhood. The published experience on NB and PET is limited to one preclinical study (a single NB xenograft)6 and three small clinical studies (a total of < 20 patients studied with PET using FDG).7-9 The FDG avidity evident in those studies attracted our attention because of our interest in enhancing NB detection capabilities.10-13 We therefore decided to investigate whether the benefits (as listed above) of PET using FDG in patients with carcinomas might be extended to patients with NB. We also welcomed the rapidity of results with PET and the relative lack of radioactivity exposure—an important consideration in the young patient population (and their young parents) affected by NB. We now report on an extensive experience using FDG-PET in patients with high-risk NB. The data indicate that FDG-PET can supplant standard imaging modalities (CT, MRI, bone scan, MIBG scan) in the routine follow-up of this patient population and can thereby simplify restaging. PET may also assist in the assessment of the proliferative or malignant potential of NB.
Fifty-one patients (24 males and 27 females; median age, 8 years) with high-risk NB underwent a total of 92 PET scans as part of a staging evaluation that, in accordance with international criteria,2 consisted of an MIBG scan (53 with iodine-123 [123I], 39 with iodine-131 [131I]), a bone scan, CT, and/or MRI, urine VMA and HVA measurements, and examination of BM specimens from bilateral iliac crests. We determined the minimum number of tests sufficient to detect NB. Consent for staging studies was obtained in accordance with hospital rules, but there was not a specific protocol for PET. By international criteria,2 48 patients had stage 4 NB (42 with metastases in BM and bones before or at the time of PET scans, six with metastases in lungs, liver, and/or distant lymph nodes), two had stage 3 (with MYCN amplification), and one had multiply recurrent stage 2B disease. Disease status was defined by international criteria2: complete remission (CR), no evidence of NB; very good partial remission (PR), primary mass reduced by 90% to 99%, no evidence of distant NB except for skeletal residua, catecholamines normal; PR, more than 50% decrease in measurable disease and less than one positive BM site; mixed response (MR), more than 50% decrease of any lesion with less than 50% decrease in any other; no response (NR), less than 50% decrease but less than 25% increase in any existing lesion; progressive disease (PD), new lesion or more than 25% increase in an existing lesion. PET was preceded by a 6-hour period of fasting except for water. The dosage of 18F-FDG was 10 mCi (370 MBq) per 1.73 m2 of body surface area. Whole-body scans were acquired on a dedicated PET scanner 45 minutes after the infusion of 18F-FDG. Transmission images were obtained after the emission scan. Images were reconstructed with filtered back-projection and iterative reconstruction with segmented attenuation correction. A standardized uptake value (SUV), which is a quantitative measure of tumor uptake of the 18F-FDG adjusted for injected dose and body weight, was calculated for each lesion using vendor-provided software. MIBG scans were performed with 131I through November 1999 and with 123I thereafter. Patients ingested a solution of potassium iodide (1 g/mL) to block 131I or 123I uptake by thyroid glands. The dosages per 1.73 m2 of body surface area were 1 mCi (37 MBq) for 131I-MIBG and 10 mCi (370 MBq) for 123I-MIBG scans. Multiple spot images of the entire body were obtained 24 and 48 hours after injection of 131I-MIBG and 24 hours after injection of 123I-MIBG. For bone scans, patients were imaged 2 hours after injection of technetium-99m methylene diphosphonate at 25 mCi (925 MBq) per 70 kg of body weight. CT was performed with intravenous (IV) and (for abdominal-pelvic imaging) oral contrast. MRI was performed with IV contrast. To ensure optimal imaging, young patients were sedated with pentobarbital plus hydroxyzine or diphenhydramine or were placed under general anesthesia with propofol. Scans were read by radiologists who were unaware of the patient’s clinical status or history.
Surveillance for NB Among patients who underwent two (n = 11), three (n = 7), four (n = 4), or five (n = 1) staging evaluations with PET (Table 1), sequential PET scans documented the following: (1) achievement of CR, PR, or MR in 12 patients (ie, PET scan findings normalized or improved); (2) development of PD in nine patients (ie, follow-up PET scans showed new lesions); (3) continuing CR in five patients (ie, no evidence of NB in successive PET scans); and (4) persistence of refractory disease, rather than PD, in five patients (ie, PET showed no new lesions and SUVs were stable). In the 28 patients who underwent one PET scan, results correlated well with disease status as established by standard imaging studies (Table 2).
Eleven patients were in CR during each of their staging evaluations with PET, and 40 patients had evidence of NB in at least one staging evaluation (Tables 1 and 2). PET confirmed extensive NB in four of four newly diagnosed patients, CR in 28 of 28 evaluations, PD in 30 of 31 evaluations, and residual or refractory NB (PR, MR, NR) in 22 of 28 evaluations. PET was falsely negative in one patient (patient no. 42) with early PD and in six patients (patients no. 10, 32, 33, 35, 36, and 37) who had minimal BM disease. Thus, only one patient (patient no. 42) had NB that would have been missed had testing been limited to PET and BM studies, which gives a 2.5% (one of 40 patients) false-negative rate for NB detection with the use of this two-part work-up; by comparison, four patients (patients no. 20 [fourth study], 21 [first, second, and third studies], 22 [first and third studies], and 23 [first study]) had NB that would have been missed had testing been limited to MIBG scans, BM studies, and urine tests. In 13 (32.5%) of the 40 patients who were not in CR, 19 (30%) of 64 staging evaluations revealed newly relapsed NB (n = 10; patients no. 7 [first study], 14 [third], 16 [second], 18 [first], 19 [second], 20 [third], 21 [first and second studies], 43, 48, and 49) or residual/refractory NB (n = 8; patients no. 4 [first study], 14 [second], 16 [first], 18 [second], 20 [fourth], 21 [third], 23 [first], and 34) that was evident by PET but not by BM or urine tests. PET and MIBG scans were comparably sensitive in screening for the presence of NB in a given patient: both positive in 46 evaluations (30 patients), both negative in 31 evaluations (22 patients), PET positive/MIBG negative in 10 evaluations (seven patients), and PET negative/MIBG positive in three evaluations (three patients). PET and MIBG each gave one false-positive result, as noted in Table 2 (patients no. 31 and 35).
NB in Soft Tissue
Among the four newly diagnosed patients, PET and 131I-MIBG scans showed similar results in three (patients no. 1, 13, and 14), but PET showed more extensive soft tissue disease in one (patient no. 12 Fig 1). SUVs of primary tumors (4.4 to 8.0) were comparable with those of distant nodal lesions (3.4 to 7.1). Among patients with PD, eight had soft tissue lesions detected by PET and MIBG scans, and eight had soft tissue disease better defined by PET than by MIBG scans (Figs 2 and 3), including three who had NB in soft tissue detected by PET but not by MIBG scans (patients no. 10, 21 [first, second, and fourth studies; three separate relapses], and 41). In the only two patients (patients no. 10 and 51) with liver metastases, these were detected by PET but not by MIBG scans.
Among patients with residual/refractory NB, three had soft tissue disease equally well seen by PET and by MIBG scans (patients no. 16 [first study], 18 [second and third studies], and 20 [first study]); two (patients no. 17 [three studies] and 40) had long-standing stable tumors (one ganglioneuroma, one heavily calcified) not detected by PET or by MIBG scans; four had soft tissue disease seen by PET but not by MIBG scans (patients no. 20 [fourth study], 21 [third], 23 [first], and 38); and one patient (patient no. 14 [second]) had more extensive soft tissue disease by PET than by MIBG scan.
NB Metastatic to Cortical Bone and/or BM
Among the 23 patients with histologically proven BM disease, 19 PET scans of 14 patients showed diffusely increased FDG skeletal uptake reflective of BM involvement. Concurrent MIBG scans were also abnormal, but the extent of osteomedullary disease was better defined with PET in five patients (patients no. 5, 11, 21 [fourth study], 46 [Fig 3], and 50 [Fig 4]). In contrast, nine of the 23 patients had no PET or MIBG findings suggestive of BM disease: six (patients no. 10, 32, 33, 35, 36, and 37) had minimal residual NB in BM, and three (patients no. 9 [first], 41, and 45) were in early relapse. One of the nine patients had focal skeletal lesions detected by PET but not by MIBG (Fig 2).
Ten patients underwent 14 evaluations that showed focal skeletal lesions but no histologic evidence of BM disease: PET failed to detect focal lesions in two patients (patients no. 38 and 42); PET and MIBG scans showed lesions not evident by bone scans in four patients (patients no. 19 [second study], 22 [second], 34, and 49 [Fig 5]), one of whom had a site detected by MIBG scan but not by PET (patient no. 34); PET, bone scans, and MRI but not MIBG scans revealed two separate relapses in one patient (patient no. 22 [first and third studies]); PET showed more lesions than MIBG or bone scans in one patient (patient no. 4 [first]); and PET, MIBG, and bone scans showed similar findings in five patients (patients no. 4 [second], 7 [first], 9 [second], 19 [third], and 47) except for failure of PET to detect cranial vault lesions (patients no. 4 [second] and 9 [second]).
Twelve patients had skull (cranial vault) lesions evident by MIBG scan plus bone scan, CT, and/or MRI. These lesions were not detected by PET due to the normally high physiologic brain activity. PET showed extracranial NB in 11 of the 12 patients; in the exception (patient no. 36, who had BM involvement), abnormal MIBG and bone scan findings were limited to the cranial vault.
Nononcologic Causes of Increased FDG Uptake
In our 51 patients with high-risk NB, 92 staging evaluations showed that PET scan findings correlated well with disease status as determined by standard imaging modalities, BM tests, urine VMA and HVA levels, and clinical history. In patients who underwent more than two PET scans, the sequential studies accurately depicted treatment effects and disease evolution (Table 1). The utility of PET for surveillance purposes was shown by (1) the detection of NB by PET but not by BM and urine tests in nearly one third (32.5%) of the patients who were not in CR and (2) the 2.5% false-negative rate for NB detection with use of a follow-up evaluation limited to PET and BM studies. Because of the higher spatial resolution of the PET scanner and the tomographic nature of PET images, PET was better than 123I-MIBG or 131I-MIBG scans for identifying small lesions (eg, foci in ribs or vertebral bodies) and for delineating the extent or localizing the anatomic sites of disease (Figs 1 through 5). PET might hold an advantage over MIBG for detecting metastases to the liver where the normally intense accumulation of MIBG can obscure disease. PET may also yield useful clinical information in NB patients beyond anatomic localization of disease. Via its depiction of the metabolic state of NB cells, PET can provide insights into the proliferative or malignant potential of disease in a given patient. The findings can influence treatment decisions. For example, in NB patients receiving cytotoxic therapy, but with persistence of measurable lesions by standard staging studies, PET scans with normal or with faintly abnormal distribution of FDG might be indicative of quiescent or responding, rather than actively proliferating or aggressive, disease; the impact would be support for continuation of the treatment program. PET showed more osteomedullary abnormalities than bone scans (Table 4). PET matched or surpassed the sensitivity of MIBG scans for detecting NB in extracranial skeletal structures (Table 5). PET and MIBG scans showed similar patterns of diffusely abnormal skeletal findings in patients with extensive BM involvement, but neither imaging modality detected minimal BM disease (a prior report described this same limitation of PET and MIBG scans17). A major drawback of PET was, as expected, the lack of visualization of lesions in the cranial vault because of the normally high physiologic brain activity. All patients in our series with cranial vault lesions had other evidence of NB, including FDG-avid lesions elsewhere, biopsy-proven BM disease, or both. All imaging modalities can give false-positive and false-negative results in patients with NB. Among the various causes of false-positive MIBG scans, increased radiotracer uptake in the remaining adrenal gland after an adrenalectomy (to resect NB) is the most difficult to resolve.14 Causes of false-negative MIBG scans include lack of MIBG avidity of some tumors and nonvisualization of lesions because of intense radiotracer uptake in normal liver, myocardium, salivary glands, and gut.14-19 Imaging with somatostatin analogs is less sensitive than MIBG scans for detecting NB,20,21 possibly because of downregulation of somatostatin-receptor expression in more aggressive tumors.22 Bone scans can be problematic because of intense uptake of bone-seeking agents in the normal growth plates of children (Fig 5). CT cannot distinguish between residual tumor in the surgical bed versus postoperative changes. MRI shows cortical bone or BM abnormalities even after eradication of the neoplastic cells.11,23 We saw increased FDG uptake in gut, thymus, urinary tract, sites of inflammation (skin, lungs, liver), and hyperactive BM—all are well-recognized nonmalignant causes or sites of FDG accumulation.3,4 Clinical history and physical examination help prevent misinterpretation of false-positive findings of PET. For example, in NB patients, there should be little difficulty in distinguishing between inflammatory versus malignant causes of lung lesions seen by PET and CT: these patients often have documented or suspected systemic infections consequent to myelosuppressive therapy, and NB rarely metastasizes to lungs, especially when the disease is responding to treatment. There should also be little difficulty in recognizing a benign cause for the faint diffuse FDG uptake in skeletal structures that can occur with cytokine-induced enhanced hematopoiesis (hyperactive BM) after chemotherapy (and no NB in BM specimens). A potential role for PET in staging NB patients emerges from our experience. PET cannot replace standard imaging modalities in newly diagnosed patients. CT or MRI is needed to delineate masses before surgery. Bone scan helps distinguish between bone and BM metastases (with possible prognostic implications). MIBG scan remains mandatory in part because PET can miss cranial vault lesions that, if present, require follow-up with CT or MRI. In the absence of or after the resolution of cranial vault disease, and once the primary tumor is resected, PET and BM tests are sufficient for follow-up (although it may be prudent to repeat MIBG scans every 6 months in patients deemed to be at especially high risk for recurrence in cranial bones). This two-part work-up requires only a single day, with one session of heavy sedation or general anesthesia, rather than the minimum of 2 or 3 days needed to implement the standard NB staging evaluation (see Introduction).2 Interference with normal life activities is minimized. Fewer clinic visits and fewer sedation/anesthesia sessions reduce costs, especially because PET scan charges are now on a par with those of MRI or MIBG scan. The simplified work-up eliminates the sometimes onerous task of administering oral contrast (for CT) and potassium iodide solution (with MIBG scans) to very young patients, and it avoids the allergic and renal risks of IV contrast. In conclusion, the FDG-avidity of NB, the sensitivity of PET, the accurate anatomic delineation of tumors and the insights into tumor behavior afforded by PET, the low radioactivity exposure associated with PET, the absence of a need for oral agents, and the cost savings all combine to make PET an attractive staging modality in patients with NB.
Supported in part by the Laurent and Alberta Gerschel Foundation, Robert Steel Foundation, Katie’s Find-A-Cure Fund, and Justin Zahn Fund, New York, NY.
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Manil L, Edeline V, Lumbroso J, et al: Indium-111-pentetreotide scintigraphy in children with neuroblast-derived tumors. J Nucl Med 37: 893-896, 1996 21. Shalaby-Rana E, Majd M, Andrich MPL: In-111 pentetreotide scintigraphy in patients with neuroblastoma: Comparison with I-131 MIBG, N-myc oncogene amplification, and patient outcome. Clin Nucl Med 22: 315-319, 1997[Medline] 22. Woltering EA, O’Dorisio MS, O’Dorisio TM: The role of radiolabeled somatostatin analogs in the management of cancer patients, in DeVita VT, Hellman S, Rosenberg SA (eds): Principles and Practice of Oncology, PPO Updates ( vol 9 ). Philadelphia, PA, Lippincott-Raven, 1995, pp 1-16 23. Corbett R, Olliff J, Fairley N, et al: A prospective comparison between magnetic resonance imaging, metaiodobenzylguanidine scintigraphy and marrow histology/cytology in neuroblastoma. Eur J Cancer 27: 1560-1564, 1991 This article has been cited by other articles:
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
