SHORT COMMUNICATION Annals of Nuclear Medicine Vol. 15, No. 2, 171-177, 2001 Thallium-201 scintigraphy of neuroblastoma: Different results for primary tumors and skeletal lesions Chio OKUYAMA, Yo USHUIMA, Tomoki NAKAMURA, Masayuki KIKKAWA and Tsunehiko NISHIMURA Department of Radiology, Kyoto Prefectural University of Medicine Thallium-201 scintigraphy was performed in 8 children with neuroblastoma, and uptake by the tumors was evaluated in comparison with the results of 123 I-MIBG scintigraphy, No primary tumors or metastatic lymph nodes showed 201 Tl accumulation, but in 4 cases of bone marrow metastases accompanied by focal cortical invasion, the metastatic lesion was demonstrated more clearly on the early image than on the delayed image. In another case of bone metastases infiltrating cortical bone revealed by 123 I-MIBG scintigraphy and biopsy before treatment, 201 Tl scintigraphy performed after chemotherapy showed abnormal accumulation in the tibia, but the second 123 I-MIBG scintigraphy performed I week after the 201 Tl scintigraphy showed no abnormal uptake. 201 Tl does not appear to have good affinity for neuroblastoma, but it accumulates in metastatic skeletal lesions. A reactive hypermetabolic bone marrow, and/or inflammatory process and periosteal reaction due to the presence of metastatic foci may have induced the 201 Tl accumulation. It seems that 201 Tl is not useful for the diagnosis. Nevertheless, the discordance between 201 Tl uptake in primary tumors and skeletal lesions allows speculation on the mechanism of 201 Tl accumulation in skeletons. Key words: 201 Tl scintigraphy, neuroblastoma, skeletal lesion INTRODUCTION NEUROBLASTOMA is a representative solid tumor in infants or children, and it is derived embryonically from the neural crest. It has high malignant potential, but the prognosis varies with cases. There are some neuroblastomas which show spontaneous regression without any treatment in the natural course; on the other hand some cases show very progressive features. 1 Many factors are known as the prognostic factor, and age and clinical stage at diagnosis are thought to be the most significant.2 But cases of widespread disease do not always have a poor outcome. 3 Received August 28, 2000, revision accepted December 18, 2000. For reprint contact: Chio Okuyama, M.D., Department of Radiology, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, JAPAN. E-mail: cokuyama@rad.kpu-m.ac.jp Meta-iodobenzylguanidine (MIBG) labeled with I-13l or I-123 is widely used for the diagnosis 4 staging,5 and the follow-up of neuroblastoma 6 and its utility has been demonstrated because of its high sensitivity and specificity. But according to our experience with more than 40 patients of 123-I-MIBG scintigraphy (a total of more than 200 studies), there seems no correlation between the avidity of the radiopharmaceutical for the tumor and its mallgnant potential. Thallium-201 chloride (201 Tl) scintigraphy has recently become widely accepted for imaging malignant tumors, especially for the diagnosis or identification of the pathological type or grade of tumors of the lung, thyroid, bone, soft tissue, and brain. 7-12 We performed 201-Tl scintigraphy in 8 patients with neuroblastoma and discussed the findings retrospectively to evaluate the utility of 201-Tl from the prognostic viewpoint if possible. Our unexpected but interesting results are discussed. MATERIALS AND METHODS 201 Tl scintigraphy was performed in 8 patients with known or suspected neuroblastoma, aged 0.7-11 years, 5 boys and 3 girls. Seven patients had been admitted for the first time, and scintigraphy was performed for diagnosis and staging before treatment. In 3 of them the tumor was localized in the adrenal gland and no metastatic lesion was detected by any other examination, including 123I-MIBG scintigraphy, bone scan, bone marrow aspiration or biopsy, or abdominal computed tomography (CT). The other 4 had bone marrow metastases with partial cortical bone invasion revealed by 123I-MIBG scintigraphy, bone scan, bone marrow aspiration, X-ray radiographs, and magnetic resonance imaging (MRI). Biopsy or operative section of the tumor prior to chemotherapy confirmed the diagnosis of neuroblastoma in these 7 patients. The remaining patient (Patient 8) had proven metastatic neuroblastoma in his left tibia that was first detected 3 months after intensive chemotherapy and peripheral blood stem cell transplantation (PBSCT). 201Tl scintigraphy was performed after 2 cycles of chemotherapy for recurrence. 201Tl scintigraphy was performed after fasting for more than three hours to avoid intestinal accumulation. Ten minutes and 4 hours after intravenous administration of 1-2 mCi (37-74 MBq) 201Tl, the whole body scans and SPECT of the abdomen or other required site were performed with a dual-head gamma camera (PRISM2000XP, Picker) with low-energy high-resolution parallel collimators. In case 7, no delayed whole body scan was obtained, but SPECT of the abdomen and head were performed instead. 123I-MIBG images were obtained 30 hours after intravenous administration of 37-80 MBq, and the whole body scans and abdominal SPECT were performed with the same equipment as the 201Tl studies. These two studies were performed with an interval of 3-8 days between the two studies in each case. For patients with abnormal accumulation in the skeletal lesions, additional bone scintigraphy was performed to differentiate bone metastases from bone marrow metastases. Bone scintigrams were obtained about 3 hours after intravenous injection of 185-555 MBq of 99mTc-HMDP. Images were visually estimated by two experienced nuclear physicians, who reached a consensus. In all cases, the parents of patients, who well understood about the features of neuroblastoma, were informed that 201Tl scintigraphy is thought to have high affinity for many kinds of tumors and that there is still the possibility of its usefulness for this disease. They consented to the study for the patients in addition to many other examinations. RESULTS The overall patient characteristics and results are shown in Tables 1 and 2. Seven preoperative primary tumors, including enlarged lymph nodes, concentrated 123I-MIBG, but not 201 TlCl. In 4 cases 123I-MIBG demonstrated a total of 23 skeletal lesions, and in these cases the bone marrow aspiration or biopsy revealed tumor involvement. Out of the 23 lesions, only 14 were demonstrated by bone scans, and of these 14 lesions 11 were shown to be smaller by bone scan than by 123I-MIBG. The lesions in which only 123I-MIBG accumulated were interpreted as bone marrow metastases, and the lesions with both tracer accumulations were estimated as bone metastases. Of these 23 skeletal lesions, 21 were visualized on 201Tl early images. Although the 201Tl intensity was weaker than the intensity of 123I-MIBG accumulation 201Tl distribution resembled the 123I-MIBG accumulation (not like the accumulation in bone scintigrams), but they were not seen on the delayed images. Patient 8 had a biopsy which confirmed recurrent neuroblastoma at the diaphysis of the left tibia. The abnormal 123I-MIBG accumulations in the lesion, which were observed on admission, were no longer seen in the second study performed after 2 cycles of chemotherapy, but 201Tl accumulated in the lesion despite the absence of MIBG uptake, but it was not retained on the delayed image. After the 201Tl studies, patients 1 , 2 and 3 underwent resection of the tumor and no additional chemotherapy. Patients 4 and 5 underwent chemotherapy at first, and then a second look operation, and chemotherapy after tumor resection again. Chemotherapy is now being repeated for patients 6 and 7. For patient 8, who had already undergone the chemotherapy, second look operation, and re-chemo-therapy with PBSCT, another chemotherapy regimen, was performed. Patients 1,2,3 and 4 remain well without any evidence of disease for 5,3, 0.5 and 3 years without therapy. Patients 5,6 and 7 had very refractory diseases; patient 5 died after 1.5-years of hospitalization, and patients 6 and 7 are still undergoing intensive chemotherapy. Patient 8 has been free from disease for 4 months since the second PBSCT. Case Reports Patient 1 A 2-year-old boy was admitted to the hospital for further examination of increased urinary catecholamine metabolites discovered in a mass-screening examination at 18 months. He was asymptomatic, but abdominal ultrasonography and MRI demonstrated a left suprarenal abnormal mass. I-123-MIBG accumulated in the tumor, but 201-Tl scintigraphy showed no abnormal accumulation (Fig.1 ). Preoperative biopsy of the tumor confirmed the diagnosis of neuroblastoma, rosette-fibrillary type. Patient 7 An 11-year-old girl was admitted with a head mass and a continued low-grade fever lasting over 2 weeks. She had been treated first with antibiotics, because osteomyelitis had been suspected, but her symptoms did not changed. CT images of the skull showed focal osteolytic change with mild periosteal reaction in the left frontal bone. On her bone scintigrams, many abnormal accumulations were seen in her vertebrae, ribs, and pelvic bones as well as in the left frontal bone. Physical examination revealed a large abdominal mass, and abdominal CT showed a large tumor occupying the right retroperitoneal suprarenal space. Since urinary vanillylmandelic acid (VMA) and homovanillic acid (HVA) levels were very high, neuroblastoma was suspected. An 123-i-MIBG scintigram showed an abnormal hot spot in the head, and ring-like uptake by the abdominal tumor, and diffuse accumulation was seen in bone marrow or the bone of vertebrae, and proximal extremities, which meant that she had progressed neuroblastoma with metastases in diffuse bone marrow and several cortical bones. There was an especially intense hot spot on the parietal bone, which corresponded to the initially noticed lesion. The early 201Tl scintigram showed no abnormal accumulation by the abdominal tumors, but diffuse bone marrow uptake was seen as in the MIBG scintigram. As to the skull lesion, a hot spot in the diffuse accumulation pattern was seen on the 201Tl early images as in the 123I-MIBG images. Although a delayed whole body scan could not be obtained, the alternatively obtained delayed SPECT images of the head and the abdomen demonstrated no abnormal accumulation (Fig. 2). Bone marrow aspiration from the iliac crest and open biopsy of the abdominal tumor confirmed the diagnosis of neuroblastoma, rosette-fibrillary type. Patient 8 A 5-year-old boy who had undergone resection of abdominal neuroblastoma and 3 months previously achieved complete remission after intensive chemotherapy and peripheral blood stem cell transplantation (PBSCT), was readmitted for left leg pain. An X-ray radiograph showed an osteolytic lesion with obvious cortical disruption and periosteal reaction in the distal metaphysis of the left tibia. I-123-MIBG accumulated at the same site, and the biopsy confirmed the diagnosis of the metastatic neuroblastoma. 201TI scintigraphy was performed after 2 cycles of chemotherapy, and demonstrated abnormal uptake in the lesion on the early image and reduced activity that was indistinguishable from the background on the delayed image. The second MIBG scintigraphy, perfomed one week after the 201Tl scintigraphy, demonstrated no abnormal distribution, even though there had been no treatment between the two studies (Fig. 3). Although periosteal reaction continued on the X-ray radiographs, no tumor cell was detected by bone marrow aspiration. DISCUSSION 201Tl was first used for myocardial perfusion imaging in the early 1970s.13,14 It behaves like potassium, and it is thought to be transported through a similar Na-K ATPase pump, Ca ion channel, and co-transport system, instead of potassium ion.7,14 It now has another significant role as a positive indicator for tumors in various organs. The exact mechanism of 201Tl uptake by tumors is not completely known, but the activity of 201Tl uptake is thought to be influenced by many factors: i) blood flow to the tumor and the nature of the tumor vessels, ii) tumor cell viability; iii) cell membrane permeability, iv) tumor cellularity, v) proliferation potential, and vi) some tumor types.7 A number of clinical investigations have shown that the accumulation in potentially malignant lesions persists longer than in benign lesions,7-9,15 and because of this feature 201Tl scintigraphy is now being used to differentiate between benign and malignant lesions, but it is not always entirely reliable, and some exceptions have been reported. The above rule does not apply to certain types of soft tissue tumors, and Tonami et al. reported that in cases of lung cancers the degree of 201Tl accumulation to the malignant lesion and the clearance from lesions vary according to the histological type. 9 It must be borne in mind that 201-Tl does not always accumulate in malignant tumors and, that the tumor affinity differs. The authors retrospectively evaluated the 201-Tl findings in 8 patients with neuroblastoma in order to elucidate its clinical usefulness in this disease. In our 7 cases of neuroblastoma, as stated above, none of the primary tumors or metastatic lymph nodes concentrated 201 Tl. We paid careful attention not to overlook faint uptake by the abdominal tumor, since there is normal intense physiological distribution of 201-Tl in both kidneys, the liver, and intestines. In all cases 201-Tl activity in the abdominal tumors was less than not only in the adjacent 201-Tl avid organs but also in the surrounding background tissue, and the tumors were identified as cold areas. Previously Montravers et al. and Howman-Giles et al, also reported on the lesser avidity of 201-Tl for neuroblastoma, 16,17 but the reason for the absence of 201-Tl accumulation has not yet been clarified. Some features of neuroblastomas, perhaps ion-transport systems, tumor cell-membrane permeability, tumor cellularity, viability, or some other factors, would interfere with the mechanism of 201-Tl accumulation. Our results for primary lesions are in accordance with previously published reports, and it seems that the lack of 201-Tl uptake would be one of the characteristics of neuroblastoma, irrespective of the degree of malignant behavior of the individual tumor. These results made us less enthusiastic about examining more patients. On the other hand, interestingly, the 201-Tl scintigraphy findings in the bone marrow and cortical bone lesions differed from those in the intra-abdominal tumors. Skeletal metastatic lesions were visualized on the early 201-Tl scans, and the accumulation showed fast washout. Normally there is no significant physiological accumulation of 201-Tl by bone or bone marrow 13 except for uptake in the normal growth plates of the long bones in children. Clear accumulation in the vertebrae and the diaphyses of long bones indicates a pathological condition. There have been reports of 201-Tl accumulation in the bone marrow in relation to tumor cell infiltration in myeloma l8 and Hodgkin's lymphoma.19 As a tumorseeking agent, 201-Tl is a useful tool for evaluating patients with malignancy, and it detects the affected bone marrow, but it is difficult to understand why 201-Tl accumulates only in bone marrow and bone metastatic lesions and not in abdominal neuroblastomas. Metastatic tumor cells may have almost the same characteristics as the primary and lymph node lesions in terms of cell membrane permeability or ion transport systems, cellularity and tumor viability. If there is any difference between the features of intraabdominal lesions and skeletal lesions, it would be the vascularity and capillary formation in the tumor. A solid mass is usually fed by one or more vessels, whereas in the bone marrow the tumor cells are disseminated and are surrounded by an abundant blood supply. This form of blood supply may be one of the reasons why only the bone marrow lesions showed 201-Tl uptake on the early images. Accumulation would not be related to the ability of the neuroblastoma cells to pick up 201-Tl, but would be caused by regional blood flow, in the same way that 201-Tl is known to accumulate in inflammation on early images.20 There is also a report on diffuse 201-Tl uptake by bone marrow after treatment with granulocyte stimulating factor in an AIDS patient with Kaposi's sarcoma. 21 In that report the authors mentioned that bone marrow hypermetabolism induced 201-Tl accumulation. Increased cell production and metabolism may cause the Na-K ATPase activity to increase and result in 201-Tl uptake. Thus, in our cases, the form of regional blood supply, reactive inflammation or hyperfunction of the bone marrow associated with the presence of the metastatic foci may have contributed to the 201-Tl accumulation in the bone marrow, rather than the characteristics of the tumors themselves. As to the cortical Involvement, the periosteal reaction may contribute to the 201-Tl uptake. There is no conclusive proof of these hypotheses, but the fact that the bone marrow uptake did not persist confirms that the uptake mechanism is independent of the malignant behavior of the tumor. In case 8, after the resolution of MIBG accumulation, inflammation of the bone and persisting periosteal reaction may have led to the 201-Tl accumulation. It is noteworthy that 201-Tl accumulation by the skeleton does not always mean tumor cell infiltration. Lebtahi et al. reported that on MRI studies abnormal bone marrow signals often persist after chemotherapy for neuroblastoma, despite complete normalization of the MIBG scan, and that an abnormal MRI signal does not necessarily indicate the presence of disease.22 It may also be true that early 201-Tl early accumulation in the bone marrow or bone does not necessarily indicate the presence of a viable tumor, and this might be observed in other tumors besides neuroblastoma. In cases of suspected malignant tumor, the mechanism of early 201-Tl uptake by skeletal lesions would include the tumor characteristics and other factors. But when uptake does not persist on the delayed image, it may indicate that the early uptake reflects hypervascularity, inflammation, hypermetabolism of the bone marrow, or periosteal reactions. Careful attention must be paid to the interpretation of skeletal 201-Tl distribution. Many more cases need to be examined to describe the reliable features of 201-Tl scintigraphy in neuroblastoma. The experience described here suggests that 201-TI scintigraphy is not very useful in the diagnosis or follow-up of neuroblastoma, but it shows one interesting possible mechanism of 201-Tl accumulation in bone marrow and bone. The uptake by affected bone marrow or bone might be independent of the tumor characteristics, so we must take care in the interpretation of skeletal 201-Tl accumulation. REFERENCES l. D'Angio GJ, Evans AE. Koop CE. 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