Value of thallium-201 scintigraphy in bone and soft tissue tumors

201 JO.Orthop 3:297–303 Sato etSci al.:(1998) Tl scanning in musculoskeletal tumors

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Original articles Value of thallium-201 scintigraphy in bone and soft tissue tumors Osamu Sato, Akira Kawai, Toshifumi Ozaki, Toshiyuki Kunisada, Tomoyuki Danura, and Hajime Inoue Department of Orthopaedic Surgery, Okayama University Medical School, 2-5-1 Shikata-cho, Okayama 700, Japan

Abstract: The potential role of thallium-201 (201Tl) scintigraphy in the imaging of various musculoskeletal tumors was investigated in 80 patients. Uptake of 201Tl was observed in 17 (100%) malignant bone tumors, 6 (100%) giant cell tumors, and 2 of 8 (25%) benign bone tumors. Nineteen of 30 malignant soft tissue tumors (63%) were positive for 201Tl scintigraphy, while 2 of 14 benign soft tissue tumors (14%) yielded positive results. None of 6 liposarcomas were visualized by 201Tl scintigraphy. There was no 201Tl uptake in the tissues of 5 non-tumorous conditions. Ten patients with osteosarcoma were evaluated by 201Tl scintigraphy both pre- and post-chemotherapy. There was a significant correlation between changes in tumor-to-normal count ratio and percent necrosis of the resected tumor. The mean decrease in tumor-to-normal count ratio was 71% for patients with $90% tumor necrosis and 26% for those with ,90% tumor necrosis. Serial 201Tl scintigraphy, with quantitative analysis of alterations in 201Tl uptake, may provide a quantitative and objective measure of the effect of preoperative chemotherapy in patients with malignant bone tumors. Key words: 201Tl-scintigraphy, bone and soft tissue tumor, preoperative chemotherapy, histologic effect

published data is available regarding the uptake of 201Tl in various histologic subtypes of musculoskeletal tumors.4,19,27 Tumor detection by 201Tl scintigraphy is dependent upon a combination of characteristics of blood flow, Na1, K1-aderosine triphosphatase (ATPase) activity, and cellular viability.3,24 Kaplan et al.11 showed that 201Tl uptake correlated with the viability of brain tumors.9 Ramanna et al.18 found that 201Tl scintigraphy was superior to gallium-67 (67Ga) and technetium-99m (99mTc) bone scans in predicting the response of bone sarcomas to preoperative chemotherapy. We observed that 201Tl scintigraphy was similar in capacity to dynamic magnetic resonance (MR) imaging for assessing the response of bone and soft tissue sarcomas to preoperative chemotherapy.12,13 Compared with dynamic MR imaging, however, 201Tl scintigraphy had shortcomings in quantitative assessment. With these considerations in mind, we investigated the potential value of 201Tl scintigraphy for imaging various musculoskeletal tumors and for quantitatively assessing the effectiveness of preoperative chemotherapy, in a prospective study of 80 patients.

Introduction Thallium-201 (201Tl), a radionuclide potassium analogue, has been used for myocardial imaging since the mid-1970s. Since it has an affinity for a variety of neoplasms, there has been growing interest in using 201Tl for tumor imaging.2,7,9,26 201Tl does not accumulate in the underlying osseous structures, and the scintigraphic findings appear to reflect actual tumor burden more accurately than bone scintigraphy.25 However, little

Offprint request to: O. Sato Received for publication on March 9, 1998; accepted on June 17, 1998

Patients and methods Patients A total of 80 patients (38 males and 42 females, aged 7– 85 years) with various bone and soft tissue abnormalities were studied. There were 31 bone tumors (17 malignant, 6 intermediate, 8 benign), 44 soft-tissue tumors (30 malignant, 14 benign) and 5 non-tumorous conditions (Table 1). Giant-cell tumors were regarded as intermediate (potentially malignant) grade bone tumors. All lesions were at least 3 cm in size. Ten patients with osteosarcoma (oseteoblastic type in 7, fibroblastic type in 2, chondroblastic type in 1) who

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Table 1. Results of thallium-201 (201Tl) scintigraphy according to histology in 80 patients with bone and soft-tissue abnornalitiesa 201

Bone tumors Osteosarcoma Cancer metastasis MFH Malignant lymphoma GCT Osteochondroma Osteoid osteoma Fibrous dysplasia Desmoplastic fibroma Non-ossifying fibroma Solitary bone cyst Soft tissue tumors MFH Liposarcoma Synovial sarcoma Ewing’s sarcoma Cancer metastasis Osteosarcoma Clear-cell sarcoma Malignant schwannoma Leiomyosarcoma Malignant mesenchymoma Schwannoma Hemangioma Neurofibroma Desmoid Lipoma Synovial osteochondroma Non-tumorous conditions Bursitis Myositis ossificans

Tl scintigraphy grade

Positive (%)

n

Average

Range

13 2 1 1 6 3 1 1 1 1 1

2.9 2 3 2 2.2 0 2 2 0 0 0

2–4 2 3 2 2–3 0 2 2 0 0 0

17/17 (100)

10 6 5 2 2 1 1 1 1 1 4 4 2 2 1 1

1.8 0 1.2 2.5 2 2 2 2 2 2 0 0 1 1 0 0

0–3 0 0–2 2–3 2 2 2 2 2 2 0 0 0, 2 0, 2 0 0

19/30 (63)

0 0

0 0

4 1

6/6 (100) 2/8 (25)

2/14 (14)

0/5 (0)

n, Number of tumors; MFH, malignant fibrous histocytoma; GCT, giant-cell tumors. See text for explaration of 201Tl scintigraphy grade. a Some patients had more than one tumor

underwent preoperative chemotherapy were evaluated both before and after chemotherapy. The preoperative chemotherapy was multi-drug combination therapy: doxorubicin (60 mg/m2), cisplatin (120 mg/m2), and high-dose methotrexate (10–12 g/m2) with or without ifosfamide (14 g/m2). All drugs were administered intravenously. Thallium scintigraphy Radioisotope imaging sequences included a total body scan and static scans of selected regions of interest (ROI) starting 5–10 min after intravenous administration of 2 mCi (74 Mbq) of 201Tl. A scanning Anger camera (GCA 901A/WG; Toshiba, Tokyo, Japan), at a speed of 20 cm/ min, was used for total body imaging. A larger field-ofview rectilinear camera with a 3/8 inch sodium iodine crystal was used to obtain static views. Low-energy high

resolution collimators (LEHR MODEL RDC-901HA; Toshiba, Tokyo, Japan) were used. Image analysis Thallium uptake in the lesion was visually evaluated by two independent observers. Thallium uptake was semiquantitated on a scale of 0–4 in comparison with its activity in the myocardium: grade 0, background activity; grade 1, equivocal activity, weak but discernible from the contralateral normal anatomic area; grade 2, definitive activity, less than in the myocardium; grade 3, definitive activity, equal to the myocardium; grade 4, activity greater than in the myocardium.16 For quantitative evaluation, image data counts from the spot images were obtained from a computer (GMS5500A; Toshiba). The average counts per pixel were determined for the ROI, one drawn inside the

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Tl scanning in musculoskeletal tumors

Fig. 1. Giant cell tumor, distal femur in a 33-years-old man. Marked uptake of thallium-201 (201Tl) is observed in the tumor (201Tl scintigraphy grade 3 [see text for explation of grades])

outer border of the tumor and the other on the normal contralateral area. Care was taken to precisely reproduce the positioning of the patient and the drawing of the ROI before and after chemotherapy. The tumor-tonormal (T/N) count ratio was calculated by dividing the average counts for the tumor by those for the contralateral normal area. The decrease in T/N ratio (∆T/N) as a result of the course of chemotherapy (chemo) was calculated by the equation: ∆T/N (%) 5 (Pre-chemo T/N ratio 2 Post-chemo T/N ratio)/Pre-chemo T/N ratio 3 100

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Fig. 2. Myxoid liposarcoma, buttock in a 73-year-old woman. There is no uptake of 201Tl in the tumor (grade 0)

by an experienced pathologist who had no knowledge of the results of scintigraphic assessment. At least 90% necrosis was considered to indicate effective preoperative chemotherapy. Statistical analysis The statistical significance of thallium uptake was assessed using Student’s t-test. Linear regression and Pearson’s estimate of the correlation coefficient were used to describe the relationship between thallium uptake and the histologic effect in the resected specimens. A P value ,0.05 was considered significant.

Histologic evaluation The resected specimen was sliced coronally and/or axially to represent the largest portion of the tumor. The slices were fixed in 10% neutral buffered formalin and embedded separately in paraffin. A grid map based on the topography of sectioning was prepared to allow macroscopic and microscopic comparison. The sections were stained with hematoxylin and eosin, and examined

Results Uptake of 201Tl was observed in all 17 (100%) malignant bone tumors, all 6 (100%) giant cell tumors (Fig. 1), and 2 of the 8 (25%) benign bone tumors (Table 1). Nineteen of the 30 (63%) malignant soft tissue tumors were positive on 201Tl scintigraphy, and two of the 14 (14%)

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benign soft tissue tumors yielded positive results. None of 6 liposarcomas (2 myxoid liposarcomas and 4 well differentiated liposarcomas were visualized by 201Tl scintigraphy (Fig. 2). There was no 201Tl uptake in the tissues from non-tumorous conditions. The sensitivity, specificity, and accuracy of 201Tl scintigraphy in detecting malignancy was 100%, 43%, and 74%, respectively, for the bone lesions, and 60%, 89%, and 71% for the soft tissue masses. The average grade of 201Tl uptake was 2.8 for malignant bone tumors, 2.2 for giant cell tumors, and 0.5 for benign bone tumors. 201Tl uptake in malignant bone tumors was significantly higher than that in benign bone tumors (P 5 0.0011), as well as being significantly higher in malignant soft tissue tumors (1.4) than in benign soft tissue tumors (0.3) (P 5 0.026). The grade of 201 Tl uptake was significantly lower in benign (0.36 6 0.77) than malignant (1.9 6 1.0) tumors overall (P 5 0.0055). Scintigraphic assessment in the ten patients with osteosarcoma evaluated both pre- and postchemotherapy by 201Tl scintigraphy are shown in Table 2. There was no significant difference in prechemotherapeutic 201Tl uptake among osteosarcoma subtypes (osteoblastic type, 201Tl uptake grade, 2.9; T/N ratio, 4.8; chondroblastic type, grade 3.0; T/N ratio, 3.0; fibroblastic type, grade, 3.0; T/N ratio, 4.6). Visual comparison of the scans made before and after chemotherapy revealed a 201Tl uptake decrease of at least one grade in eight patients (decrease by one grade in six patients; decrease of two grades in two patients) after chemotherapy (Fig. 3). Both patients who had a twograde drop in scintigraphic response showed $90% tumor necrosis, while none of the six patients with onegrade drop exhibited a favorable histologic effect. The two patients with no improvement according to 201Tl scintigraphy had no significant tumor necrosis.

Table 2.

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The mean decrease in tumor-to-normal count ratio was 71% in the patients with $90% tumor necrosis and 26% in those with ,90% tumor necrosis (P 5 0.027). Figure 4 shows the relationship between the decrease in tumor-to-normal count ratio and percent necrosis of the resected tumor. There was a significant correlation between the decrease in tumor-to-normal count ratio and percent necrosis of the resected tumor (r 5 0.725; P 5 0.015). The decreases in tumor-to-normal count ratio in fibroblastic osteosarcomas were low. In these patients, there was no histologic effect of the preoperative chemotherapy. There were no significant differences in the changes in tumor-to-normal count ratio between osteoblastic and chondroblastic subtypes of the tumor after the chemotherapy.

Discussion Scintigraphy has been used to differentiate malignant from benign lesions, distinguish tumor recurrence from post-treatment tissue necrosis, and evaluate the response of adjuvant treatment. The clinical utility of 99m Tc bone scanning has been reported extensively. While 99mTc bone scintigraphy is exquisitely sensitive for detecting both primary bone tumors and metastatic lesions, the bone scan tends to overestimate the extent of disease, because osseous uptake of 99mTc is reflected by blood flow as well as the healing response of the bone.5,6,22 In addition to its use in the evaluation of myocardial perfusion, 201Tl scintigraphy has been used since the 1980s as a functional imaging tool in clinical oncology.2,7,9,26 A series of studies at Memorial SloanKettering Cancer Center (New York, United States) and Cedars-Sinai Medical Center group (Los Angeles, US) has shown that 201Tl scintigraphy has an affinity for

Tl scintigraphy in relation to tumor necrosis after chemotherapy 201

Patient no. 1 2 3 4 5 6 7 8 9 10

Age/Sex

Site

Histologic subtype

19/M 9/M 17/F 16/F 17/M 21/M 21/M 14/M 24/F 16/M

Femur Tibia Tibia Femur Tibia Femur Tibia Femur Femur Femur

Osteoblastic Osteoblastic Osteoblastic Osteoblastic Osteoblastic Osteoblastic Osteoblastic Chondroblastic Fibroblastic Fibroblastic

T/N, Tumor-to-normal ratio; m, male; F, female

Tl scintigraphy grade

T/N ratio

Before

After

Before

After

∆T/N (%)

% Necrosis

3 3 2 3 3 3 3 3 3 3

1 1 1 2 2 2 2 2 3 3

4.6 5.2 3.6 6.6 5.4 6.5 2.0 3.0 5.8 3.3

1.3 1.6 3.0 4.5 3.0 3.3 1.2 1.8 6.0 3.6

72 69 17 32 44 49 40 40 23 29

100 99 85 70 60 45 30 20 0 0

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a

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b Fig. 3a,b. Osteosarcoma, distal femur in a 19-year-old man. a 201 Tl scintigraphy before chemotherapy shows marked uptake of the radioisotope in the tumor (grade 3). b After chemotherapy, 201Tl uptake was not shown (grade 1). The chemo-

Fig. 4. Relationship between decrease in tumor-to-normal (T/N) count ratio and percent necrosis of the resected tumor (r 5 0.725; P 5 0.015)

therapy was evaluated as effective by thallium scintigraphy. Histologic examination revealed no viable tumor cells in the resected specimen

bone and soft tissue sarcomas and reflects postchemotherapeutic tumor necrosis more accurately than flow-dependent modalities.15,16,18,21 Because the uptake of 201Tl is not affected by the osseous healing response, 201Tl scintigraphy is expected to indicate tumor viability more accurately than 99mTc bone scintigraphy. However, 201Tl scintigraphy findings in individual histologic subtypes of musculoskeletal tumors are not well defined. Moreover, evaluation of the effect of preoperative chemotherapy based on the semiquantitative visual grading of 201Tl uptake may be difficult to reproduce by different investigators and institutions. In this study we analyzed 201Tl scintigraphy in 80 patients with various bone and soft tissue lesions, and quantified the scintigraphic assessment of the effect of preoperative chemotherapy, using a computerassisted pixel-by-pixel analysis of 201Tl uptake. Thirty six of 47 malignant lesions were detected by localized increased uptake of 201Tl. Seventeen of 17

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(100%) malignant bone tumors showed increased uptake of 201Tl, whereas only 19 of 30 (63%) malignant soft tissue tumors were visualized with 201Tl. The results confirm previous findings that preferential uptake of 201Tl is to be expected in malignant bone tumors.19,27 Sensitivity for identification of malignancy in soft tissue lesions, however, was unexpectedly low. The results of the current study were inferior to the results of gallium scintigraphy for soft tissue sarcomas (sensitivity, 96%) reported by Schwartz and Jones23 and others.14,19 A notable finding in this study was the lack of 201Tl uptake in low-grade liposarcomas. Ganz et al.8 reported that a low-grade liposarcoma had a lower tumor-tonormal 201Tl uptake ratio (ratio, 1.6) than high-grade malignancies (ratio, .3.0). 201Tl uptake is considered to reflect local blood flow, ATPase activity, the sodium pump, and the cellularity of the lesion.3,24 Most malignant lesions are hypercellular and consist of cells with higher metabolic activity, and, accordingly, have a higher 201Tl uptake. However, low-grade sarcomas, such as well differentiated and myxoid liposarcomas, are hypocellular and have diminished blood supply. These lesions may also be less active metabolically. Consequently, they may exhibit little or no uptake of 201 Tl. If we exclude the liposarcomas and two low-grade myxoid malignant fibrous histiocytomas from our results, the sensitivity of our results for soft tissue sarcomas is 86%. All the giant cell tumors of bone were positive for 201 Tl scintigraphy. Although giant cell tumor is not malignant, it is characterised by hypercellularity and hypervascularity. These histologic features may contribute to the consistent 201Tl uptake in giant cell tumors. It should be noted that the results of 201Tl scintigraphy reflect a combination of local blood flow and cellular viability irrespective of whether the lesion is benign or malignant. If we exclude the six giant cell tumors, the specificity and accuracy of 201Tl scintigraphy for detecting malignant bone lesions in our study is 75% and 92%, respectively. Preoperative chemotherapy is now a common treatment for malignant bone tumors, such as osteosarcoma.10 The effect of preoperative chemotherapy influences not only overall survival but also subsequent surgical procedures and chemotherapeutic regimens.20 201 Tl scintigraphy has been reported to be a useful method for evaluating the effect of chemotherapy prior to surgery.15,17,21 Menendez et al.16 reported that whenever there was a decrease in 201Tl uptake after chemotherapy, there was a good histological response. In previous comparative studies, we found that 201Tl scintigraphy was superior to angiography and equivalent to dynamic magnetic resonance imaging in assessing the response of bone and soft tissue sarcomas to preoperative treatment.12,13

O. Sato et al.: 201Tl scanning in musculoskeletal tumors

However, semiquantitative visual grading of 201Tl uptake in comparison with that in the myocardium, the method which has been used to evaluate the effect of chemotherapy,16,21 may be difficult to standardize among investigators and institutions. In contrast to the findings of Menendez et al.,16 the current study showed that patients who had a one-grade drop in scintigraphic response after preoperative chemotherapy did not show a good histological effect of the preoperative chemotherapy. In patients with lowgrade 201Tl uptake before chemotherapy in particular, difficulty is anticipated in evaluating changes in 201 Tl uptake. Moreover, the myocardial uptake of 201 Tl varies in the presence of several physiological and abnormal conditions, including ischemic heart disease. In this study, changes in 201Tl uptake were determined objectively (quantitatively) using a computer-assisted calculation of changes in tumor-to-normal count ratios. There was a statistically significant relationship between the decrease in tumor-to-normal count ratio and the percent necrosis of the resected specimen. Tumors with more than a 60% decrease in this ratio had excellent histologic responses. Some technical aspects of this computer-based method have yet to be refined, however, including the definition of “region of interest” and the type of images (planar or singlephoton emission tomograms) employed for calculating 201 Tl uptake ratios.1 Further, comparative studies are needed to establish the guidelines for evaluating the changes in tumor-to-normal count ratio by which we can predict the histologic effect of the preoperative chemotherapy. In conclusion, 201Tl scintigraphy provides valuable information that may help to identify malignant bone and soft tissue lesions. When the results of scans are evaluated, it should be borne in mind that the scintigram reflects a combination of local blood flow and cellular viability characteristics, which would explain some false-negative and false-positive findings. Serial 201Tl scintigraphy using quantitative analysis of changes in 201 Tl uptake offers a quantitative and objective evaluation of the effect of preoperative chemotherapy for malignant bone tumors.

Acknowledgments. The authors are grateful to Dr. Kohji Taguchi for histologic examination of the resected specimens, and to Dr. Patrick P. Lin for reviewing the manuscript. This work was supported in part by a Grant-in-Aid for Cancer Research (8-231) from the Ministry of Health and Welfare of Japan and a grant from the Japan orthopaedics and Traumatology Foundation, Inc. No. 0073.

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