Original article
Both a visual and a semiquantitative analysis for differentiating benign from malignant chondrogenic bone tumors using Tc-99m (V) DMSA scintigraphy: a prospective study Takayoshi Shinyaa, Shuhei Satoa, Toshiyuki Kunisadac, Ryota Inaia, Hiroyuki Yanaib, Toshifumi Ozakid and Susumu Kanazawaa Objective The aims of this prospective study were to assess the relationship between tumor aggressiveness and Tc-99m (V) dimercaptosuccinic acid (DMSA) uptake in chondrogenic bone tumors and the value of Tc-99m (V) DMSA scintigraphy for differentiating benign from malignant tumors.
correlation was found between tumor aggressiveness and TBC. A significant difference was seen in TBC between benign and malignant tumors. With the chosen cutoff value of TBC equal to 0.611, the sensitivity was 80.0%, specificity was 78.9%, the positive predictive value was 50.0%, and the negative predictive value was 93.8%.
Methods Twenty-four patients with chondrogenic tumors (19 benign and five malignant) underwent Tc-99m DMSA (V) scintigraphy. Radiopharmaceutical uptake was classified using a three-point scale to allow a visual-only analysis, and a tumor-to-background contrast (TBC) was computed using regions of interest to provide a semiquantitative analysis. Spearman’s correlation coefficient was used to assess the correlation between tumor aggressiveness and TBC. The difference in TBC between benign and malignant tumors was analyzed with the Mann–Whitney U-test. An appropriate cutoff value of TBC was chosen for the diagnosis of malignancy of a tumor using receiver operating characteristic analysis.
Conclusion Tc-99m (V) DMSA scintigraphy may have the potential to improve diagnostic methods for detecting chondrosarcomas using visual and/or semiquantitative analyses. Nucl Med Commun 36:802–807 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Results Six benign tumors showed negative uptake (uptake score 0), whereas 13 benign tumors showed positive uptake (n = 10 uptake score 1; n = 3 uptake score 2). All chondrosarcomas showed positive uptake (n = 2 uptake score 1; n = 3 uptake score 2). A significant
Introduction Chondrogenic tumors are the second largest group of bone tumors. Their histologic pattern suggests a relationship to hyaline cartilage [1,2]. The state of malignancy, benignity, and grade is determined from history, radiography, and histologic examination [3–5]. The recognition of high-grade malignancy is not difficult with typical findings on radiography, computed tomography (CT), and MRI. However, no sufficiently reliable method has been established, and the differentiation between benign and low-grade chondrogenic tumors can present diagnostic dilemma in terms of the diagnostic gold standard [2,6]. Moreover, malignant transformation of benign chondrogenic tumors could occur [7]. Therefore, making a diagnosis of malignant chondrogenic tumor is sometimes not easy with conventional imaging techniques [8,9]. 0143-3636 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Nuclear Medicine Communications 2015, 36:802–807 Keywords: bone tumor, cartilaginous, chondrogenic, chondrosarcoma, Tc-99m (V) DMSA scintigraphy Departments of aRadiology, bPathology, Okayama University Hospital, Departments of cMedical Materials for Musculoskeletal Reconstruction and d Orthopaedic Surgery, Okayama University Graduate School of Medicine, Okayama, Japan Correspondence to Takayoshi Shinya, PhD, MD, Department of Radiology, Okayama University Hospital, 2-5-1 Shikatacho, Kita-ku, Okayama-city, Okayama 700-8558, Japan Tel: + 81 862 357 313; fax: + 81 862 357 316; e-mail: [email protected] Received 9 January 2015 Revised 1 March 2015 Accepted 4 April 2015
Pentavalent Tc-99m (V) dimercaptosuccinic acid (DMSA) is a Tc-99m-labeled tumor-seeking agent [10] that has been reported to be very useful for the detection of soft tissue tumors, especially amyloid tumors [11], lowgrade sarcomas [12], head and neck tumors [13], and synovial giant cell tumors [14]. It is supposed to be related to blood flow and phosphate metabolism or pH, although the mechanism of accumulation of Tc-99m (V) DMSA needs further study [15]. In previous studies [16, 17], the visual extent of Tc-99m (V) DMSA uptake had potential for distinguishing malignant from benign chondrogenic bone tumors and an increase in Tc-99m (V) DMSA uptake indicated the possibility of malignant transformation of benign cartilage tumors. However, no previous report has assessed the relationship between tumor aggressiveness and extent of Tc-99m (V) DMSA uptake with a semiquantitative analysis, nor evaluated DOI: 10.1097/MNM.0000000000000328
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Tc-99m (V) DMSA in chondrogenic tumor Shinya et al. 803
Summary of Tc-99m (V) DMSA scintigraphic data of 24 patients with chondrogenic bone tumors
the diagnostic capacity of Tc-99m (V) DMSA for differentiation between benignity and malignancy in chondrogenic bone tumors using a semiquantitative analysis.
Table 1
The aims of this prospective study were to determine whether a correlation existed between tumor aggressiveness and Tc-99m (V) DMSA uptake and to evaluate the value of Tc-99m (V) DMSA scintigraphy with the visual scoring system and semiquantitative analysis along with tumor-to-background contrast (TBC) for the differentiation of benign from malignant chondrogenic bone tumors, when the determination of benignity or malignancy was difficult from evaluation of history, symptoms, and conventional imaging results.
No./age/sex
Methods Study population
This prospective study was approved by the institutional review board and ethics committee and was conducted in a single institution. A written informed consent form was signed by all patients. We included patients older than 20 years with chondrogenic bone tumors, in which the determination of benignity or malignancy was difficult from evaluation of history, symptoms, and conventional imaging results. Between April 2006 and January 2012, 24 patients with chondrogenic bone tumors underwent Tc-99m (V) DMSA scintigraphy [10 male and 14 female; age (mean ± SD), 50.75 ± 11.61; range, 24–68 years]. All 24 patients were diagnosed with a chondrogenic bone tumor on conventional imaging and/or histopathological findings. Nine of 19 benign chondrogenic bone tumors were proven by histological examination (six enchondromas, two osteochondromas, and one periosteal chondroma), whereas 10 presumed enchondromas were followed up for a mean of 40 months (range 14–57 months) and diagnosed on clinical and radiological grounds to indeed be enchondromas. All five chondrosarcomas were proven histologically (n = 2 grade I chondrosarcomas; n = 3 grade II chondrosarcomas). Sixteen enchondromas were located in the humerus (n = 12), femur (n = 3), and fibula (n = 1). Two osteochondromas and one periosteal chondroma were located in the iliac bone (n = 1), tibia (n = 1), and intermediate phalanges (n = 1). Five chondrosarcomas were located in the coxal bone (n = 2), femur (n = 1), rib (n = 1), and fibula (n = 1). No significant difference was found between the size of the benign chondrogenic tumors (56.92 ± 29.96 mm in maximum diameter) and that of malignant chondrogenic tumors (79.20 ± 19.32 mm in maximum diameter) (P = 0.0594). No patients had received any therapy for chondrogenic bone tumors before Tc-99m (V) DMSA. A summary of Tc-99m (V) DMSA scintigraphic data is given in Table 1. All patients were examined with planar radiography and planar Tc-99m (V) DMSA scintigraphy.
Score of visual uptake
TBC
Humerus Humerus Humerus Femur Fibula Humerus Femur Humerus Humerus Femur Humerus Humerus Humerus Humerus Humerus Humerus Ilium Tibia Intermediate palanges
1 1 1 0 0 0 2 1 1 1 1 2 0 1 0 1 1 2 0
0.460 0.344 0.475 0.241 0.226 0.113 1.032 0.404 0.528 0.361 0.769 0.938 0.074 0.503 0.116 0.300 0.391 1.135 0.237
Femur
2
8.969
Coxal bone
2
0.823
Coxal bone
1
0.694
Rib
1
0.435
Fibula
2
1.873
Diagnosis
A. Benign bone tumors 1/64/F Enchondroma 2/44/F Enchondroma 3/47/F Enchondroma 4/48/F Enchondroma 5/63/M Enchondroma 6/54/F Enchondroma 7/60/M Enchondroma 8/42/F Enchondroma 9/42/F Enchondroma 10/65/M Enchondroma 11/55/F Enchondroma 12/27/M Enchondroma 13/47/M Enchondroma 14/45/F Enchondroma 15/58/M Enchondroma 16/68/F Enchondroma 17/61/F Osteochondroma 18/42/M Osteochondroma 19/55/F Periosteal chondroma B. Malignant bone tumors 20/24/F Chondrosarcoma, grade I 21/52/M Chondrosarcoma, grade I 22/43/F Chondrosarcoma, grade II 23/67/M Chondrosarcoma, grade II 24/63/M Chondrosarcoma, grade II
Site
DMSA, dimercaptosuccinic acid; F, female; M, male; TBC, tumor-to-background contrast.
Tc-99m (V) DMSA scintigraphy
A lyophilized kit of Tc-99m (V) DMSA (Daiichi Radioisotopes Laboratories Ltd, Tokyo, Japan), containing 1.36 mg of DMSA, 1.26 mg of NaHCO3, 0.11 mg of SnCl2·(2H2O), and 30 mg of glucose, was made available. Labeling was performed by adding 0.1 ml of 7% NaHCO3 with 2–3 ml of pertechnetate with the desired activity to the kit [10,14]. Purity of Tc-99m derivation was analyzed by thin-layer chromatography, and no free pertechnetate or other Tc-99m derivative was detected. An easily available method for preparation of Tc-99m (V) DMSA using a kit for Tc-99m (III) DMSA renal scintigraphy has been previously reported by Watkinson et al. [13]. All scans of Tc-99m (V) scintigraphy were taken 2 h after intravenous administration of 370 MBq (10 mCi) Tc-99m (V) DMSA using a conventional gamma camera system (GCA-7200A/DI; Toshiba, Tokyo, Japan). A low-energy, high-resolution, parallel-hole collimator was used, and images were acquired in a 512 × 512 matrix for 10 min. Image data analysis
The planar images of Tc-99m (V) DMSA scintigraphy were classified using a three-point scale for visual
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analysis: 0, radioactivity equal to that of the area adjacent to the tumor; 1, radioactivity slightly higher than that of the area adjacent to the tumor; and 2, radioactivity obviously higher than that of the area adjacent to the tumor. Scoring was carried out by two experienced nuclear medicine physicians who were unaware of the histologic results. The score was determined by consensus. Two equal-sized regions of interest (ROIs) were located on an image for the semiquantitative analysis (Fig. 1). The first ROI was placed on the uptake site of the tumor and the second ROI was placed on the contralateral side to assess background [18,19]. When Tc-99m (V) DMSA uptake was not detectable on the image, the ROI was placed on the area corresponding to that in images obtained from planar radiography, CT, and MRI. On planar images, the counts in the ROI on the uptake site of the tumor represented the total counts of the lesion and background. Attenuating the impact of the background activity, the TBC was calculated by dividing the difference in the average counts per pixel in the ROI for the uptake site of the tumor (T) and that in the ROI for the background (BG) by BG: that is, TBC = (T − BG)/BG. Statistical analysis
All statistical analyses were performed using IBM SPSS Statistics 22 for Windows (IBM Corp., Armonk, New York, USA). Spearman’s correlation coefficient was used to determine whether any correlation existed between tumor aggressiveness and the TBC in chondrogenic
tumors (benign chondrogenic tumor, grade I, II chondrosarcoma). Differences in TBC were analyzed with the Mann–Whitney U-test. Probability values less than 0.05 were taken to indicate significant differences. Receiver operating characteristic analysis was used to determine an appropriate TBC value for malignant chondrogenic bone tumors, and the related area under the curve was calculated.
Results From the visual analysis, five enchondromas and one periosteal chondroma were classified with an uptake score of 0; 10 benign chondrogenic tumors were classified with an uptake score of 1 (nine enchondromas and one osteochondroma); and two enchondromas and one osteochondroma were classified with an uptake score of 2. All five malignant chondrosarcomas showed positive uptake of Tc-99m (V) DMSA. Two of them were classified as having an uptake score of 1 and three were classified as having an uptake score of 2. From the visual analysis, the sensitivity and specificity of Tc-99m (V) DMSA scintigraphy in patients with chondrogenic bone tumors were 100.0 and 31.6%, respectively. Moreover, significant correlation was found between tumor aggressiveness and the TBC in chondrogenic tumors (ρ = 0.919, P < 0.01). Representative Tc-99m (V) DMSA images of scores 1 and 2 are demonstrated in Figs 1 and 2. From the semiquantitative analysis, the TBC value for benign chondrogenic tumors was determined to be 0.391 ± 0.071 (median ± SEM). The TBC for chondrosarcoma was
Fig. 1
(a)
(b)
∗∗
∗
(a) MRI (T2-weighted image) of an enchondroma in the left femur. (b) Planar image of Tc-99m (V) DMSA (anterior view). The enchondroma of the left femur was classified to an uptake score of 1. The first ROI (*) was placed on the outer border of the lesion and the second ROI (**) was placed on the contralateral side, which served as the control. DMSA, dimercaptosuccinic acid; ROI, region of interest.
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Tc-99m (V) DMSA in chondrogenic tumor Shinya et al. 805
Fig. 2
(a) MRI (T2-weighted image) of a grade I chondrosarcoma of the right femur. (b) Planar image of Tc-99m (V) DMSA (anterior view). The grade I chondrosarcoma of the right femur was classified to an uptake score of 2.
Fig. 4
Fig. 3
1.0
P = 0.019
10.000000 ∗ 8.000000
0.8 TBC
6.000000 0.6 TPR
4.000000 2.000000
0.4 0.000000 Chondrosarcoma
Benign chondrogenic tumor
A correlation between the tumor-to-background contrast (TBC) for benign and malignant chondrogenic tumors. The TBC in malignant chondrogenic tumor (chondrosarcoma) was significantly higher than the TBC in benign chondrogenic tumor (P = 0.019). TBCs are 0.391 ± 0.071 for benign chondrogenic tumor and 0.823 ± 1.621 for chondrosarcoma. *Represents an outlier.
0.823 ± 1.621 (median ± SEM). A significant difference was identified in TBC between benign and malignant chondrogenic tumors (P = 0.019, Fig. 3). The receiver operating characteristic curve analysis showed that the appropriate cutoff value of TBC for identifying malignant chondrogenic tumor was 0.611, with 80.0% sensitivity and 78.9% specificity (area under
0.2
0.0 0.0
0.2
0.4
0.6
0.8
1.0
FPR Receiver operating characteristic (ROC) curve shows the performance of tumor-to-background contrast (TBC) for malignant chondrogenic bone tumor. ROC curves were plotted from pairs of true-positive rate (TPR) and false-positive rate (FPR) corresponding to the cutoff values of TBC for diagnosis of malignant chondrogenic tumor.
the curve = 0.842, Fig. 4). At the same cutoff value, the negative predictive value (NPV) was 93.8% and the positive predictive value was 50.0%.
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Discussion The present study assessed the usefulness of both visual analysis and semiquantitative analysis of Tc-99m (V) DMSA scintigraphy in patients with chondrogenic bone tumors in which the determination of benignity or malignancy was difficult from evaluation of history, symptoms, and conventional imaging results. All five chondrosarcomas and 13 of 19 benign chondrogenic tumors had positive DMSA (V) scans. The discrimination of the state of benignity and malignancy is difficult only with the visual analysis of Tc-99m (V) DMSA uptake. However, the TBC for chondrosarcomas was significantly higher than the TBC for benign chondrogenic tumors, and the cutoff value of TBC was set for the diagnosis of chondrosarcoma at 0.611, with 80.0% sensitivity, 78.9% specificity, 50.0% positive predictive value, and 93.8% NPV. The diagnoses of malignant chondrogenic bone tumors or detection of the malignant transformation of benign chondrogenic tumors is not always easy with conventional radiologic modalities such as radiography, CT, and MRI, which provide excellent morphologic delineation and localization of bone tumors. Functional nuclear scans reflect the metabolic activity of tumors and may provide important information regarding the biologic behavior. Tl-201 uptake was related to tumor grade in chondrosarcoma; that is, increased Tl-201 uptake was seen for grade II–III chondrosarcoma, but no grade I tumor had Tl-201 uptake in previous reports [17,20]. Therefore, Tl201 cannot resolve the problem of differentiating between benign chondrogenic tumor and grade I chondrosarcoma. The first finding of our study was that all five chondrosarcomas and 13 of 19 benign chondrogenic tumors had positive DMSA (V) scans and six benign chondrogenic bone tumors had negative DMSA (V) scans in this population, in which the determination of the state of benignity and malignancy was difficult when compared with conventional diagnostic methods. The finding is similar to that in previous publications covering the usefulness of Tc-99m (V) DMSA [16,17], in which all 46 chondrosarcomas and 34 of 74 benign chondrogenic tumors had positive DMSA (V) scans. Moreover, in those reports, all tumors without Tc-99m (V) DMSA uptake were benign chondrogenic tumors [16,17]. Those findings confirmed that all chondrosarcomas were DMSA (V) positive and all chondrogenic tumors without Tc-99m (V) DMSA uptake were benign. However, visual analysis alone revealed false-positive DMSA (V) scans in benign chondrogenic tumors and the differentiation between benignity and malignancy remained a diagnostic dilemma in patients with DMSA (V)-positive tumors. The visual evaluation of Tc-99m (V) DMSA uptake is thus limited in usefulness for chondrogenic tumors.
The second important finding of our study was that a significant correlation was found between the TBC and tumor aggressiveness. Malignant chondrogenic tumors appeared to have a higher vascularity and higher metabolic rate compared with benign tumors, and increased uptake of Tc-99m (V) DMSA has often been found in rapidly growing and/or malignant-transformed tumors [16]. These findings suggest that Tc-99m (V) DMSA scintigraphy might have potential to predict biologic aggressiveness in chondrogenic tumors and to point out the malignant transformation of benign chondrogenic tumors on follow-up Tc-99m (V) DMSA scintigraphy. The third major finding of our study was that the TBC for chondrosarcoma was significantly higher than that for benign chondrogenic tumor. Moreover, we could set the cutoff value of TBC for the diagnosis of malignant chondrogenic tumor at 0.611 and achieve a relatively high specificity and high NPV. These findings suggest that TBC might aid in differentiating between benign and malignant chondrogenic tumors with a noninvasive method, especially when there are subtleties in differential diagnosis between benign and low-grade malignant states from conventional imaging modalities as in our study population. The results of this study reveal that DMSA (V)-negative tumor can be diagnostic of a benign chondrogenic bone tumor on the basis of visual evaluation with negative uptake, and the calculation of TBC can be a useful diagnostic method for differentiating between benign and malignant chondrogenic bone tumors in patients with DMSA-positive tumor. The low TBC for the chondrogenic bone tumor might indicate a high likelihood of being a benign tumor and a relatively indolent tumor. These could be followed closely without invasive biopsy and without treatment. This conjecture is supported by the significant correlation between tumor aggressiveness and the TBC and by the relatively high specificity and the high NPV for malignant chondrogenic bone tumors. Our study has several limitations. First, the study population comprised a small number of patients who had been selected from among the cases in which the determination of the state of benignity or malignancy was difficult from general diagnostic techniques. Examination of a larger number of consecutive patients in a prospective study would be useful for further investigation of the appropriate TBC in Tc-99m (V) DMSA for assessing the state of malignancy or benignity and the tumor aggressiveness in patients with chondrogenic tumor according to the visual scoring system. Second, there was absence of histopathological confirmation by biopsy or surgery in several patients with enchondroma. However, despite these limitations, our results suggest that Tc-99m (V) DMSA scintigraphy has potential to predict biologic aggressiveness before
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Tc-99m (V) DMSA in chondrogenic tumor Shinya et al. 807
surgery in patients with chondrogenic bone tumor, in which the determination of the state of benignity or malignancy is difficult from general diagnostic techniques, and to distinguish benign chondrogenic tumor from chondrosarcoma.
9 10
Conclusion
11
The findings of the present study show that there is an increase in Tc-99m (V) DMSA uptake for malignant chondrogenic tumors compared with benign chondrogenic tumors. The use of a Tc-99m (V) DMSA scan could be a marker for increased biologic activity with semiquantitative analysis and could have potential to improve the radiological diagnostic methods for chondrogenic tumors.
7 8
12
13
14
Acknowledgements Conflicts of interest
15
This work was supported by Daiichi Radioisotopes Laboratories Ltd, Tokyo, Japan.
16
References 1 Lucas DR, Bridge JA. Chondromas: enchondroma, periosteal chondroma. In: Fletcher CDM, Bridge JA, Hogendoorn PCW, Mertens F, editors. WHO classification of tumours of soft tissue and bone, 4th ed. Lyon: IARC Press; 2013. pp. 252–254. 2 Bertoni F, Bacchini P. Classification of bone tumors. Eur J Radiol 1998; 27 (Suppl 1):74–76. 3 Coughlan B, Feliz A, Ishida T, Czerniak B, Dorfman HD. p53 expression and DNA ploidy of cartilage lesions. Hum Pathol 1995; 26:620–624. 4 Springfield DS, Gebhardt MC, McGuire MH. Chondrosarcoma: a review. Instr Course Lect 1996; 45:417–424. 5 Dirix LY, Van Oosterom AT. Chondrosarcoma and other rare bone sarcomas. Curr Opin Oncol 1991; 3:694–699. 6 Hasegawa T, Seki K, Yang P, Hirose T, Hizawa K, Wada T, et al. Differentiation and proliferative activity in benign and malignant cartilage tumors of bone. Hum Pathol 1995; 26:838–845.
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Dahlin DC, Unni KK. Bone tumors: general aspects and data on 8542 cases, 4th ed. Springfield: Charles C. Thomas; 1986. Greenfield GB. The solitary lesion in radiology of bone disease, 5th ed. Philadelphia: JB Lippincott; 1990. Jaffe HL. Hereditary multiple wxostoses. Arch Pathol 1943; 36:335. Ohta H, Endo K, Fujita T, Konishi J, Torizuka K, Horiuchi K, et al. Clinical evaluation of tumour imaging using 99Tc(V)m dimercaptosuccic acid, a new tumour-seeking agent. Nucl Med Commun 1988; 9:105–116. Kobayashi H, Sakahara H, Itoh T, Kudoh T, Takagi T, Shibuya K, et al. Technetium-99m(V) dimercaptosuccinic acid uptake in intra-abdominal massive deposit of amyloid protein. J Nucl Med 1993; 34:815–817. Kobayashi H, Sakahara H, Hosono M, Shirato M, Endo K, Kotoura Y, et al. Soft-tissue tumors: diagnosis with Tc-99m (V) dimercaptosuccinic acid scintigraphy. Radiology 1994; 190:277–280. Watkinson JC, Lazarus CR, Mistry R, Shaheen OH, Maisey MN, Clarke SE. Technetium-99m (V) dimercaptosuccinic acid uptake in patients with head and neck squamous carcinoma: experience in imaging. J Nucl Med 1989; 30:174–180. Kobayashi H, Sakahara H, Hosono M, Shirato M, Konishi J, Kotoura Y, et al. Scintigraphic evaluation of tenosynovial giant cell tumor using technetium-99m (V) dimercaptosuccinic acid. J Nucl Med 1993; 34:1745–1747. Yokoyama A, Hata N, Horiuchi K, Masuda H, Saji H, Ohta H, et al. The design of a pentavalent Tc-99m dimercaptosuccinate complex as a tumor imaging agent. Int J Nucl Med Biol 1985; 12:273–279. Kobayashi H, Kotoura Y, Hosono M, Sakahara H, Hosono M, Yao ZS, et al. Diagnostic value of Tc-99m (V) DMSA for chondrogenic tumors with positive Tc-99m HMDP uptake on bone scintigraphy. Clin Nucl Med 1995; 20:361–364. Choong PF, Kunisada T, Slavin J, Schlicht S, Hicks R. The role of thallium201 and pentavalent dimercaptosuccinic acid for staging cartilaginous tumours. Int Semin Surg Oncol 2004; 1:10. Kunisada T, Ozaki T, Kawai A, Sugihara S, Taguchi K, Inoue H. Imaging assessment of the responses of osteosarcoma patients to preoperative chemotherapy: angiography compared with thallium-201 scintigraphy. Cancer 1999; 86:949–956. Kawakami N, Kunisada T, Sato S, Morimoto Y, Tanaka M, Sasaki T, et al. Thallium-201 scintigraphy is an effective diagnositic modality to distinguish malignant from benign soft-tissue tumors. Clin Nucl Med 2011; 36:982–986. Kayo GC, Demir Y, Ozkal S, Sengoz T, Manisali M, Baran O, et al. Tumor grade-related thallium-201 uptake in chondrosarcomas. Ann Nucl Med 2010; 24:279–286.
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Both a visual and a semiquantitative analysis for differentiating benign from malignant chondrogenic bone tumors using Tc-99m (V) DMSA scintigraphy: a prospective study Takayoshi Shinyaa, Shuhei Satoa, Toshiyuki Kunisadac, Ryota Inaia, Hiroyuki Yanaib, Toshifumi Ozakid and Susumu Kanazawaa Objective The aims of this prospective study were to assess the relationship between tumor aggressiveness and Tc-99m (V) dimercaptosuccinic acid (DMSA) uptake in chondrogenic bone tumors and the value of Tc-99m (V) DMSA scintigraphy for differentiating benign from malignant tumors.
correlation was found between tumor aggressiveness and TBC. A significant difference was seen in TBC between benign and malignant tumors. With the chosen cutoff value of TBC equal to 0.611, the sensitivity was 80.0%, specificity was 78.9%, the positive predictive value was 50.0%, and the negative predictive value was 93.8%.
Methods Twenty-four patients with chondrogenic tumors (19 benign and five malignant) underwent Tc-99m DMSA (V) scintigraphy. Radiopharmaceutical uptake was classified using a three-point scale to allow a visual-only analysis, and a tumor-to-background contrast (TBC) was computed using regions of interest to provide a semiquantitative analysis. Spearman’s correlation coefficient was used to assess the correlation between tumor aggressiveness and TBC. The difference in TBC between benign and malignant tumors was analyzed with the Mann–Whitney U-test. An appropriate cutoff value of TBC was chosen for the diagnosis of malignancy of a tumor using receiver operating characteristic analysis.
Conclusion Tc-99m (V) DMSA scintigraphy may have the potential to improve diagnostic methods for detecting chondrosarcomas using visual and/or semiquantitative analyses. Nucl Med Commun 36:802–807 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Results Six benign tumors showed negative uptake (uptake score 0), whereas 13 benign tumors showed positive uptake (n = 10 uptake score 1; n = 3 uptake score 2). All chondrosarcomas showed positive uptake (n = 2 uptake score 1; n = 3 uptake score 2). A significant
Introduction Chondrogenic tumors are the second largest group of bone tumors. Their histologic pattern suggests a relationship to hyaline cartilage [1,2]. The state of malignancy, benignity, and grade is determined from history, radiography, and histologic examination [3–5]. The recognition of high-grade malignancy is not difficult with typical findings on radiography, computed tomography (CT), and MRI. However, no sufficiently reliable method has been established, and the differentiation between benign and low-grade chondrogenic tumors can present diagnostic dilemma in terms of the diagnostic gold standard [2,6]. Moreover, malignant transformation of benign chondrogenic tumors could occur [7]. Therefore, making a diagnosis of malignant chondrogenic tumor is sometimes not easy with conventional imaging techniques [8,9]. 0143-3636 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Nuclear Medicine Communications 2015, 36:802–807 Keywords: bone tumor, cartilaginous, chondrogenic, chondrosarcoma, Tc-99m (V) DMSA scintigraphy Departments of aRadiology, bPathology, Okayama University Hospital, Departments of cMedical Materials for Musculoskeletal Reconstruction and d Orthopaedic Surgery, Okayama University Graduate School of Medicine, Okayama, Japan Correspondence to Takayoshi Shinya, PhD, MD, Department of Radiology, Okayama University Hospital, 2-5-1 Shikatacho, Kita-ku, Okayama-city, Okayama 700-8558, Japan Tel: + 81 862 357 313; fax: + 81 862 357 316; e-mail: [email protected] Received 9 January 2015 Revised 1 March 2015 Accepted 4 April 2015
Pentavalent Tc-99m (V) dimercaptosuccinic acid (DMSA) is a Tc-99m-labeled tumor-seeking agent [10] that has been reported to be very useful for the detection of soft tissue tumors, especially amyloid tumors [11], lowgrade sarcomas [12], head and neck tumors [13], and synovial giant cell tumors [14]. It is supposed to be related to blood flow and phosphate metabolism or pH, although the mechanism of accumulation of Tc-99m (V) DMSA needs further study [15]. In previous studies [16, 17], the visual extent of Tc-99m (V) DMSA uptake had potential for distinguishing malignant from benign chondrogenic bone tumors and an increase in Tc-99m (V) DMSA uptake indicated the possibility of malignant transformation of benign cartilage tumors. However, no previous report has assessed the relationship between tumor aggressiveness and extent of Tc-99m (V) DMSA uptake with a semiquantitative analysis, nor evaluated DOI: 10.1097/MNM.0000000000000328
Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.
Tc-99m (V) DMSA in chondrogenic tumor Shinya et al. 803
Summary of Tc-99m (V) DMSA scintigraphic data of 24 patients with chondrogenic bone tumors
the diagnostic capacity of Tc-99m (V) DMSA for differentiation between benignity and malignancy in chondrogenic bone tumors using a semiquantitative analysis.
Table 1
The aims of this prospective study were to determine whether a correlation existed between tumor aggressiveness and Tc-99m (V) DMSA uptake and to evaluate the value of Tc-99m (V) DMSA scintigraphy with the visual scoring system and semiquantitative analysis along with tumor-to-background contrast (TBC) for the differentiation of benign from malignant chondrogenic bone tumors, when the determination of benignity or malignancy was difficult from evaluation of history, symptoms, and conventional imaging results.
No./age/sex
Methods Study population
This prospective study was approved by the institutional review board and ethics committee and was conducted in a single institution. A written informed consent form was signed by all patients. We included patients older than 20 years with chondrogenic bone tumors, in which the determination of benignity or malignancy was difficult from evaluation of history, symptoms, and conventional imaging results. Between April 2006 and January 2012, 24 patients with chondrogenic bone tumors underwent Tc-99m (V) DMSA scintigraphy [10 male and 14 female; age (mean ± SD), 50.75 ± 11.61; range, 24–68 years]. All 24 patients were diagnosed with a chondrogenic bone tumor on conventional imaging and/or histopathological findings. Nine of 19 benign chondrogenic bone tumors were proven by histological examination (six enchondromas, two osteochondromas, and one periosteal chondroma), whereas 10 presumed enchondromas were followed up for a mean of 40 months (range 14–57 months) and diagnosed on clinical and radiological grounds to indeed be enchondromas. All five chondrosarcomas were proven histologically (n = 2 grade I chondrosarcomas; n = 3 grade II chondrosarcomas). Sixteen enchondromas were located in the humerus (n = 12), femur (n = 3), and fibula (n = 1). Two osteochondromas and one periosteal chondroma were located in the iliac bone (n = 1), tibia (n = 1), and intermediate phalanges (n = 1). Five chondrosarcomas were located in the coxal bone (n = 2), femur (n = 1), rib (n = 1), and fibula (n = 1). No significant difference was found between the size of the benign chondrogenic tumors (56.92 ± 29.96 mm in maximum diameter) and that of malignant chondrogenic tumors (79.20 ± 19.32 mm in maximum diameter) (P = 0.0594). No patients had received any therapy for chondrogenic bone tumors before Tc-99m (V) DMSA. A summary of Tc-99m (V) DMSA scintigraphic data is given in Table 1. All patients were examined with planar radiography and planar Tc-99m (V) DMSA scintigraphy.
Score of visual uptake
TBC
Humerus Humerus Humerus Femur Fibula Humerus Femur Humerus Humerus Femur Humerus Humerus Humerus Humerus Humerus Humerus Ilium Tibia Intermediate palanges
1 1 1 0 0 0 2 1 1 1 1 2 0 1 0 1 1 2 0
0.460 0.344 0.475 0.241 0.226 0.113 1.032 0.404 0.528 0.361 0.769 0.938 0.074 0.503 0.116 0.300 0.391 1.135 0.237
Femur
2
8.969
Coxal bone
2
0.823
Coxal bone
1
0.694
Rib
1
0.435
Fibula
2
1.873
Diagnosis
A. Benign bone tumors 1/64/F Enchondroma 2/44/F Enchondroma 3/47/F Enchondroma 4/48/F Enchondroma 5/63/M Enchondroma 6/54/F Enchondroma 7/60/M Enchondroma 8/42/F Enchondroma 9/42/F Enchondroma 10/65/M Enchondroma 11/55/F Enchondroma 12/27/M Enchondroma 13/47/M Enchondroma 14/45/F Enchondroma 15/58/M Enchondroma 16/68/F Enchondroma 17/61/F Osteochondroma 18/42/M Osteochondroma 19/55/F Periosteal chondroma B. Malignant bone tumors 20/24/F Chondrosarcoma, grade I 21/52/M Chondrosarcoma, grade I 22/43/F Chondrosarcoma, grade II 23/67/M Chondrosarcoma, grade II 24/63/M Chondrosarcoma, grade II
Site
DMSA, dimercaptosuccinic acid; F, female; M, male; TBC, tumor-to-background contrast.
Tc-99m (V) DMSA scintigraphy
A lyophilized kit of Tc-99m (V) DMSA (Daiichi Radioisotopes Laboratories Ltd, Tokyo, Japan), containing 1.36 mg of DMSA, 1.26 mg of NaHCO3, 0.11 mg of SnCl2·(2H2O), and 30 mg of glucose, was made available. Labeling was performed by adding 0.1 ml of 7% NaHCO3 with 2–3 ml of pertechnetate with the desired activity to the kit [10,14]. Purity of Tc-99m derivation was analyzed by thin-layer chromatography, and no free pertechnetate or other Tc-99m derivative was detected. An easily available method for preparation of Tc-99m (V) DMSA using a kit for Tc-99m (III) DMSA renal scintigraphy has been previously reported by Watkinson et al. [13]. All scans of Tc-99m (V) scintigraphy were taken 2 h after intravenous administration of 370 MBq (10 mCi) Tc-99m (V) DMSA using a conventional gamma camera system (GCA-7200A/DI; Toshiba, Tokyo, Japan). A low-energy, high-resolution, parallel-hole collimator was used, and images were acquired in a 512 × 512 matrix for 10 min. Image data analysis
The planar images of Tc-99m (V) DMSA scintigraphy were classified using a three-point scale for visual
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Nuclear Medicine Communications 2015, Vol 36 No 8
analysis: 0, radioactivity equal to that of the area adjacent to the tumor; 1, radioactivity slightly higher than that of the area adjacent to the tumor; and 2, radioactivity obviously higher than that of the area adjacent to the tumor. Scoring was carried out by two experienced nuclear medicine physicians who were unaware of the histologic results. The score was determined by consensus. Two equal-sized regions of interest (ROIs) were located on an image for the semiquantitative analysis (Fig. 1). The first ROI was placed on the uptake site of the tumor and the second ROI was placed on the contralateral side to assess background [18,19]. When Tc-99m (V) DMSA uptake was not detectable on the image, the ROI was placed on the area corresponding to that in images obtained from planar radiography, CT, and MRI. On planar images, the counts in the ROI on the uptake site of the tumor represented the total counts of the lesion and background. Attenuating the impact of the background activity, the TBC was calculated by dividing the difference in the average counts per pixel in the ROI for the uptake site of the tumor (T) and that in the ROI for the background (BG) by BG: that is, TBC = (T − BG)/BG. Statistical analysis
All statistical analyses were performed using IBM SPSS Statistics 22 for Windows (IBM Corp., Armonk, New York, USA). Spearman’s correlation coefficient was used to determine whether any correlation existed between tumor aggressiveness and the TBC in chondrogenic
tumors (benign chondrogenic tumor, grade I, II chondrosarcoma). Differences in TBC were analyzed with the Mann–Whitney U-test. Probability values less than 0.05 were taken to indicate significant differences. Receiver operating characteristic analysis was used to determine an appropriate TBC value for malignant chondrogenic bone tumors, and the related area under the curve was calculated.
Results From the visual analysis, five enchondromas and one periosteal chondroma were classified with an uptake score of 0; 10 benign chondrogenic tumors were classified with an uptake score of 1 (nine enchondromas and one osteochondroma); and two enchondromas and one osteochondroma were classified with an uptake score of 2. All five malignant chondrosarcomas showed positive uptake of Tc-99m (V) DMSA. Two of them were classified as having an uptake score of 1 and three were classified as having an uptake score of 2. From the visual analysis, the sensitivity and specificity of Tc-99m (V) DMSA scintigraphy in patients with chondrogenic bone tumors were 100.0 and 31.6%, respectively. Moreover, significant correlation was found between tumor aggressiveness and the TBC in chondrogenic tumors (ρ = 0.919, P < 0.01). Representative Tc-99m (V) DMSA images of scores 1 and 2 are demonstrated in Figs 1 and 2. From the semiquantitative analysis, the TBC value for benign chondrogenic tumors was determined to be 0.391 ± 0.071 (median ± SEM). The TBC for chondrosarcoma was
Fig. 1
(a)
(b)
∗∗
∗
(a) MRI (T2-weighted image) of an enchondroma in the left femur. (b) Planar image of Tc-99m (V) DMSA (anterior view). The enchondroma of the left femur was classified to an uptake score of 1. The first ROI (*) was placed on the outer border of the lesion and the second ROI (**) was placed on the contralateral side, which served as the control. DMSA, dimercaptosuccinic acid; ROI, region of interest.
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Tc-99m (V) DMSA in chondrogenic tumor Shinya et al. 805
Fig. 2
(a) MRI (T2-weighted image) of a grade I chondrosarcoma of the right femur. (b) Planar image of Tc-99m (V) DMSA (anterior view). The grade I chondrosarcoma of the right femur was classified to an uptake score of 2.
Fig. 4
Fig. 3
1.0
P = 0.019
10.000000 ∗ 8.000000
0.8 TBC
6.000000 0.6 TPR
4.000000 2.000000
0.4 0.000000 Chondrosarcoma
Benign chondrogenic tumor
A correlation between the tumor-to-background contrast (TBC) for benign and malignant chondrogenic tumors. The TBC in malignant chondrogenic tumor (chondrosarcoma) was significantly higher than the TBC in benign chondrogenic tumor (P = 0.019). TBCs are 0.391 ± 0.071 for benign chondrogenic tumor and 0.823 ± 1.621 for chondrosarcoma. *Represents an outlier.
0.823 ± 1.621 (median ± SEM). A significant difference was identified in TBC between benign and malignant chondrogenic tumors (P = 0.019, Fig. 3). The receiver operating characteristic curve analysis showed that the appropriate cutoff value of TBC for identifying malignant chondrogenic tumor was 0.611, with 80.0% sensitivity and 78.9% specificity (area under
0.2
0.0 0.0
0.2
0.4
0.6
0.8
1.0
FPR Receiver operating characteristic (ROC) curve shows the performance of tumor-to-background contrast (TBC) for malignant chondrogenic bone tumor. ROC curves were plotted from pairs of true-positive rate (TPR) and false-positive rate (FPR) corresponding to the cutoff values of TBC for diagnosis of malignant chondrogenic tumor.
the curve = 0.842, Fig. 4). At the same cutoff value, the negative predictive value (NPV) was 93.8% and the positive predictive value was 50.0%.
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Nuclear Medicine Communications 2015, Vol 36 No 8
Discussion The present study assessed the usefulness of both visual analysis and semiquantitative analysis of Tc-99m (V) DMSA scintigraphy in patients with chondrogenic bone tumors in which the determination of benignity or malignancy was difficult from evaluation of history, symptoms, and conventional imaging results. All five chondrosarcomas and 13 of 19 benign chondrogenic tumors had positive DMSA (V) scans. The discrimination of the state of benignity and malignancy is difficult only with the visual analysis of Tc-99m (V) DMSA uptake. However, the TBC for chondrosarcomas was significantly higher than the TBC for benign chondrogenic tumors, and the cutoff value of TBC was set for the diagnosis of chondrosarcoma at 0.611, with 80.0% sensitivity, 78.9% specificity, 50.0% positive predictive value, and 93.8% NPV. The diagnoses of malignant chondrogenic bone tumors or detection of the malignant transformation of benign chondrogenic tumors is not always easy with conventional radiologic modalities such as radiography, CT, and MRI, which provide excellent morphologic delineation and localization of bone tumors. Functional nuclear scans reflect the metabolic activity of tumors and may provide important information regarding the biologic behavior. Tl-201 uptake was related to tumor grade in chondrosarcoma; that is, increased Tl-201 uptake was seen for grade II–III chondrosarcoma, but no grade I tumor had Tl-201 uptake in previous reports [17,20]. Therefore, Tl201 cannot resolve the problem of differentiating between benign chondrogenic tumor and grade I chondrosarcoma. The first finding of our study was that all five chondrosarcomas and 13 of 19 benign chondrogenic tumors had positive DMSA (V) scans and six benign chondrogenic bone tumors had negative DMSA (V) scans in this population, in which the determination of the state of benignity and malignancy was difficult when compared with conventional diagnostic methods. The finding is similar to that in previous publications covering the usefulness of Tc-99m (V) DMSA [16,17], in which all 46 chondrosarcomas and 34 of 74 benign chondrogenic tumors had positive DMSA (V) scans. Moreover, in those reports, all tumors without Tc-99m (V) DMSA uptake were benign chondrogenic tumors [16,17]. Those findings confirmed that all chondrosarcomas were DMSA (V) positive and all chondrogenic tumors without Tc-99m (V) DMSA uptake were benign. However, visual analysis alone revealed false-positive DMSA (V) scans in benign chondrogenic tumors and the differentiation between benignity and malignancy remained a diagnostic dilemma in patients with DMSA (V)-positive tumors. The visual evaluation of Tc-99m (V) DMSA uptake is thus limited in usefulness for chondrogenic tumors.
The second important finding of our study was that a significant correlation was found between the TBC and tumor aggressiveness. Malignant chondrogenic tumors appeared to have a higher vascularity and higher metabolic rate compared with benign tumors, and increased uptake of Tc-99m (V) DMSA has often been found in rapidly growing and/or malignant-transformed tumors [16]. These findings suggest that Tc-99m (V) DMSA scintigraphy might have potential to predict biologic aggressiveness in chondrogenic tumors and to point out the malignant transformation of benign chondrogenic tumors on follow-up Tc-99m (V) DMSA scintigraphy. The third major finding of our study was that the TBC for chondrosarcoma was significantly higher than that for benign chondrogenic tumor. Moreover, we could set the cutoff value of TBC for the diagnosis of malignant chondrogenic tumor at 0.611 and achieve a relatively high specificity and high NPV. These findings suggest that TBC might aid in differentiating between benign and malignant chondrogenic tumors with a noninvasive method, especially when there are subtleties in differential diagnosis between benign and low-grade malignant states from conventional imaging modalities as in our study population. The results of this study reveal that DMSA (V)-negative tumor can be diagnostic of a benign chondrogenic bone tumor on the basis of visual evaluation with negative uptake, and the calculation of TBC can be a useful diagnostic method for differentiating between benign and malignant chondrogenic bone tumors in patients with DMSA-positive tumor. The low TBC for the chondrogenic bone tumor might indicate a high likelihood of being a benign tumor and a relatively indolent tumor. These could be followed closely without invasive biopsy and without treatment. This conjecture is supported by the significant correlation between tumor aggressiveness and the TBC and by the relatively high specificity and the high NPV for malignant chondrogenic bone tumors. Our study has several limitations. First, the study population comprised a small number of patients who had been selected from among the cases in which the determination of the state of benignity or malignancy was difficult from general diagnostic techniques. Examination of a larger number of consecutive patients in a prospective study would be useful for further investigation of the appropriate TBC in Tc-99m (V) DMSA for assessing the state of malignancy or benignity and the tumor aggressiveness in patients with chondrogenic tumor according to the visual scoring system. Second, there was absence of histopathological confirmation by biopsy or surgery in several patients with enchondroma. However, despite these limitations, our results suggest that Tc-99m (V) DMSA scintigraphy has potential to predict biologic aggressiveness before
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Tc-99m (V) DMSA in chondrogenic tumor Shinya et al. 807
surgery in patients with chondrogenic bone tumor, in which the determination of the state of benignity or malignancy is difficult from general diagnostic techniques, and to distinguish benign chondrogenic tumor from chondrosarcoma.
9 10
Conclusion
11
The findings of the present study show that there is an increase in Tc-99m (V) DMSA uptake for malignant chondrogenic tumors compared with benign chondrogenic tumors. The use of a Tc-99m (V) DMSA scan could be a marker for increased biologic activity with semiquantitative analysis and could have potential to improve the radiological diagnostic methods for chondrogenic tumors.
7 8
12
13
14
Acknowledgements Conflicts of interest
15
This work was supported by Daiichi Radioisotopes Laboratories Ltd, Tokyo, Japan.
16
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