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DOI:10.2214/AJR.06.0292
AJR 2007; 188:572-578
© American Roentgen Ray Society

Original Research

The Cause and Clinical Significance of Central Tumor Photopenia on Thallium Scintigraphy of Pediatric Osteosarcoma of the Extremity

M. Beth McCarville1, Ellen H. Barton1,2, Jason R. Cameron1,3, Xiaoping Xiong4, Najat C. Daw5, Sue C. Kaste1, Shenjie Wu4, John O. Glass1 and Wilburn E. Reddick1

1 Department of Radiological Sciences, Division of Diagnostic Imaging, St. Jude Children's Research Hospital, 332 N Lauderdale St., Memphis, TN 38105-2974.
2 Present address: Methodist University Hospital, Memphis, TN.
3 Present address: Abercrombie Radiological Consultants, Knoxville, TN.
4 Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN.
5 Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN

Received February 27, 2006; accepted after revision May 30, 2006.

 
Address correspondence to M. B. McCarville (Beth.McCarville{at}stjude.org).


Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
OBJECTIVE. The objectives of our study were to determine whether central tumor photopenia on thallium-201 (201Tl) scintigraphy of primary osteosarcoma results from central tumor necrosis or dense central tumor ossification and to determine the relation of this finding to tumor response to chemotherapy and to patient survival.

MATERIALS AND METHODS. After the institutional review board approved our study and waived the need for patient or parental consent, two radiologists independently reviewed 201Tl scans, conventional radiographs, and MR images of 57 patients obtained at diagnosis of extremity primary nonmetastatic osteosarcoma to detect the presence of central tumor photopenia on 201Tl scintigraphy and estimate outer tumor ossification versus inner tumor ossification and enhancement. The dynamic enhanced MRI parameters dynamic vector magnitude (DVM) and kep (measure of the exchange rate between plasma and extracellular fluid space) were compared for outer tumor versus inner tumor, and the relation among 201Tl scintigraphy, conventional radiography, MRI, and the dynamic enhanced MRI parameters was analyzed. We examined whether central tumor photopenia on 201Tl imaging was related to histologic response or to patient survival.

RESULTS. Thirty-three patients (58%) had central tumor photopenia on 201Tl imaging that was not associated with central tumor ossification (p = 0.8) or with the difference between outer tumor and inner tumor contrast enhancement (p = 0.4). Central tumor photopenia on 201Tl scintigraphy was significantly associated with an increasing difference between outer tumor DVM and inner tumor DVM (i.e., outer tumor DVM minus inner tumor DVM) (p = 0.05), an increasing difference between outer tumor kep and inner tumor kep (i.e., outer kep minus inner kep) (p = 0.01), and an increasing outer kep-inner kep ratio (p = 0.02). We found no relation between central tumor photopenia and histologic response (p ≥ 0.2). Older patients (age, ≥ 13 years) with central tumor photopenia were least likely to survive, whereas younger patients (age, < 13 years) without central tumor photopenia were most likely to survive (p = 0.07).

CONCLUSION. Central tumor photopenia on 201Tl scintigraphy of primary osteosarcoma is unlikely to reflect central ossification but may be due to central necrosis reflected by higher outer tumor DVM and kep than inner tumor DVM and kep and may be negatively associated with survival in older patients. Prospective studies are needed to determine the value of this information in planning treatment.

Keywords: dynamic enhanced MRI • musculoskeletal system • oncologic imaging • osteosarcoma • pediatric imaging • scintigraphy • thallium scintigraphy


Introduction
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 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Osteosarcoma is the most common primary malignant bone tumor in children and adolescents in the United States [1]. The standard treatment for nonmetastatic osteosarcoma is neoadjuvant chemotherapy followed by surgical resection of the primary tumor and adjuvant chemotherapy. Some investigations have found a greater probability of event-free survival among patients whose resected tumors are more than 90% necrotic [2-5]. Factors that predict the histologic response of tumors to chemotherapy may help to distinguish candidates for limb-sparing surgery versus amputation or early resection and to predict the therapeutic response of unresectable tumors, thus allowing tailored clinical management [1].

Thallium-201 (201Tl) is a radionuclide that is thought to be a potassium analog; it probably enters tumor cells via the adenosine triphosphatase system, which extrudes sodium in exchange for potassium [6-9]. The avidity of osteosarcoma for 201Tl probably reflects the degree of cellular activity and, to a lesser extent, tumor perfusion [10]. A previous study found central tumor photopenia on 201Tl scintigraphy (Fig. 1) in 52% of primary nonmetastatic osteosarcomas at diagnosis, and patients who had this finding at diagnosis or during neoadjuvant therapy had a lower 3-year event-free survival estimate than did others [11]. Therefore, central photopenia of primary osteosarcoma on 201Tl imaging may predict survival or tumor response to chemotherapy and may be useful in individualizing clinical management.


Figure 1
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  		Fig. 1 —Lateral projection image obtained during thallium-201 (201Tl) scintigraphy of distal femoral osteosarcoma shows central photopenia, defined as photopenic center surrounded by 201Tl activity.

 


Figure 2
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  		Fig. 2 —Anteroposterior radiograph shows dense central tumor ossification in proximal humeral osteosarcoma of 13-year-old boy; this finding is postulated cause of central photopenia on thallium-201 scintigraphy.

 
We postulated that central tumor photopenia on 201Tl imaging reflects reduced blood flow in the center of the tumor caused by either central tumor necrosis or dense central tumor ossification (Fig. 2). To test these possibilities, we compared the findings of 201Tl scintigraphy with those of conventional radiography, conventional contrast-enhanced MRI, and dynamic contrast-enhanced MRI. On the basis of previous reports, we investigated the dynamic enhanced MRI parameters dynamic vector magnitude (DVM) and kep as markers of central tumor viability [12-14]. DVM is a measure of both the initial rate of contrast uptake and the maximum contrast enhancement. The kep is a measure of the exchange rate of contrast agent between plasma and extracellular fluid space and is a function of the tumor's microvascular density [13, 14]. To determine the clinical significance of central tumor photopenia on 201Tl imaging, we investigated the relation of this finding at diagnosis to the histologic response of the primary tumor to preoperative chemotherapy and to patient survival.


Materials and Methods
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 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Patient Selection and Clinical Information
After the institutional review board approved our study and waived the need for parental and patient consent and in compliance with the Health Insurance Portability and Accountability Act of 1996, the solid tumor database of our institution was searched for patients who had received a diagnosis of nonmetastatic osteosarcoma of the extremity from October 1991 through October 2002. Patients who had undergone conventional radiography, 201Tl scintigraphy, conventional contrast-enhanced MRI, and dynamic enhanced MRI of the primary tumor within a single 3-week period at the time of diagnosis were included in this study. The patients were treated as part of two consecutive trials, OS-91 and OS-99, for newly diagnosed osteosarcoma. Patients treated on the OS-91 trial were previously evaluated in a study that suggested decreased survival among patients whose primary osteosarcoma exhibited central photopenia on 201Tl scintigraphy at the time of diagnosis [11].

Treatment consisted of neoadjuvant chemotherapy followed by definitive surgery and adjuvant chemotherapy. The treatment for patients participating in the OS-91 trial included three courses of neoadjuvant carboplatin and ifosfamide, and adjuvant chemotherapy comprised high-dose metho-trexate, doxorubicin, and additional carboplatin and ifosfamide. The treatment for patients participating in the OS-99 trial included three courses of carboplatin and ifosfamide and one course of doxorubicin in the neoadjuvant phase and the same agents in the adjuvant phase. Each patient's demographic information, treatment protocol, Rosen grade of primary tumor response to preoperative chemotherapy, and outcome were recorded by a departmental data manager.

Patient Characteristics
Twenty-seven female and 30 male patients met the inclusion criteria. The mean age at diagnosis was 12.7 years (range, 3.1-18.3 years; median, 13.1 years). Thirty-five patients were treated as part of the OS-91 trial and 22 as part of the OS-99 trial.

Image Acquisition
Thallium-201 scintigraphy was performed by injecting 201Tl IV in doses adjusted for body surface area, up to a maximum of 4 mCi. Starting 15 minutes after injection, planar images of the primary tumor in the anteroposterior and lateral projections were obtained until 600,000 counts were acquired. Patients were imaged using one of the following cameras: October 1991 through 1993, a Star Cam single-head camera (GE Healthcare); October 1991 through 2000, an Orbiter single-head camera (Siemens Medical Solutions); February 1994 through October 2002, a Multispec dual-head camera (Siemens); and January 2000 through October 2002, an E-cam Duet dual-head camera (Siemens).

Dynamic enhanced MRI was performed by acquiring sequential 10-mm-thick coronal T1-weighted images (TR/TE, 23/10) of the primary tumor in the plane that showed the largest tumor dimensions. One image was acquired every 12 seconds over approximately 6 minutes. An IV bolus injection of contrast agent (2 mL/10 kg of body weight; maximum dose, 20 mL), followed by a 20-mL flush of normal saline, was given 1 minute after the start of imaging. From October 1991 through 1993, we used the low-molecular-weight contrast agent gadopentetate dimeglumine (Magnevist, Berlex Laboratories) and, after 1993, the low-molecular-weight agent gadodiamide (Omniscan, Amersham Health). Immediately after dynamic enhanced MRI, conventional contrast-enhanced fat-suppressed axial T1-weighted images (TR/TE, 730/13) of the entire tumor were acquired. All MRI examinations were performed on one of four 1.5-T MR scanners, all of which were manufactured by Siemens: a Helicon MR scanner was used from October 1991 to January 2000; a Magnetom 4000, from September 1992 to January 1997; a Vision, from January 1997 through October 2002; and a Symphony, from January 2000 through October 2002.

Image Review
All 201Tl scans, conventional radiographs, and contrast-enhanced MR images were independently retrospectively reviewed by two third-year radiology residents who were trained for the purposes of this study by the principal investigator. The reviewers were blinded to patient history and outcome and to dynamic enhanced MRI results, but they were not blinded to conventional contrast-enhanced MRI or radiography findings. They assessed 201Tl scans for the presence of central tumor photopenia—that is, a tumor with a photopenic center surrounded by 201Tl activity (Fig. 1). To simulate the spatial configuration of this finding for comparison on conventional radiographs and contrast-enhanced MR images, reviewers divided the tumors into inner and outer halves. The reviewers were aware that when tumors are divided in this manner the inner half subjectively appears larger than the outer half even though the areas of each half are approximately equal (Figs. 3A, 3B, 3C, 3D and 4A, 4B, 4C).


Figure 3
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  		Fig. 3A —12-year-old boy with osteosarcoma of distal tibia. Anteroposterior radiograph shows primary tumor.

 

Figure 4
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  		Fig. 3B —12-year-old boy with osteosarcoma of distal tibia. Two reviewers visually divided each tumor into inner half and outer half as indicated by regions of interest (ROIs) (circled areas) shown. Each reviewer estimated percentage of ossification in inner and outer halves of tumor. Discrepancies of more than 10% between reviewers were resolved by principal investigator.

 

Figure 5
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  		Fig. 3C —12-year-old boy with osteosarcoma of distal tibia. Axial conventional contrast-enhanced T1-weighted MR image obtained through primary tumor.

 

Figure 6
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  		Fig. 3D —12-year-old boy with osteosarcoma of distal tibia. Two reviewers visually divided each tumor into inner and outer halves as indicated by ROIs (circled areas). Each reviewer estimated percent enhancement within each ROI. Discrepancies of more than 10% between reviewers were resolved by principal investigator.

 

Figure 7
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  		Fig. 4A —13-year-old girl with distal femoral osteosarcoma. Baseline coronal T1-weighted image obtained before contrast administration during dynamic contrast-enhanced MRI shows unenhanced primary tumor.

 

Figure 8
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  		Fig. 4B —13-year-old girl with distal femoral osteosarcoma. Coronal dynamic contrast-enhanced MR image obtained at peak contrast enhancement shows tumor.

 

Figure 9
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  		Fig. 4C —13-year-old girl with distal femoral osteosarcoma. Image shown in B with regions of interest (circled areas) outlining inner and outer halves of tumor. Tumor periphery was outlined by radiologist. Computer software then divided tumor area into inner and outer halves, and dynamic vector magnitude (measure of both initial rate of contrast uptake and maximum contrast enhancement) and kep (measure of exchange rate of contrast agent between plasma and extracellular fluid space) for these regions were determined.

 

The percentage of ossification in only the outer half and in only the inner half of the tumor was estimated on conventional radiographs (Fig. 3A, 3B, 3C, 3D). The pattern of enhancement was assessed on a single axial contrast-enhanced MR image obtained through the tumor's largest diameter. The pattern was defined as peripheral if more than 50% of the total tumor enhancement was in the outer half of the tumor, central if more than 50% of total tumor enhancement was in the central half, and mixed if enhancement was not primarily either peripheral or central. The estimated percentage of enhancement in only the outer half and in only the inner half of the tumor was also assessed (Fig. 4A, 4B, 4C). Discrepancies or differences of more than 10% in these interpretations were resolved by the principal investigator before statistical analysis.

Dynamic enhanced MRI images were evaluated using in-house software. A nonstudy radiologist used an interactive display to outline a region of interest (ROI) defined by the margins of the tumor. To simulate central tumor photopenia on 201Tl imaging, the ROI was divided by the computer software into inner and outer halves (Fig. 5), and the DVM and kep of each half were determined by the method described by Reddick et al. [13].


Figure 10
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  		Fig. 5 —Graph shows Kaplan-Meier survival estimates of young (age, < 13 years) patients with central tumor photopenia on thallium-201 scintigraphy (thin line, n = 17) compared with that of young patients without central tumor photopenia (thick line, n =10).

 
Statistical Analysis
To investigate the cause of central tumor photopenia on 201Tl scintigraphy of primary osteosarcoma, we compared the frequency of this finding with the magnitude of the difference between outer tumor ossification and inner tumor ossification on conventional radiography, measured as outer minus inner percent tumor ossification; the difference between outer tumor enhancement and inner tumor enhancement on MRI, measured as outer minus inner percent tumor contrast enhancement; the difference between outer tumor DVM and kep and inner tumor DVM and kep, measured as outer minus inner DVM or kep, respectively; and the ratios of the outer-inner DVM and kep.

The ratios and the differences between outer and inner values were continuous variables. The points defining the 25th, 33rd, 50th, 67th, and 75th percentiles of their distributions were identified. For each difference or ratio, a cutoff point that maximized the frequency of central tumor photopenia on 201Tl scintigraphy with the variable was identified. The association of MRI or dynamic enhanced MRI cutoff points with central photopenia was tested by the two-tailed Fisher's exact test. Interobserver agreement in identifying 201Tl central photopenia was estimated by determining the percentage of concordant diagnoses of the finding and the SE. The Cochran-Armitage trend test was used to test the relationship of central photopenia to the magnitude of the difference between peripheral and central tumor ossification, enhancement, DVM, and kep and the magnitude of the ratios of peripheral and central tumor DVM and kep.

We investigated whether occurrence of central photopenia was associated with the Rosen grade of tumor response or with patient survival. Tumors were categorized as nonresponders (Rosen grade I or II, < 90% tumor necrosis) or responders (Rosen grade III or IV, ≥ 90% tumor necrosis). Survival was defined as the interval between the date of diagnosis and the date of last follow-up or death due to any cause. Survival distributions were estimated by the method of Kaplan and Meier and were compared using the log-rank test [15] and the proportional hazards model. The association of central photopenia with the survival estimate was assessed by using the log-rank test with a proportional hazards survival regression model. The association of central photopenia with histologic response (vs nonresponse) and with survival was assessed with one-sided and two-sided Fisher's exact tests. All analyses were conducted using a statistical software package (SAS/STAT, SAS Institute). The p values that were ≤ 0.05 were considered significant.


Results
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 Materials and Methods
 Results
Discussion
 References
 
Imaging Findings
Central tumor photopenia on 201Tl scintigraphy was identified in 33 (58%) of 57 patients at diagnosis, with a 91.2% (52/57; SE = 3.7%) rate of interobserver agreement. Thirty-four tumors (60%) showed a peripheral enhancement pattern, 23 (40%) had a mixed pattern, and none had a central enhancement pattern. Table 1 shows the cutoff points for the five percentiles for each imaging variable.


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  		TABLE 1: Cutoff Points for the Percentiles of the Outer Versus Inner Tumor Parameters of Primary Osteosarcoma on Conventional Radiography, MRI, and Dynamic Enhanced MRI

 

Central photopenia was not found to be significantly related to central tumor ossification on conventional radiographs at any of these cut points (all, p ≥ 0.3). There was also no significant relation between central photopenia and the difference between outer and inner contrast enhancement on conventional MRI at any cutoff point (all, p ≥ 0.13).

Central photopenia was significantly related to the difference between outer tumor DVM and inner tumor DVM and kep and to outer tumor-inner tumor DVM and kep ratios at several points, most significantly at a DVM difference of 0.78 (p = 0.02), a DVM ratio of 1.25 (p = 0.004), a kep difference of 0.069 (p = 0.01), and a kep ratio of 1.06 (p = 0.01). These points best distinguished the tumors that had central photopenia from those that did not. The Cochran-Armitage trend test showed no significant association between central photopenia and increased central tumor ossification (p = 0.8) or peripheral enhancement (p = 0.4) on MRI (Table 2). There was a significant association between central photopenia and an increasing difference between outer tumor DVM and inner tumor DVM (p = 0.05), an increasing difference between outer tumor kep and inner tumor kep (p = 0.01), and an increasing outer tumor kep-inner tumor kep ratio (p = 0.02) (Table 2).


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  		TABLE 2: Cochran-Armitage Trend Test Assessment of the Relationship Between Central Tumor Photopenia on Thallium-201 Scintigraphy and Percentile Groups Shown in Table 1

 

Response and Survival Analysis
The median duration of follow-up was 48 months (range, 12-136 months). No relation was observed between histologic tumor response (vs nonresponse) and patient survival (p = 0.4). The histologic response was not found to be associated with central tumor photopenia on 201Tl scintigraphy at diagnosis by either the two-sided (p = 0.4) or the one-sided (p = 0.2) Fisher's exact test. The first proportional hazards survival regression model assessed the relation between central photopenia and patient survival. Patients whose primary tumor exhibited central photopenia (n =33) had a slightly smaller probability of survival than did the others (n =24) (p = 0.09). The second survival regression model included both the presence of central tumor photopenia and patient age as a continuous variable. In this model, older patients with central tumor photopenia were least likely to survive, whereas younger patients without it were most likely to survive (p = 0.07). To illustrate this continuous relationship, Kaplan-Meier estimates of survival were obtained for four subgroups (Figs. 5 and 6) by stratifying patients according to age (older or younger than the median age of 13 years) and the presence of central tumor photopenia (yes vs no).


Figure 11
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  		Fig. 6 —Graph shows Kaplan-Meier survival estimates of older patients (age, ≥ 13 years) with central tumor photopenia on thallium-201 scintigraphy (thin line, n = 16) compared with that of older patients without central tumor photopenia (thick line, n =14).

 


Discussion
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Our findings suggest that central tumor photopenia on 201Tl scintigraphy of primary osteosarcoma is not caused by central ossification but is likely to reflect central necrosis. Thallium-201 accumulates mainly in viable tumor and is barely detectable in necrotic tumor tissue [15]. Further, 201Tl avidity is greater in highly vascular, aggressive tumors than in relatively indolent tumors [6]. It is possible that central photopenia on 201Tl imaging of primary osteosarcoma reflects central necrosis caused by tumor aggressiveness—that is, by tumor growth sufficiently rapid to outstrip the blood supply. If so, tumors exhibiting central photopenia on 201Tl imaging at diagnosis may also be less responsive to preoperative chemotherapy. Although we did not observe an association between central photopenia and histologic tumor response, neither did we find a significant relation between histologic response and survival. An important finding is that patients whose tumors exhibited central photopenia on 201Tl imaging were less likely to survive than the others. Therefore, central tumor photopenia at diagnosis may be a better predictor of survival than the histologic response of the tumor to neoadjuvant chemotherapy.

Although our findings are contrary to those of other investigations [2-5], they are consistent with earlier reports from our institution [11, 16]. The usefulness of histologic response as a predictor of survival is limited by its determination at a time when tumor necrosis is likely to reflect the combined effects of tumor aggressiveness and neoadjuvant chemotherapy. Baseline assessment of tumor aggressiveness using thallium scintigraphy or dynamic enhanced MRI may provide a more accurate predictor of outcome than does histologic response. Further, we found that older patients whose tumors had central photopenia on 201Tl imaging at diagnosis had a poorer chance of survival than did the other patients. This result agrees with that of a recent large study by Mankin and colleagues [17] showing that, in general, older patients (including adults) with osteosarcoma have a poorer chance of survival than younger patients.

We investigated whether central tumor photopenia on 201Tl scintigraphy is caused by central tumor necrosis by examining the relation of this sign both to a qualitative assessment of inner tumor-versus-outer tumor MRI contrast enhancement and to the quantitative dynamic enhanced MRI parameters DVM and kep. Primary osteosarcomas that are centrally necrotic would be expected to lack central contrast enhancement and to have higher measures of DVM and kep at the tumor periphery than at the center. As we anticipated, we found that central tumor photopenia was significantly related to greater peripheral than central DVM and kep. Interestingly, we found no relation between central photopenia and the qualitative assessment of tumor enhancement on contrast-enhanced MRI. These findings suggest that dynamic enhanced MRI may be a better method than conventional MRI to estimate tumor viability.

The clinical utility of the finding of central tumor photopenia on 201Tl imaging is limited by the subjective nature of its definition and detection. However, we found a high rate of inter-observer agreement (91.2% [52/57]; SE = 3.7%) in identifying this finding, as did the authors of a previous study [11]. To reduce potential bias in our study, we used the consensus opinion (resolved by a third reviewer when necessary) to indicate the presence of central tumor photopenia. Because the study was performed retrospectively, we were not able to quantify the 201Tl activity in the inner and outer halves of the primary tumor; such information might have provided a more accurate assessment of relative tumor viability. Although the precise relation of the qualitative and quantitative assessments of relative 201Tl avidity is unknown, the significant association between the finding of central photopenia and dynamic enhanced MRI parameters suggests that this finding is a valuable indicator of tumor viability.

In conclusion, central tumor photopenia on 201Tl scintigraphy of primary osteosarcoma is not associated with central tumor ossification but is likely to be associated with central necrosis. Central tumor photopenia was associated with a poor outcome and may be an indication of tumor aggressiveness. Because central photopenia on 201Tl scintigraphy at the time of diagnosis is significantly related to dynamic enhanced MRI parameters and is substantially related to patient outcome, centers that cannot perform dynamic enhanced MRI may benefit from 201Tl imaging of the primary tumor. Although it is simpler to perform and interpret 201Tl scintigraphy than dynamic enhanced MRI, the inherent risk of radiation exposure should be weighed against the potential benefit of the former. We are currently investigating the risk-benefit ratio of 201Tl scintigraphy in pediatric patients with osteosarcoma. Further prospective clinical trials will be useful in validating our findings and in defining the role of these imaging techniques in tailoring the management of osteosarcoma.


Acknowledgments
 
We thank Eric Romano for assistance with image review and data collection.


References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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