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Departments of Pathology [A. L. F.] and Biostatistics [R. H. L.], Emory University Medical Center, Atlanta, Georgia 30322, and Departments of Pathology [J. T. S.], Orthopedic Surgery [E. U. C.], and Nuclear Medicine [J. F. E.], University of Washington Medical Center, Seattle, Washington 98185
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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FDG-PET2 is increasingly used for the detection and management of soft tissue and bone sarcoma. FDG-PET has been shown to be useful for detection of local recurrence (1) and metastatic disease in patients with sarcoma (2) and has been used to evaluate response to neoadjuvant chemotherapy in sarcoma patients (3 , 4) . Several small studies have also shown significant differences between tumor FDG-PET values in benign versus high-grade malignant soft tissue tumors and between low- and high-grade soft tissue sarcomas (5, 6, 7, 8, 9) . A similar relationship has not been shown for bone tumors (10) . More recently, we have shown in a large heterogeneous series of adult bone and soft tissue tumors that both the MRFDG and the DUR increase with increasing histopathological grade (11) .
However, despite the increasing use of FDG-PET in sarcoma management, no study to date has evaluated whether there are pathological features other than tumor grade that are related to an individual patient’s tumor FDG-PET scan values. Although traditional histopathological grading remains a cornerstone of sarcoma management (12) , some have questioned whether a single grading system is necessarily applicable to all sarcomas (13) . For this reason there has been great interest in whether measures of proliferative activity, such as flow cytometrically determined SPF or immunohistochemical detection of Ki-67 protein, and measures of cell cycle control integrity, such as p53, p21, and mdm2 expression, are useful adjuncts for sarcoma prognostication and patient management (14) . No study to date has evaluated the relationship between FDG-PET scanning in sarcomas and these proliferative and cell cycle variables.
Because FDG-PET is essentially a measure of metabolic activity within a tumor, we hypothesized that factors that might influence FDG-PET values would include not only the tumor grade, but also the level of cellularity, the rate of cell proliferation, and the integrity of the normal mechanisms of cell cycle control. We further hypothesized that if a strong association was present between FDG-PET values and these pathological variables, then PET could serve as a valuable tool in patient management by guiding biopsy to the most biologically relevant areas and possibly by alerting the pathologist and clinician to under- or overgrading of sarcomas. To test this hypothesis, we evaluated 89 adult bone and soft tissue tumors that had undergone FDG-PET, biopsy and/or resection, and complete pathological evaluation at the University of Washington Medical Center. For each tumor, we examined the histological variables of tumor grade and cellularity, cell proliferation as measured by mitotic figure counts, immunohistochemical staining for the Ki-67 proliferative marker, flow cytometry, and cell cycle control integrity, as measured by immunohistochemical staining for p53, mdm2, and p21WAF1. For this study, we chose to look at SUV, which was derived directly from summed tomographic images. SUV results are tightly correlated with MRFDG (15) .
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PATIENTS AND METHODS |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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PET Scanning.
All patients underwent PET imaging with FDG in the week before
initiation of neoadjuvant chemotherapy or resection. Detailed methods
for PET imaging of sarcoma patients are published elsewhere
(11)
. Briefly, patients fasted for 
2 h before the
procedure. They then signed informed consent for the procedure and
received 7–10 mCi of FDG i.v. over 2 min. After a 45-min
equilibration period during which the patient was at rest, attenuation
corrected emission images over the tumor were acquired on a General
Electric Advance PET scanner. Typically, the tumor extent was captured
in two adjoining 15-cm fields of view. Reconstructed attenuation
corrected images were viewed in the transaxial, coronal, and sagittal
planes. On the transaxial planes, hand drawn regions of interest were
placed over the tumor for calculation of the SUV. Regions of interest
were drawn to follow the contours of the elevated FDG activity as
compared to normal tissue, contralateral to the tumor site. The SUV is
generated by the tomograph software as the ratio of activity in the
tumor:normal tissue corrected by the amount of radioactivity infused,
and the patient weight. The highest SUV for the tumor region, rather
than the average SUV, was recorded for analysis in this study. This is
both because we expected the most metabolically active regions of the
tumor to drive the overall behavior and because the averaging of areas
of cystic change and necrosis (areas with very low SUV) would be
expected to result in falsely low overall values for the tumor.
Pathological Evaluation.
All sarcomas were graded as part of the routine work-up of the biopsies
or resection specimens, and the pathologists were unaware of the PET
findings. The soft tissue tumors were graded according to the National
Cancer Institute grading system (18)
. In brief, under this
system, well-differentiated sclerosing and lipocytic liposarcoma, and
myxoid liposarcomas without a "round-cell’ component are regarded as
grade I tumors. Rare smooth muscle tumors and myxoid fibrosarcomas
(myxofibrosarcoma or myxoid malignant fibrous histiocytoma) with only
minimal atypism may also be regarded as grade I under this system
(24)
. Almost all other soft tissue sarcomas are regarded
as being either grade II (<15% necrotic) or grade III (15%
necrotic). The National Cancer Institute system does not specifically
address Ewing’s sarcoma and primitive neuroectodermal tumor; at our
institutions, these are regarded as grade III sarcomas. Osteo- and
chondrosarcomas were graded in accordance with the grading system of
Unni and Dahlin (25)
, with the modification that grades
III and IV were combined into a single grade III.
For sarcomas that received neoadjuvant chemotherapy before definitive resection, tumor grading was based on the initial needle core biopsy examination. All other tumors were graded after evaluation of multiple sections from various regions of the resected specimen, and a single grade was given, reflecting the highest-grade areas. In difficult cases, intradepartmental consultation was used to arrive at a final grade.
Tumor cellularity was estimated as "high", "moderate", or "low" by two observers (A. L. F. and J. T. S.) independently. Discrepancies in this evaluation were resolved by re-evaluation of the case at a dual headed microscope. Mitotic figure counts were performed by the same two observers using the dual headed microscope; twenty 400x microscopic fields were evaluated, with both observers agreeing on all mitotic figures in all fields. These results were expressed as mitotic figures per 10 high-powered fields.
Immunohistochemistry.
Immunohistochemical studies for Ki-67 (MIB-1, 1:50; AMAC), p53 (D07,
1:1000; Dako), mdm2 (IF2, 1:100; Calbiochem), and
p21WAF1 (EA10, 1:200; Calbiochem) were performed
using 4–6-µm deparaffinized sections. The sections underwent
heat-induced epitope retrieval using a microwave oven for 5 min in a
0.01 M citrate buffer (pH 6). Additional buffer was added
as needed. The sections were then microwaved for 3 additional min and
allowed to cool for 20 min. Antigens were localized using a standard
avidin-biotin or streptavidin-biotin immunoperoxidase technique with
nickel chloride enhanced 3,3'-diaminobenzidine as a chromogen. For
Ki-67, the estimated percentage of positive nuclei was determined by
the two observers and was based on the evaluation of a single
representative slide. Cases showing immunohistochemical evidence of P53
and mdm2 overexpression were defined as those that showed 20%
positive nuclei. Cases with 10% positive nuclei were regarded as
showing normal p21/waf1 constitutive expression. These cutoffs were
similar to those used in previous studies of Ki-67, p53, p21/waf1, and
mdm2 expression (14
, 24
, 26, 27, 28)
, and they were used to
allow comparison of data between studies.
Flow Cytometry.
Flow cytometry was performed on formalin-fixed, paraffin-embedded
tissue. Nuclei were isolated and stained with DAPI, as described
previously (29)
. Histograms were collected using a Becton
Dickinson fluorescence-activated cell-sorting analyzer and analyzed
using Multicycle software (Phoenix Flow Systems, San Diego, CA) using
corrections for sliced nuclei, debris, and nuclear aggregation.
Statistical Analysis.
Univariate descriptive statistics were compiled for all variables, and
the Spearman correlation coefficient was used to measure the
association between FDG-PET SUV and other nondiscrete prognostic
variables. A descriptive summary was made for the distribution of
FDG-PET SUV across levels of categorical prognostic measures, and the
association between PET SUV and each of these measures was formally
assessed using nonparametric tests. Specifically, the Wilcoxon rank sum
test was used when the categorical variable of interest had two levels,
and its extension, the Kruskal-Wallis test, was used when that variable
had three or more levels (20)
.
In addition to considering the sensitivity of the distribution of
FDG-PET SUV to the categories of the discrete prognostic variables, it
was also of interest to directly relate FDG-PET SUV values to the
category membership for these variables. Logistic regression models
were applied for this purpose after first dichotomizing prognostic
variables that afforded more than two categories (i.e.,
tumor grade, cellularity, Ki-67 labeling index, and mitoses per 10
HPF). Specifically, tumor grades of II or III were considered
high, and grades of 0 or I were taken as low. Cellularity of "high"
was taken as high and cellularity of "low" or "intermediate" as
low. For both the Ki-67 labeling index and the mitoses per 10 high
powered field, two groups were defined as follows: values above the
75th percentile were considered high and those below that percentile
were considered low. In the absence of standard cut points for these
variables, these dichotomizations were performed to insure the relative
extremity of the "high" groups in each category and to facilitate
statistical analysis. To improve the robustness of the models, FDG-PET
SUV was treated as a predictor variable after first making a
logarithmic transformation. Odds ratios were computed corresponding to
a one-logarithm increase in FDG-PET SUV. For all statistical analyses,
Ps 
0.05 were considered to be statistically
significant.
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RESULTS |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. Table 2
describes the distributions of the variables that were not strictly
categorical in nature (i.e., FDG-PET SUV, SPF, S +
G2-M, Ki-67 labeling index, and mitoses per 10
HPF). Table 2
also provides estimates of the correlation between PET
SUV and other variables. In Table 3
, the
distribution of FDG-PET SUV is summarized in terms of the median and
interquartile range for each level of the categorical variables. Fig. 1
displays the actual FDG-PET SUV data by
histopathological grade. Fig. 2
depicts
the scatterplot of the number of mitoses per 10 HPF by FDG-PET
SUV, and Fig. 3
depicts the
distribution of FDG-PET SUV according to the measure of cellularity.
Fig. 4
provides similar plots depicting
the association between Ki-67 labeling index and FDG-PET SUV, and Fig. 5
depicts the distribution of FDG-PET SUV
by level of p53.
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presents odds ratio estimates for a one-logarithm increase in FDG-PET
SUV. For grade, cellularity, Ki-67 labeling index, and mitoses per 10
HPF, these odds ratios refer to the ratio of the odds of being in the
high group for two hypothetical individuals, with the first person
having a one-logarithmic higher FDG-PET SUV than the second. The high
and low groups were defined as discussed in "Patients and Methods."
For ploidy, p53, p21, and mdm2, we refer to the ratio of the odds of a
tumor having an abnormal result (e.g., overexpression of
p53). Table 4
confirms that the likelihood of high pathological grade
and high cellularity was very strongly associated with the level of
FDG-PET SUV, which is qualitatively consistent with the distribution
and results in Table 3
and Figs. 1
and 2
. Significant
associations with Ki-67 labeling index, mitoses per 10 HPF, and p53
overexpression were also observed.
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, the
median SUV for intermediate- and high-grade sarcomas was 6.05 and 6.85,
respectively, as compared with 2.65 for low-grade sarcomas. As indicated, FDG-PET SUV showed a weak and statistically insignificant positive correlation with SPF and S + G2-M, but stronger and highly significant positive correlations with Ki-67 labeling index and the number of mitoses per 10 HPF. We hypothesized that elevated SUV values would be seen in highly proliferative sarcomas, and the results of the present study support this. Mitotic activity, per se, is not indicative of malignancy in bone and soft tissue tumors, and it is often quite high in reactive or benign processes such as nodular fasciitis and giant cell tumors of bone. However, high-grade sarcomas generally have a higher level of mitotic activity than do tumors of lower grade.
Significantly higher values of FDG-PET SUV were seen in sarcomas with overexpression of p53, but not with mdm2 overexpression or loss of normal p21WAF1 expression. These findings suggest that some alterations in cell cycle control may contribute to elevated FDG-PET SUV values in sarcomas. p53 overexpression was present in 45% of our cases of soft tissue sarcoma, an incidence slightly higher than that seen in prior studies (14 , 16 , 30, 31, 32, 33) . This may be due to our uniform use of heat-induced epitope retrieval for immunohistochemistry (34) .
We also noted a significant association between tumor hypercellularity and FDG-PET SUV. This is not surprising because it might be expected that tumors with a greater number of metabolically active cells per unit area would have a higher SUV. Although hypercellularity has not been shown to have independent prognostic value in sarcoma (18 , 35) , hypercellularity is a common feature of malignant soft tissue and bone tumors.
We further analyzed the relationship of FDG-PET SUV with cellularity, Ki-67 labeling index, and mitotic activity separately for each group of tumors with a certain histopathological grade. For benign tumors and grade I sarcomas (n = 21), SUV was significantly higher in tumors with high mitotic figure counts (Spearman’s r = 0.44; P = 0.012) and high cellularity (P = 0.019), and there was a trend toward higher SUV values for tumors with high KI-67 labeling indices (P = 0.11). For high-grade (grades II and III) sarcomas, there was a trend toward higher SUV values for tumors with high mitotic figure counts (Spearman’s r = 0.22; P = 0.10) and high cellularity (P = 0.075), but these did not reach statistical significance. No correlation was seen between SUV values and Ki-67 labeling index in high-grade sarcomas.
Finally, we examined the relationship of a combination of cellularity
and Ki-67 labeling index with SUV values. As noted in Table 5
, a highly significant
(P = 0.009) relationship was seen, with the highest PET
SUV values in highly cellular and highly proliferative sarcomas and the
lowest values in sarcomas with low cellularity and proliferative
indices.
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DISCUSSION |
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Although these previous studies have shown a relationship between FDG-PET scan values and histopathological sarcoma grade, no study to date has examined why it is that FDG-PET values correlate with grade. Putting it another way, what do FDG-PET values tell us about a sarcoma? Because FDG-PET scans are essentially a measure of tumor metabolism, we hypothesized that pathological features such as proliferative activity, tumor cellularity, and possibly alterations in the normal mechanisms of cell cycle control might be related to PET SUV.
With regards to cell proliferation, we found strong associations between FDG-PET SUV, Ki-67 labeling index, and mitotic figure counts. Ki-67 is a 395-kDa nuclear antigen that is encoded for by a single gene on chromosome 10 and whose expression is confined to late G1, S, M, and G2 phases (37) . It appears to be localized to the nucleolus and may be a component of nucleolar preribosomes (38) . In formalin-fixed tissue, the most widely used antibody against this antigen is MIB-1. Several studies have documented a correlation between high Ki-67 labeling index and poor prognostic features in soft tissue sarcoma (22 , 16 , 39 , 40) . Most recently, Rudolph and coworkers (28) have shown significant associations between Ki-67 labeling index of >20% and high grade, shortened overall survival, and the development of metastatic disease. In high-grade sarcomas of the extremities, Heslin et al. (14) showed a Ki-67 labeling index of >20% to be an independent predictor of distant metastases and tumor mortality.
Whereas mitotic activity is not one of the parameters formally evaluated in the National Cancer Institute or Mayo Clinic grading systems (18 , 25) , it is an important component of the more recently devised FNCLCC grading scheme (35) . Recent studies have suggested that the FNCLCC system may more accurately stratify sarcoma patients in terms of metastatic risk and overall outcome (12) . Given the correlation we have shown between SUV and mitotic activity, one might hypothesize that an even tighter correlation would be seen between SUV and a grading system that incorporates mitotic activity, such as the FNCLCC system.
We were not able to show any relationship between FDG-PET SUV and flow cytometrically determined SPF or tumor ploidy. This may be because of sampling errors inherent in the use of this technique. Flow cytometry suffers from a number of drawbacks, including destruction of tissue, difficulty in assessing a small subpopulation of cells in a sample, loss of histological architecture, and inability to assign proliferative characteristics to specific cell populations. However, in general, high-grade sarcomas are more likely than low-grade sarcomas to be aneuploid (23 , 19 , 41 , 42) and to have an elevated proliferative rate (17 , 41, 42, 43) . Aneuploid sarcomas have been shown to have a greater risk of subsequent metastasis (21) and a worse clinical outcome (23) .
We observed correlations between FDG-PET SUV and p53 overexpression, but not between SUV and p21WAF1 or mdm2. The TP53 gene product, p53, is a nuclear phosphoprotein, which appears to regulate transcription by arresting cells with damaged DNA in the G1 phase (44, 45, 46, 47) . Mutations of the TP53 gene produce a mutant protein, which loses its tumor suppressing ability and has a longer half-life than wild-type p53 (44) ; this allows immunohistochemical detection of mutated p53. Overexpression of p53 has been examined in a variety of soft tissue sarcomas, with the incidence ranging from 9 to 41% (14 , 26 , 30, 31, 32 , 48 , 49) . Most studies of p53 expression in sarcomas have shown a correlation between p53 overexpression, higher tumor grade, and worse outcome; however, p53 overexpression has not been shown to have prognostic significance independent of grade (14 , 16 , 30 , 31, 32, 33) . mdm2, a nuclear phosphoprotein whose transcription is activated by the p53 gene, binds the p53 gene and removes p53’s block on the cell cycle at the G1-S checkpoint (24 , 27) . mdm2 has also been shown to exert an inhibitory effect through binding of RB protein (50) and a stimulatory effect upon the E2F family of transcription factors (51) . Although overexpression of mdm2 has been previously documented in between 33 and 37% of sarcomas, it has not yet been shown to be of prognostic significance (26 , 52 , 53) . p21WAF1 is a downstream effector of p53 and is an inhibitor of the cyclin/cyclin dependent kinase complexes (54) . Loss of normal p21WAF1 expression has been documented in a subset of liposarcomas, including dedifferentiated, myxoid, and round cell, but it has not yet been shown to be of prognostic significance (24 , 27) .
The clinical behavior of a subset of soft tissue tumors, including hemangiopericytoma, solitary fibrous tumor, and gastrointestinal stromal tumor, may be difficult to predict both clinically and pathologically, and these tumors are generally not graded, under either the National Cancer Institute or the more recent French FNCLCC system (18 , 35) . In these tumors, marked hypercellularity is a feature associated with malignant behavior (55) . We observed a strong association between SUV and hypercellularity, suggesting a possible role for FDG-PET in certain scenarios, such as that of an intra-abdominal tumor clinically regarded as likely to be a gastrointestinal stromal tumor, in which the finding of high SUV might argue in favor of neoadjuvant therapy or an extended resection.
In summary, in this study of a large number of well characterized soft tissue and bone tumors, we have shown a significant association between the tumor SUV and several important pathological features, including histopathological grade, tumor cellularity, proliferative activity as measured by mitotic figure counts and by the MIB labeling index, and overexpression of p53. As regards histopathological grade, our findings are in general agreement with the findings of our previous study, although in that study, a larger and significant difference was present between the mean tumor DUR of grade II and III tumors (11) . In that previous study, the DUR was derived from dynamic imaging data that was gathered to determine tumor the MRFDG. The tumor SUV data used in this study were similar, but were derived directly from tomograph summed image data, and values were not adjusted for patient serum glucose levels. This is the typical analysis format for a clinical imaging study. This difference in methodology probably accounts for the small difference between our two studies with regards to grade II and III sarcomas.
These findings suggest a valuable role for FDG-PET in the management of sarcomas in terms of identifying low-grade tumors that may safely be approached with conservative surgery and in identifying intermediate- or high-grade sarcomas that may require preoperative adjuvant therapy, depending on size and location. At our institutions, neoadjuvant chemotherapy and radiotherapy are offered to patients with grade III sarcomas and with very large grade II tumors.
However, there are limitations to the use of FDG-PET scanning in the management of patients with soft tissue and bone tumors. Although only grade III sarcomas had SUVs of >20, the very similar medians and the significant overlap of grade II and III sarcomas suggest that PET is not able to distinguish as well between histopathological grades II and III. Additionally, despite a strong association between elevated tumor SUV levels and higher histopathological grade, there remains a significant overlap in SUV scores between low-grade (grade I) and high-grade (grades II and III) sarcomas. Whereas 93% of neoplasms with SUVs >7.5 are high-grade sarcomas, only 42% of high-grade sarcomas have an SUV of this level. Interestingly, in this study, all of the neoplasms with SUVs >7.5 that were not high-grade sarcomas were, in fact, benign (i.e., some benign tumors, but no grade I sarcomas had an SUV >7.5). In particular, the mean SUV for giant cell tumors of bone was 11.2, and moderately elevated SUVs were seen in fibromatoses. This suggests that elevated SUV, indicative of high metabolic rates, may be seen in three subsets of bone and soft tissue tumors: high-grade sarcomas, highly cellular and proliferative tumors (e.g., giant cell tumor of bone), and perhaps in relatively hypocellular and slowly growing tumors with abundant matrix production (e.g., fibromatoses). Obviously, PET scans need to be interpreted in the overall clinical context; whereas the finding of SUVs >7.5 in a large, deeply seated soft tissue mass in an adult is highly suggestive of a high-grade sarcoma, the same is not necessarily true of a smaller, destructive epiphyseal bone tumor. We do not think that PET scans will obviate the need for biopsy and tissue diagnosis in the management of soft tissue and bone masses in the foreseeable future.
One additional area where PET scanning may be valuable is in the recognition of intratumoral heterogeneity (reflected as areas of high and low SUV). Recognition of this heterogeneity and guidance of biopsy to regions that may be of the greatest biological significance (i.e., highest SUV) may allow for more accurate sampling of these often large and heterogeneous masses and more accurate diagnosis, grading, and management of these patients. This might be particularly advantageous in centers that employ neoadjuvant treatment protocols. Our data suggest that biopsy of regions of elevated SUV is most likely to result in identification of the most clinically significant areas in sarcomas. Further clinical follow-up will be necessary to determine whether FDG-PET values have independent prognostic significance in patients with sarcoma.
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FOOTNOTES |
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1 To whom requests for reprints should be
addressed, at Department of Pathology, H-175, Emory University
Hospital, 1364 Clifton Road NE, Atlanta, GA 30322. Phone: (404)
712-1265; Fax: (404) 712-4454; E-mail: afolpe{at}emory.edu 
2 The abbreviations used are: FDG-PET,
positron emission tomography using radiolabeled FDG; FDG, (F-18)
fluorodeoxyglucose; MRFDG, FDG metabolic rate; DUR, dose uptake ratio;
SPF, S-phase fraction; SUV, standard uptake value; PET, positron
emission tomography; FNCLCC, Federation of Cancer Centers Sarcoma
Group; HPF, high-powered field.
Received 8/ 6/99; revised 12/29/99; accepted 1/18/00.
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D. J. Yang, C.-G. Kim, N. R. Schechter, A. Azhdarinia, D.-F. Yu, C.-S. Oh, J. L. Bryant, J.-J. Won, E. E. Kim, and D. A. Podoloff Imaging with 99mTc ECDG Targeted at the Multifunctional Glucose Transport System: Feasibility Study with Rodents Radiology, February 1, 2003; 226(2): 465 - 473. [Abstract] [Full Text] [PDF]
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