© The Author (2008). Published by Oxford University Press. All rights reserved
Clinicopathological and Prognostic Relevance of Uptake Level using 18F-fluorodeoxyglucose Positron Emission Tomography/Computed Tomography Fusion Imaging (18F-FDG PET/CT) in Primary Breast Cancer
1 Department of Surgery, National Defense Medical College, Tokorozawa, Saitama
2 Department of Basic Pathology, National Defense Medical College, Tokorozawa, Saitama
3 Department of Breast Oncology, International Medical Center, Saitama Medical University, Hidaka, Saitama, Japan
4 Department of Basic Traumatology, National Defense Medical College, Tokorozawa, Saitama
5 Department of Biochemistry, National Defense Medical College, Tokorozawa, Saitama
6 Tokorozawa PET diagnostic Imaging clinic, Tokorozawa, Saitama
For reprints and all correspondence: Hitoshi Tsuda, Department of Basic Pathology, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan. E-mail: htsuda{at}ndmc.ac.jp
Received January 13, 2008; accepted February 21, 2008
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Abstract |
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 TOP Abstract INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONFundingReferences |
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Objective: Using integrated 18F-fluorodeoxyglucose positron emission tomography/computed tomography fusion imaging (18F-FDG PET/CT), the clinical significance of 18F-FDG uptake was evaluated in patients with primary breast cancer.
Methods: Clinicopathological correlation with the level of maximum standardized uptake values (SUV) 60 min obtained from preoperative 18F-FDG PET/CT were examined in 152 patients with primary breast cancer. The prognostic impact of the level of SUV was explored using simulated prognosis derived from computed program Adjuvant! in 136 (89%) patients with invasive ductal carcinoma (IDC).
Results: High SUV level was significantly correlated with tumor invasive size (
2 cm) (P <0.0001), higher score of nuclear grade (P <0.0001), nuclear atypia (P <0.0001) and mitosis counts (P <0.0001), negative hormone receptor status (P = 0.001), high score of c-erbB-2 expression (P = 0.006), lymph node metastasis (P = 0.002), and IDC in comparison with invasive lobular carcinoma (P = 0.004). Multivariate analyses showed tumor invasive size, nuclear grade and estrogen receptor negativity were significantly correlated with SUV in primary breast cancer (P <0.0001,<0.0001, and <0.012, respectively), and nuclear grade was significantly correlated with SUV in tumors of invasive size 2 cm or less (P <0.0001). Tumors with high SUV (cutoff value 4.0) showed higher relapse and mortality rate compared to those with low SUV (P <0.0001).
Conclusions: High uptake of 18F-FDG would be predictive of poor prognosis in patients with primary breast cancer, and aggressive features of cancer cells in patients with early breast cancer. 18F-FDG PET/CT could be a useful tool to pretherapeutically predict biological characteristics and baseline risk of breast cancer.
Key Words: breast cancer • 18F-FDG • PET/CT • SUV • prognosis
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INTRODUCTION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONFundingReferences |
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18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET), a modality of imaging glucose metabolism in cancer cells, is a new approach for staging of primary cancer and detection of distant metastasis (1–3).
Breast cancer cells overexpress glucose transporter at the membrane and the level of active hexokinase in their cytoplasm is increased compared with adjacent normal tissues. The uptake of 18F-FDG by breast cancer cells is reported biologically to reflect their glucose hypermetabolism (4,5). Some studies suggested that the level of 18F-FDG uptake in breast cancers is significantly correlated with tumor size, higher histological grade, Ki-67 labeling index, the number of mitotic figures and abrogation of the p53. Therefore, primary breast cancers with higher levels of 18F-FDG uptake are considered to have more aggressive potential than those with low 18F-FDG uptake (6,7).
Recently, the integrated 18F-FDG PET/Computed tomography fusion imaging (18F-FDG PET/CT) has been shown to be able to visualize anatomical localization of the hypermetabolic cancer lesions more accurately than 18F-FDG PET only. Therefore, the 18F-FDG PET/CT would be more informative for pre-therapeutic staging of the entire body and for the evaluation of proliferation activity of the tumors than a single examination of 18F-FDG PET (8).
To date, the most significant prognostic parameters of breast cancer are axillary nodal status, size of the primary tumor, c-erbB-2 (HER2/neu), estrogen receptor (ER) and progesterone receptor (PgR). On the other hand, a definite conclusion remains to be reached concerning the prognostic relevance of the level of 18F-FDG uptake in breast cancer.
In the present study, we investigate the clinicopathological implications of the level of standardized uptake values (SUV) obtained from preoperative 18F-FDG-PET/CT imaging in 152 patients with newly diagnosed primary breast cancer in our institute. We assessed levels of 18F-FDG uptake to breast cancer using maximum SUV obtained 60 min later after injection of 18F-FDG. In addition, we examined the prognostic relevance of the level of 18F-FDG uptake using computed program Adjuvant!.
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PATIENTS AND METHODS |
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Eligible Patients
Between April 2005 and March 2007, 18F-FDG PET/CT scans were performed for 152 patients to determine clinical staging of breast cancer before initial therapy. Primary breast cancer was histopathologically diagnosed with fine needle aspiration cytology and/or core needle biopsy (CNB). Patients who did not have the evidence of distant metastatic spread using X-ray, ultrasonography, or 18F-FDG PET/CT were eligible for operable candidates of primary breast cancer. Patients who were pregnant, who were taken history of insulin-depended diabetes mellitus from clinical notes, or who had previously received treatment to breast cancer were excluded from indication for 18F-FDG PET/CT. All patients underwent surgery within 4 weeks after 18F-FDG PET/CT examination.
The study was carried out in accordance with the ethical principles of the Declaration of Helsinki and was approved by the institutional review board in our medical school. Informed consent was obtained from all patients with regard to 18F-FDG PET/CT examination.
18F-FDG PET/CT and Quantification of 18F-FDG uptake in Primary Breast Cancer
All patients received 18F-FDG PET/CT scans (Biograph LSO Emotion, Siemens) at Tokorozawa PET Diagnostic Imaging Clinic (Tokorozawa, Japan).
Patients were fasted at least 4 h before 18F-FDG PET study. One hour after intravenous administration of 3.7 Mbq/kg 18F-FDG, a transmission scan using CT for attenuation correction and anatomical imaging was acquired for 90 s. IV contrast was not administered to patients for the CT portion of the 18F-FDG PET/CT.
Back projection image was obtained after Gaussian filter was applied. The spatial resolution of the reconstructed images was 6.0–7.0 mm in cranio-caudal, 6.3–7.1 mm in right–left and 6.3–7.1 mm in anterior–posterior directions.
A regions of interest (ROI) was placed in the primary lesion (Fig. 1), including the highest uptake area (circle ROI, 2 cm in diameter) and SUV maximum in the ROI was calculated. The SUV was calculated using the following formula: SUV = activity in region of interest (MBq/ml)/injected dose (MBq/kg body weight).
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SUV is decay-corrected tissue activity divided by the injected dose per patient body.
Surgery
A total of 152 patients received mastectomy or breast conserving surgery with sentinel node biopsy or axillary dissection. In all patients, primary systemic therapy was not performed before surgery. Sentinel node biopsy was performed by the procedure written previously (9).
Patient Characteristics
This study consisted of 152 female patients (age range 34–81 years, mean 54 years). Patients included 3 (2%) patients with Stage 0, 46 (30%) patients with Stage I, 98 (64%) patients with Stage II, 5 (4%) patients with Stage III (Table 1). Averaged SUV stratified by pathological stages consisted 3.1 (±2.1 SD) in Stage 0, 3.3 (±2.5 SD) in Stage I, 5.6 (±3.7 SD) in Stage II and 5.7 (±4.3 SD) in Stage III (Table 2). For the purposes of this study, the following characteristics were recorded from patients' clinical charts. Primary tumor features included age, sizes of tumor invasive size (cm), histological types (invasive ductal carcinoma (IDC), invasive lobular carcinoma (ILC), ductal carcinoma in situ (DCIS), mucinous carcinoma, and apocrine carcinoma), nuclear grade with nuclear atypia score and mitotic count score, axillary lymph node involvement, ER status, PgR status and c-erbB-2 status (Table 1). Tumor invasive size was estimated by measuring a maximum diameter of tumor invasive component (cm).
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Immunohistochemistry
Formalin-fixed tumor samples obtained from surgery were routinely fixed with formalin, embedded in paraffin, cut into 4 µm-thick sections and subjected to immunohistochemistry. The expressions of ER and PgR, and c-erbB-2 were analysed immunohistochemically using specific primary antibody (Dako, Grostrup, Denmark) as previously written in our reports (10).
Scoring System of Nuclear Grade
Nuclear grade of IDC was given according to General Rules for Clinical and Pathological Recording of Breast Cancer, 15th edition by two pathologists always including one who is experienced in breast pathology (HT) (11). Nuclear grade was given by the sum of the nuclear atypia score and the mitosis counts score. Nuclear atypia score was defined as following; Score 1: Nuclei were relatively uniform in size and shape, and chromatin was inconspicuous. Score 2: Intermediate between 1 and 3. Score 3: There were considerable variations in size and shape of nuclei and the increase and unevenness of chromatin, sometimes having giant nucleoli. After selecting the area in which mitoses were the most abundant on low to intermediate magnifications, the mitotic figures were counted on a high magnification. Mitotic count score was defined as following; Score 1: 0–4 mitoses, Score 2: 5–10 mitoses, Score 3: more than 10 mitoses per 10 high power fields using eyepieces of 20 mm field of view (40x Objective).
Simulated Prognosis Derived from Ajuvant! And SUV in Breast Cancer
The computed program Adjuvant! is an assistant tool for making decisions of adjuvant therapies for women with breast cancer (http://www.adjuvantonline.com). We used the computed program Adjuvant! to simulate the prognostic significance of the level of SUV in tumor. For the entries of information including age, menopausal status, tumor size, number of positive axillary nodes and ER status, baseline prognostic estimates are given by each patient. Physical conditions of all patients were in good health. Estimated incidences of recurrence and mortality 10 years after surgical therapy was computed by this program (12). And we compared estimated prognosis in baseline risk between high and low SUV groups by showing bow and whisker plot.
Univariate Analyses According to Clinicopathological Parameters and Prognosis
The correlations between levels of SUV and clinicopathological parameters were evaluated using the Mann–Whitney U-test and the Kruskal–Wallis test. A value of P < 0.05 was defined to be statistically significant. All statistic analyses were performed using Statview5.0 software (SAS Institute Inc.). The t-value is calculated by the formula: t-value = (YA – YB)/s 
1/NA +1/NB, where YA, the mean percentage of prognosis in low SUV group; YB, the mean percentage of prognosis in high SUV group; s, standard deviation; NA, sample size of low SUV group; NB, sample size of high SUV group. T-statistics determine whether prognosis rates of the low SUV group and the high SUV group differ significantly. According to the analysis, an explanatory factor showing an absolute t-value, which is more than 2, is significantly correlated with dependent variables.
Multivariate Analysis
Multiple regression analysis was performed to select independent clinicopathological variables associated with SUV for all 152 patients with primary breast cancer and for 78 patients having primary breast cancer with tumor invasive size 2 cm or less. Multivariate models were correlated using variables with a P < 0.05 in the univariate analyses. Variables in these models were included tumor invasive size, nuclear grade, ER, HER2 and nodal status. Histology was not entered in the models because a majority of cases were IDC. SUV and tumor invasive size was analysed as continuous variables, nuclear grade was categorized as grade 1 or 2 versus grade 3, ER was categorized as negative versus positive, HER2 was categorized as scores 0 or 1+ versus score 2+ or 3+, and nodal status was categorized as nodal metastasis positive versus negative. All statistic analyses were performed using Statview5.0 software (SAS Institute Inc.).
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RESULTS |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONFundingReferences |
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Patient Characteristics
The clinicopathological features of the 152 patients are listed in Table 1. One hundred and thirty-six tumors (89%) were IDC, nine tumors (6%) were ILC and three tumors (2%) were DCIS. Other special subtypes included 2 (1%) apocrine carcinoma and 2 (1%) mucinous carcinoma.
Comparison Between SUV and Clinicopathological Parameters
In 152 primary breast cancers, the average level of SUV was 5.0 (Standard deviation, SD, 3.5). The correlations of the level of SUV with clinicopathological parameters were presented in Table 2.
The levels of SUV were significantly different between the patients tumor groups of 2 cm or less and greater than 2 cm, respectively (P < 0.0001).
The mean level of SUV was significantly lower in ILC than IDC (P = 0.004). Differences in the uptake level were not significantly between IDC and DCIS and between IDC and other special subtypes, although the mean SUV level in DCIS was relatively low.
With regard to tumor nuclear grade and its components, the mean level of SUV was significantly different among the tumor groups of Grade 1, Grade 2 and Grade 3 (P < 0.0001). The mean level of SUV elevated on stepwise manner in accordance with increase in nuclear atypia score and mitotic count (each, P < 0.0001).
Between ER-positive group (10%) and ER-negative group (10%>), the mean levels of SUV of ER-negative group was significantly higher than that of ER-positive group (P = 0.001). Between PgR-positive (10%) and PgR-negative groups (10%>), the mean SUV of the PgR-negative groups was significantly higher than that of PgR-positive groups (P = 0.04).
With regard to combined hormone receptors status, between the tumor group of ER-positive and/or PgR-positive and of ER-negative and PgR-negative in combined receptors, the mean levels of SUV of the latter were also higher than that of the former (P = 0.001).
With regard to c-erbB-2 status, the mean level of SUV was higher in the tumor groups of scores 2+ and 3+ than in the tumor groups of scores 0 and 1+ (P =0.006).
With regard to lymph nodal status, the mean level of SUV was higher in the tumor group with metastatic lymph nodes than in the group without metastatic lymph nodes (3.9 ± 3.1 SD) (P = 0.002).
Tumor invasive size (P <0.0001), nuclear grade (P <0.0001) and ER status (P = 0.012) independently influenced on the stats of SUV (4.0 or higher versus <4.0) in a multiple regression model for 152 patients (Table 3). The correlation coefficient (R2) of combination of three parameters with SUV was 0.72. In a multiple regression model for 78 patients having primary breast cancer with tumor invasive size 2 cm or less, nuclear grade only was the independent factor that influenced on the status of SUV (P <0.0001). The correlation coefficient (R2) of nuclear grade with SUV was 0.7 (Table 4).
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Patients' Prognosis and Cutoff Value of SUV
We performed a simulation of prognostic baseline risk according to 136 patients with IDC. Sixteen patients with tumors of special types including ILC, mucinous carcinoma and apocrine carcinoma were excluded from the evaluation.
The prognostic impact of the level of SUV in tumors was explored for various cutoff values in 136 IDCs. Cases were defined into two groups by six tentative thresholds (2.0, 3.0, 3.5, 4.0, 4.5 and 5.0) of SUV. Table 5 shows the number of patients who exceeded the threshold (high SUV group) and whose SUVs were the value of threshold or less (low SUV group), estimated incidence of relapse and mortality after 10 years, t-value and P value were compared.
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The P value between tentative low and high SUV groups increased in accordance with elevation of cutoff SUV up to the value of 3.0. However, the P values between the low and high SUV groups did not differ (P <0.0001) when a cutoff value between the two SUV groups exceeded 3.0. All of absolute t-values between tentative low and high SUV groups were more than 2.0 and when the cutoff SUV was 4.0, the absolute t-value was maximal. Therefore, we defined cutoff value between the low SUV group and the high SUV group as 4.0.
On a prognostic evaluations by computed program Adjuvant!, patients with the low SUV group (4.0 or less) had tendency of lower 10-year relapse rate and 10-year mortality than the high SUV group (more than 4.0).
Sixty-five patients with low SUV tumors were estimated to show a 29.5% (±18.2 SD) and a 13.4% (±17.1 SD) of 10-year recurrence rate and mortality, respectively, whereas 71 patients with high SUV tumors were estimated to show a 51.0% (±23.2 SD) and a 33.3% (±23.4 SD) of 10-year recurrence rate and mortality, respectively. Both of estimated relapse rate and mortality differed significantly between the high SUV group and the low SUV group (P < 0.0001, each).
Tumor Characteristics in the Cases that Showed Discrepancy Between SUV and Prognosis Simulated by Computed Program Adjuvant!
Table 6 shows clinicopathological characteristics of 12 patients with discrepancy between their estimated prognosis and SUV uptake values of primary tumors. Four cases (L1–L4) were estimated to be poor prognosis despite being categorized in the low SUV group (SUV 4.0 or less). In the four patients in the low SUV group, the SUV averaged 2.6 (2.14–2.82) and size of tumor invasion averaged 5.3 cm. All of the four patients had lymph node involvement in their axilla.
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Other eight cases (H1–H8) were estimated to be better prognosis despite being categorized in the high SUV group (SUV higher than 4.0). In the eight patients in the high SUV group, the SUV averaged 6.8 (4.42–14.7) and size of tumor invasion averaged 1.3 cm. All patients had no metastastic foci in their axillary lymph nodes.
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DISCUSSION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONFundingReferences |
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In the univariate analyses, we clearly demonstrated high SUV level detected with 18F-FDG PET/CT was correlated with bigger invasion size of tumor, higher nuclear grade, higher scores of nuclear atypia and mitosis counts, negative hormone receptor status, high score of c-erbB-2 expression, lymph node metastasis and IDC in comparison with ILC.
Above all, mean level of SUV was lower than 4.0 in the groups of diameter of tumor invasion with 2.0 cm or less, DCIS, ILC, mucinous carcinoma, nuclear atypia score 1, mitotic count score 1 and no nodal metastasis. Although other groups stratified by ER, PgR or c-erbB-2 might show significant differences, the mean levels of SUV in all groups were higher than 4.0.
Using a multivariate analysis, we showed bigger tumor invasive size, higher nuclear grade and ER negativity were independent variables correlated with high SUV in patients having primary breast cancer. The correlation coefficient of R2 = 0.72 indicated 72% of tumoral SUV was explained by bigger tumor invasive size, higher nuclear grade and ER negativity. Likewise, in 78 patients having tumors 2 cm or less in size, 70% of tumoral SUV was explained by nuclear grade of primary breast cancer.
Some data of correlation between the level of SUV and clinicopathological parameters were published with regard to 18F-FDG PET (5,6,13,14). In the present study, with regard to 18F-FDG PET/CT, the results were similar, and the parameters for proliferative activities and aggressiveness of cancer cells were strongly correlated with high levels of SUV in cancer cells. We suppose that the levels of the SUV from 18F-FDG uptake might be useful to predict biologically aggressive carcinoma cells.
The levels of SUV in IDC were significantly higher than that in ILC, as previously reported by other authors (5). And tumor grade was also a significant factor with a major influence on the level of SUV in breast cancer (14). Bos et al. described a significant correlation between 18F-FDG uptake and mitotic activity of tumor cells (13). In contrast, Andreas et al. found there were no correlation of the level of 18F-FDG uptake in primary breast cancers with tumor size, hormone receptors status, c-erbB-2 status or axillary lymph node involvement (6). Some parameters in the present report were inconsistent with the results described in the previous reports. Differences in criteria for judgment of positive and negative groups for c-erbB-2, hormone receptors, or those for categorization of nodal status and tumor size might have given rise to such inconsistency.
Some authors indicated that high levels of 18F-FDG uptake are a prognostic factor for recurrence in patients having primary cancer (1,15,16). In the present study, we suggested the patients' group with a high SUV level might predict poor outcome in relapse and mortality by simulation using computed program Adjuvant! (Fig. 2). We considered that the SUV of 4.0 might be one of the optimal ones to predict prognosis. Ohtsuka et al. studied the prognostic significance of SUV on 18F-FDG PET in patients with lung adenocarcinoma at pathological Stage I. They described that patients with tumor with 3.3 or higher of SUV showed higher rate of recurrence compared with patients with tumor with lower than 3.3 of SUV (17). The cutoff value of SUV 3.3 was similar with the value set in the present study.
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As shown in Table 6, there were 12 patients with tumors with substantial discrepancy between the level of SUV in primary cancer and estimated prognosis. In four patients categorized as the low SUV group, the combination of other clinicopathological parameters by the computed program Adjuvant! indicated poor prognosis. In tumors of these four cases, three patients of the low SUV group, high level of SUV in axilla was detected by 18F-FDG PET/CT and these findings could predict axillary lymph node metastasis. One remaining patient had solitary micrometastasis in an axillary sentinel node, but we could not pre-surgically detect a high level of SUV in axilla. Micrometastasis in the sentinel node was intraoperatively identified by frozen sectioning procedure. From the present results, we suppose that it might be difficult to predict metastatic potential to axillary lymph nodes by the level of SUV in primary cancer.
On the other hand, in eight patients with tumors categorized as the high SUV group, the combination of other clinicopathological parameters indicated better prognosis. All these eight patients were negative of axillary lymph node metastasis and had comparatively small sizes of tumor invasion (averaged 1.3 cm). One of the eight patients had a large sized tumor (9.2 cm in diameter), but the tumor was predominantly composed of an intraductal component, and the size of tumor invasion was only 0.2 cm in diameter. The histological types of these eight primary tumors were confirmed to be solid-tubular or papillotubular carcinoma, which were characterized by large nest, expansive growth of cancer cells and a smaller amount of stromal tissue component (data not presented).
From these results, it appeared that high density of viable cancer cells, regardless of invasive type or intraductal type, might contribute to high SUV levels of primary cancer.
Recently, primary systemic therapy has come to be widely performed for patients with early-stage breast cancer. CNB of tumor tissue becomes more important to know tumor characteristics before surgery. Many authors reported increased tumoral uptake of 18F-FDG in breast cancer is closely correlated with the density of viable carcinoma cells, microvessel density and proliferative activity (4,5,18). These reports suggest that glucose hypermetabolism detected by 18F-FDG using PET would reflect the dense proliferation of highly malignant breast cancer cells. Recently, 18F-FDG PET/CT is more widely used than 18F-FDG PET alone. The diagnostic accuracy of 18F-FDG PET/CT is superior to that of CT or 18F-FDG PET alone in the staging of patients with various cancers (19,20). Before primary systemic therapy, it might be possible to predict more precisely biological characteristics of primary breast cancer as well as the staging by the combination of 18F-FDG PET/CT and CNB.
It is especially noteworthy that nuclear grade alone accounted for level of SUV for patients having tumor size 2 cm or less in a multiple regression analysis. This finding might prompt us to do further research for applying 18F-FDG uptake in regarding an indication of primary systemic therapy of patients having early breast cancer treatment.
In conclusion, we showed significant correlation of the level of SUV in breast cancer with clinicopathological parameters and suggested its prognostic implications. It could be a useful tool to pretherapeutically predict biological characteristics and baseline risk of breast cancer.
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Funding |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONFundingReferences |
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This work was supported by a Grant-in-Aid for Promotion of Defense Medicine from the Ministry of Defense of Japan.
Conflict of interest statement
None declared.
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References |
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