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© 2002 American Society for Clinical Oncology Biologic Correlates of 18Fluorodeoxyglucose Uptake in Human Breast Cancer Measured by Positron Emission TomographyByFrom the Departments of Pathology, Medical Oncology, and Nuclear Medicine, Positron Emission Tomography Research Center, Vrije Universiteit Medical Center, Amsterdam; Department of Internal Medicine, Amstelveen Hospital, Amstelveen, the Netherlands; and Department of Pediatrics and Medicine, Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD. Address reprint request to C.F.M. Molthoff, PhD, Vrije Universiteit Medical Center, Positron Emission Tomography Research Center, Department of Nuclear Medicine, PO Box 7057, NL 1007 MB Amsterdam, the Netherlands; email: cfm.molthoff{at}vumc.nl
PURPOSE: Variable uptake of the glucose analog 18fluorodeoxyglucose (FDG) has been noticed in positron emission tomography (PET) studies of breast cancer patients, with low uptake occurring especially in lobular cancer. At present, no satisfactory biologic explanation exists for this phenomenon. This study compared 18FDG uptake in vivo with biomarkers expected to be involved in the underlying biologic mechanisms.
PATIENTS AND METHODS: Preoperative 18FDG-PET scans were performed in 55 patients. 18FDG activity was assessed visually by three observers using a four-point score. Tumor sections were stained by immunohistochemistry for glucose transporter-1 (Glut-1); Hexokinase (HK) I, II, and III; macrophages; hypoxia-inducible factor-1-alfa (HIF-1
RESULTS: There were positive correlations between 18FDG uptake and Glut-1 expression (P < .001), MAI (P = .001), amount of necrosis (P = .010), number of tumor cells/volume (P = .009), expression of HK I (P = .019), number of lymphocytes (P = .032), and microvessel density (r = .373; P = .005). HIF-1
CONCLUSION: 18FDG uptake in breast cancer is a function of microvasculature for delivering nutrients, Glut-1 for transportation of 18FDG into the cell, HK for entering 18FDG into glycolysis, number of tumor cells/volume, proliferation rate (also reflected in necrosis), number of lymphocytes (not macrophages), and HIF-1
IN 1930, WARBURG et al1 discovered that tumors are characterized by the production of lactate (caused by glycolysis) despite the presence of sufficient oxygen, indicating the importance of cell metabolism in tumor biology. A new impulse was given to interest in this phenomenon by Weber,2 who described the role of key isoenzymes in tumor metabolism. This knowledge cumulated in the use of several metabolic isoenzymes (eg, lactate dehydrogenase) for the prediction of prognosis and monitoring of treatment response.3 At the end of the last millennium, the hypoxia-inducible factor-1 (HIF-1) gene was discovered, which gave more insight into the intracellular regulation of oxygen and metabolic homeostasis.4 Hypoxia was shown to upregulate the HIF-1 complex, a transcription factor, which stimulates the cell to survive hypoxic conditions by inducing glycolysis, angiogenesis, and erythropoiesis.5 In addition, several oncogenes (eg, v-SRC and h-RAS) were found to upregulate HIF-1, providing a possible genetic explanation for the Warburg effect.6 Levels of HIF-1-alfa (HIF-1  ), one of the two subunits of the HIF-1 complex, are representative of the activity of HIF-1.5 It was demonstrated that overexpression of the HIF-1 protein occurs in ductal carcinoma-in-situ and invasive breast cancer.7 Positron emission tomography (PET) provides the opportunity to study tumor metabolism in vivo.8,9 Glucose metabolism can be assessed using the glucose analog 18F-2-fluoro-2-deoxy-D-glucose (18FDG).8 In breast cancer this technique has been used for tumor detection and staging,10 to obtain long-term prognostic information,11 and to identify tumor response to chemotherapy at an early phase of treatment.12-15 Surprisingly, after 20 years of research, the underlying mechanisms for 18FDG uptake in tumors are still a matter of debate. Interestingly, different patterns of 18FDG uptake can be distinguished between different tumor types. For example, the majority of bronchioloalveolar lung carcinomas are PET negative, in contrast to the other histologic types of lung carcinomas, which all show avid uptake.16 In breast cancer, the degree of 18FDG uptake seems to be more heterogeneous in comparison to many other cancers,10 which has been the main reason for the present investigation of the causal mechanism that determines 18FDG uptake in breast cancer. Several processes determine glucose and, thus, 18FDG uptake by the cell. Of major importance is the integrity of the vascular network that is necessary for the supply of nutrients, including glucose, and oxygen to the cell.17 Subsequent cellular uptake of the nutrients is regulated by various transporters at the cell membrane.18 The most common glucose transporter expressed in all tissues is glucose transporter-1 (Glut-1), which is insulin independent.19 When glucose has entered the cell, hexokinases (HKs) are necessary to phosphorylate glucose into glucose-6-phosphate. This is the last key regulatory step, and from here glucose follows the process of glycolysis. 18FDG follows the same pathway as glucose, but, after phosphorylation, 18FDG is not further metabolized. The proportion of cellular metabolic rate and oxygen status will further determine whether glycolysis will occur under aerobic or anaerobic conditions. These essential features for glucose metabolism (angiogenesis, transmembrane transport, phosphorylation of glucose, and cellular metabolic rate) are all known to be upregulated in cancer.20 Upregulation of glucose transporters, HKs, and vascular endothelial growth factor (VEGF), which induces angiogenesis, is also known to be part of the downstream effects of HIF-1 activation, which, therefore, serves as a promising therapeutic target.21
In the search for a biologic explanation of the variable 18FDG uptake in breast cancer, several biomarkers representing the above-described biologic model can be considered. We determined several parameters that are involved in the rate of glucose metabolism in the primary tumor of 55 breast cancer patients who underwent PET scanning: Glut-1 as the key glucose membrane transporter; the HKs I, II, and III as key glucose phosphorylators; HIF-1
Patients The study group comprised 54 women diagnosed with primary breast cancer between 1998 and 2000 at the Amstelveen Hospital (42 patients), Amstelveen, and the Vrije Universiteit Medical Center (12 patients), Amsterdam, the Netherlands. Only patients with cytologically-proven (fine-needle biopsy) or histologically-proven (core biopsy) breast cancer were invited to participate in this study and provided informed consent. No other selection criteria were applied. As PET scans were primarily performed for diagnostic reasons, special ethical approval was not required. One patient had two primary breast cancers, one in each breast. The patients’ ages ranged from 34 to 85 years, with a mean of 60.4 years, 10 patients (19%) being premenopausal and 44 (81%), postmenopausal at the time of diagnosis. None of the patients had diabetes mellitus. After PET scanning, excision biopsy or mastectomy with sentinel node guided axillary lymph node dissection were the surgical procedures used for all patients (except for two who did not undergo lymph node dissection). All specimens were fixed in neutral 4% buffered formaldehyde for at least 12 hours. The group included 29 (54%) lymph node–negative and 24 (43%) lymph node–positive cancers, and the nodal status was not investigated for two cancers. None of the patients received any preoperative chemotherapy, hormonal therapy, or radiotherapy. The 55 primary tumors were histologically classified as invasive ductal (n = 39); invasive lobular (n = 11); invasive mucinous carcinoma (n = 2); and one each of invasive cribriform, medullary, and papillary carcinoma. The mean tumor diameter was 2.4 cm, ranging from 0.5 to 5.5 cm (after the tumor-node-metastasis system classification: four T1, 27 T2, and 24 T3 tumors).
PET Imaging
Immunohistochemistry
Data Analysis PET images were analyzed visually, using 10 slices in axial, coronal, and sagittal axes, by three independent observers blinded to clinical history and outcome. Scoring was graded as negative (grade 0), weak (grade 1), moderate (grade 2), or intense (grade 3) for the primary tumor. The score of the three observers were summed to obtain a score between 0 and 9. The interobserver correlation was high (intraclass coefficient, 0.92; 95% confidence interval, 0.88 to 0.98). On the basis of the median PET intensity score of all patients, patients were regarded to have high 18FDG accumulation when all three observers independently scored the maximum intensity (grade 3); all other patients were classified as having low 18FDG accumulation. For statistical tests based on nominal values, the sum of the three scores were used.
Also, tumor to nontumor (T/N) ratios were determined by image analysis as follows. The hot spot of the tumor was interactively marked in the plane where the tumor was best visible, and regions of interest were then automatically set, using a region-growing algorithm, around the tumor area and in the corresponding normal tissue in the contralateral breast in all the planes where the tumor was found. The three-dimensional volumes of interest included all pixels within a 50% isocontour of the maximum pixel value of the tumor. The automatic results were interactively corrected if necessary. A good correlation (
The fraction of nuclei with expression of HIF-1 In the hematoxylin-eosin–stained sections, the percentage of necrotic tumor volume was estimated, and the degree of lymphocyte infiltration was semiquantitatively scored as none, slight, moderate, or severe. In the same slide, the MAI was assessed as described before,26 by counting the total number of mitoses in 10 adjacent high-power fields (1.6 mm2 in total). Tumor cell density was semiautomatically assessed with an interactive digitizing video overlay system (QPRODIT; Leica, Cambridge, United Kingdom) as described before.27 Using a four-point Weibel grid overlaid on the microscope image of the computer screen, grid points that overlaid tumor epithelium or stroma were registered in 100 fields, systematically spread over the whole tumor area, and the area percentage tumor epithelium was calculated. All cases were scored with researches blinded to all other biomarkers and 18FDG-uptake.
Statistical Methods
Variable 18FDG uptake was seen between patients, as shown by the distribution of nominal PET values in Fig 1. In 24 of 55 cancers, intense 18FDG uptake was noted. Overexpression of Glut-1 and HIF-1 was observed both around necrosis and also heterogeneously in some areas of the tumor. The intensity of expression of the HKs and VEGF165 was sometimes heterogeneous within the tumor, but most tumors had a rather homogeneous expression throughout the tumor. In Tables 2 and3, the descriptive statistics for all variables are shown.
The results of the statistical comparison between 18FDG uptake (low v high) and the biomarkers are described in Table 4. MAI (P = .001), Glut-1 membrane staining (P < .001), presence of necrosis (P = .010) as well as tumor cell density (P = .009), the intensity of cytoplasmic HK I (P = .019), and the presence of lymphocytic infiltrate (P = .032) all yielded a statistically significant positive correlation. Using  2 tests, the intensity of HK II, HK III, HIF-1 expression, VEGF165 expression, the microvessel density (both hot spot and global counts), and the presence of macrophages were not significantly correlated with 18FDG uptake. In Table 5, the correlation coefficients of nominal variables compared with nominal PET scores are shown. This test confirmed the previously found significant associations in 2 tests. More interestingly, a significant (although weak) positive correlation between microvessel density (hotspot count) and PET score (r = .373, P = .005) was found, as shown in Fig 2.
In stepwise logistic regression, the MAI, Glut-1, HIF-1 , and HK II seemed to be the strongest combination (P < .001) of variables to predict 18FDG positivity (85.5% accuracy). Analyzing the bioprofile of lobular cancer (Table 6), the ability to detect PET seemed to depend especially on Glut-1, MAI, tumor cell density, and necrosis.
This is the most comprehensive study so far to address the role of various biomarkers that were expected to be involved in 18FDG uptake in human breast cancer, which confirmed the role for Glut-1 and HK I in tumor biology in vivo.
The results indicate, however, that uptake of glucose by breast cancer is also related to proliferation rate; tumor cell density; and the presence of necrosis, lymphocytes, angiogenesis, and, to some degree, HIF-1 Facilitated transport of glucose through the cellular membrane is mainly carried out by Glut-1. In 1974, Hatanaka28 had already reported an increase of glucose transporters as a possible explanation of the Warburg effect. This finding was confirmed in vitro29 and in vivo.30 In the present study, 32% of the 55 breast cancers were Glut-1 positive, which is in agreement with previous reports. Younes et al31 showed Glut-1 positivity in 42% of 118 breast cancers, and Avril et al32 found Glut-1 positivity in 30% of 46 patients. Only in the smaller study of Brown and Wahl33 were all 12 breast cancers and eight lymph node metastases Glut-1 positive. Differences in expression can be explained by differences in antibodies (monoclonal or polyclonal) and detection methods used. More importantly, special attention should be paid to the method of quantification of biomarkers. In the present study Glut-1 activity was only based on membrane staining because this is the location of biologically active Glut-1. Brown et al34 showed that tritiumfluorodeoxyglucose uptake was correlated to Glut-1 expression in rat breast cancer, and Higashi et al16 showed the same for lung cancer. In concordance with these findings, we found in the present study a strong positive correlation between presence of Glut-1 and uptake of 18FDG. Interestingly, Avril et al32 could not detect such a correlation between 18FDG and Glut-1. This could be a result of the fact that they used intensity of cytoplasmic staining rather than membrane staining for quantifying Glut-1. Differences in PET methodology might also play a role. Avril et al32 used a semiquantitative method, standardized uptake value, that reflected the mean uptake in the tumor of 18FDG. We applied a reproducible visual scoring for the present study, which primarily depended on the maximal contrast between tumor and surrounding tissue, demonstrated by assessment of T/N ratios. Increased cell proliferation demands energy and, thus, glucose. The proliferation rate was assessed using mitotic activity. Presence of glycolytic metabolism has already been linked to proliferation in vitro, and it has been proposed that the switch from oxidative to glycolytic metabolism serves as an alternative route during mitogen-stimulated proliferation to avoid the formation of DNA-damaging reactive oxygen species.35 The results confirmed the importance of proliferation for glucose metabolism because the MAI strongly correlated with 18FDG uptake in agreement with previous reports.32,36 An HK phosphorylates glucose when it enters the cell. Of the four isoforms, HK II is said to be the most prominent one associated with cancer.37 It can be upregulated at the transcriptional and posttranslational level.38 Its property to bind to the outer membrane of the mitochondria results in a higher affinity for glucose and a reduced feedback inhibition by glucose-6-phosphate.39 The involvement of HK II in 18FDG uptake was, however, limited compared with the rate of proliferation and Glut-1 expression, although in logistic regression, HK II added value to proliferation and Glut-1, and the univariate relation between HK I and 18FDG was much stronger. In fact, many tumors showed expression of HK I. To the best of our knowledge, this is the first time overexpression of HK I is reported in breast cancer. Further research to confirm these results and to explore the role of HKs in breast cancer is, therefore, warranted. Tumor cell density was measured because the need for glucose and, therefore, 18FDG uptake correlated linearly with the number of tumor cells per unit volume of tissue (in case of an equal glucose need per cell). In fact, a study in astrocytomas showed such a relationship.40 In the present study, a large variation in tumor cell density was found in breast cancer (from 12% to 70% of cancers), with a strong positive correlation indeed with 18FDG uptake. Further, it was investigated whether the presence of lymphocytes, macrophages, or necrosis could explain 18FDG accumulation. Little is known about their influence on 18FDG uptake in humans. Lymphocytes and macrophages were investigated because inflammatory cells may have a major impact on 18FDG uptake,41,42 abscesses and infections being pitfalls in the clinical diagnostic use of PET.43,44 Indeed, in this study, the number of lymphocytes was correlated positively with 18FDG uptake, in contrast to the presence of macrophages. Studying syngeneic rat mammary cancers grown in immunocompetent rats, Brown et al45 found a low tritiumfluorodeoxyglucose uptake in lymphocytes and macrophages in contrast to the strong uptake by breast cancer cells. Kubota et al41 noted the opposite and found that 29% of glucose utilization was non–tumor-associated in breast cancer–bearing mice. Angiogenesis may promote 18FDG uptake by enhanced tracer delivery. Surprisingly, no correlation between glucose metabolism and the expression of the angiogenesis-inducing growth factor VEGF165 could be detected. So, although VEGF is an important prognostic indicator in breast cancer, its presence (ie, a basic level) seems to be sufficient and doesn’t rate limiting in breast tumor metabolism.46 In contrast, a direct correlation between 18FDG uptake and the intratumoral microvessel density was found, a correlation also seen in human gliomas.47 Tumors that grow too rapidly or have a deficient vascular system are characterized by the formation of necrosis. Necrosis reflects cell death caused by hypoxia, and hypoxia increases the 18FDG uptake in vitro.48 It is, therefore, not surprising that a positive correlation between the presence of necrosis and 18FDG uptake was found, which confirmed the results of a previous study that showed that prenecrotic changes in cells do correlate positively with 18FDG uptake.49 Further evidence for this relation can be found in the predominant presence of Glut-1 and HIF-1 around necrosis seen in the present study and reported previously.7,50
Overexpression of HIF-1 Analysis of the profile of the biomarkers described above with 18FDG uptake for all lobular cancers confirmed the associations already described for all cases. However, here, tumor cell density in particular played an important role.
Intuitively, one can wonder if prescan biopsies might influence PET signal intensity, ie, 18FDG uptake. We are not aware of any direct scientific data to test this hypothesis. However, the combination of already known facts (mean tumor volume of a core biopsy) and our own observations (no histologic reactivity to biopsy in operation specimens) provides some decent clues. Krebs et al53 described that the mean volume of a 14-gauge needle ranged from 9.9 to 17.9 mm3, which is approximately 1/600 of the mean tumor volume (diameter, 2.4 cm; [0.5 x 2.4]3 x [4
In conclusion, the amount of 18FDG uptake in breast cancer is determined by the presence of several credible biologic variables: microvessels that provide glucose, Glut-1 that transports 18FDG into the cell, HKs to enter 18FDG into glycolysis, number of tumor cells per unit volume, rate of tumor cell proliferation (also reflected in necrosis), amount of inflammatory cells within the tumor, and, to some extent, HIF-1
Supported by AEGON International Scholarship in Oncology, an exchange program for scholars in oncology between the Johns Hopkins Oncology Center, Baltimore, MD, and the Vrije Universiteit Medical Center, Amsterdam, The Netherlands (R.B. and P.vdG.). We thank Avi Shvarts, PhD, Department of Medical Oncology, Vrije Universiteit Medical Center for critical reading of the manuscript. We also thank R.P.A. Boom, MD, and D. van Geldere, MD, Department of Surgery, Amstelveen Hospital, and S. Meijer, MD, PhD, Department of Surgery, Vrije Universiteit Medical Center, for referring patients and M. van der Vijver, MD, PhD, and J.L. Peterse, MD, PhD, Department of Pathology, the Netherlands Cancer Institute, who provided tumor material from some of the patients.
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ABSTRACT
INTRODUCTION
:3] = 7238 mm3) as described in our study. So, we argue that removal of the tumor tissue by a biopsy can by itself in no way lead to a significant loss of tumor volume and, thus, of PET signal. On the other hand, enhancement of 18FDG uptake could, theoretically, be a result of a biopsy-caused hematoma or infection, but we did not observe any such reactions in the operation specimens, nor were there any clinical signs for this. The frequency of such complications is indeed low (1 in 1,000), according to Parker et al.
