Biologic correlates of (18)fluorodeoxyglucose uptake in human breast cancer measured by positron emission tomography.
OBJECTIVE
Variable uptake of the glucose analog (18)fluorodeoxyglucose (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 (18)FDG uptake in vivo with biomarkers expected to be involved in the underlying biologic mechanisms.


METHODS
Preoperative (18)FDG-PET scans were performed in 55 patients. (18)FDG 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-1alpha); vascular endothelial growth factor (VEGF(165)); and microvessels. Mitotic activity index (MAI), amount of necrosis, number of lymphocytes, and tumor cells/volume were assessed.


RESULTS
There were positive correlations between (18)FDG 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-1alpha, VEGF(165), HK II, HK III, and macrophages showed no univariate correlation with (18)FDG. In logistic regression, however, HIF-1alpha and HK II added value to MAI and Glut-1.


CONCLUSIONS
(18)FDG uptake in breast cancer is a function of microvasculature for delivering nutrients, Glut-1 for transportation of (18)FDG into the cell, HK for entering (18)FDG into glycolysis, number of tumor cells/volume, proliferation rate (also reflected in necrosis), number of lymphocytes (not macrophages), and HIF-1alpha for upregulating Glut-1. Together, these features explain why breast cancers vary in (18)FDG uptake and elucidate the low uptake in lobular breast cancer.
Bos
Reinhard
R
Department of Pathology, Positron Emission Tomography Research Center, Vrije Universiteit Medical Center, Amsterdam, the Netherlands.
van Der Hoeven
Jacobus J M
JJ
van Der Wall
Elsken
E
van Der Groep
Petra
P
van Diest
Paul J
PJ
Comans
Emile F I
EF
Joshi
Urvi
U
Semenza
Gregg L
GL
Hoekstra
Otto S
OS
Lammertsma
Adriaan A
AA
Molthoff
Carla F M
CF
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000098:blood supply / Q000000981:diagnostic imaging* / Q000503:physiopathology; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000494:pharmacology; D005260:Female; D019788:Fluorodeoxyglucose F18 / Q000493:pharmacokinetics*; D006801:Humans; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007150:Immunohistochemistry; D008214:Lymphocytes; D008833:Microcirculation; D008875:Middle Aged; D009004:Monosaccharide Transport Proteins / Q000096:biosynthesis / Q000494:pharmacology; D009336:Necrosis; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000494:pharmacology; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics*; D012039:Regional Blood Flow; D014055:Tomography, Emission-Computed / Q000379:methods*; D014157:Transcription Factors
D004268:DNA-Binding Proteins; C497442:HIF1A protein, human; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009004:Monosaccharide Transport Proteins; D009687:Nuclear Proteins; D019275:Radiopharmaceuticals; D014157:Transcription Factors; D019788:Fluorodeoxyglucose F18