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Letters to the Editor |
Division of Diagnostic Radiology, National Cancer Center Hospital, 5–1-1 Tsukiji, Chuo-Ku, Tokyo 104-0045, Japan. e-mail: utateish@ncc.go.jp
Editor:
In the October 2004 issue of Radiology, Dr Yi and colleagues (1) report their experience with dynamic contrast material–enhanced multi–detector row computed tomography (CT) and comparison of findings with vascular endothelial growth factor (VEGF) in solitary pulmonary nodules. The authors reported extent of VEGF-related angiogenesis in both malignant (n = 38) and benign (n = 16) pulmonary nodules compared with microvessel density by using pathologic specimens. Results from our own study (2) would support their observations with contrast-enhanced dynamic CT, but we suggested that such correlations between CT measurements and VEGF-related angiogenesis were evident in patients with malignant pulmonary neoplastic nodules.
Benign pulmonary nodules often contain active inflammatory process, which also shows angiogenic activity. Angiogenesis of benign lesions is attributable to increased concentration of various molecules released by epithelial and mesenchymal cells. Although lesion molecules with regard to inflammatory process also include VEGF, the pattern of angiogenesis and microvascular remodeling of benign lesions is transient and mainly found in the active phase during the course of disease. This evidence is fundamentally different from the pattern shown in malignant neoplasm, because tumor cells themselves can continuously produce VEGF-related peptides and can affect tumor proliferation and aggressiveness. Therefore, benign lesions should be evaluated and discussed separately from malignant lesions.
The authors used monoclonal VEGF antibodies for evaluation of tumor angiogenesis in the study. The VEGF family, consisting of VEGF-A, VEGF-B, VEGF-C, VEGF-D, and VEGF-E on the basis of DNA splicing, is known as a potent neoangiogenic factor involved in the development and growth of vascular endothelial cells. VEGF-A and VEGF-B are major mediators of both angiogenesis and vasculogenesis, though their receptor VEGFR-1 and VEGF-C and VEGF-D regulate lymphangiogenesis through VEGFR-3. VEGF-A is a strong lymphangiogenic factor that promotes proliferation of lymphatic microvessels and vascular permeability. If we select the monoclonal antibody for VEGF subtype in the evaluation of tumor angiogenesis, the result of the study will depend on the selection of VEGF agonist and will be causative of bias in study analysis. In addition, in the evaluation of in vitro tumor angiogenesis with monoclonal antibody for VEGF subtype, it is considered difficult to analyze the distinction between tissue angiogenesis and lymphangiogenesis solely by means of contrast-enhanced dynamic CT.
References
Department of Radiology and Center for Imaging Science, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Ilwon-Dong, Kangnam-Ku, Seoul 135–710, South Korea e-mail: kyungs.lee@samsung.com
Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Ilwon-Dong, Kangnam-Ku, Seoul 135–710, South Korea
We thank Dr Tateishi for expressing his interest in our article on dynamic enhanced multi–detector row CT and the comparison with VEGF and microvessel density in solitary pulmonary nodules (1). As he correctly indicated, angiogenesis in benign lesions is transiently present in the active phase and is presumably associated with VEGF among various molecules released by epithelial and mesenchymal cells. In contrast, angiogenesis in malignant tumors is persistent and influential in tumor proliferation and is spread as a result of continuous shedding of VEGF from tumor cells.
VEGF is a group of families that involve the regulation of endothelial cell growth and contains members of VEGF-A, VEGF-B, VEGF-C, and VEGF-D. The classification of the family mainly depends on its DNA slicing. VEGF-A plays an essential role in angiogenesis—thus, tumor growth. VEGF-C facilitates entry of tumor cells into the lymph vasculature by regulating lymphatic vessel growth. The roles of VEGF-B and VEGF-D are not clear at the moment. VEGF-B appears to be involved in lymph node metastasis and progression of adenocarcinoma of the lung in the setting of low levels of VEGF-D (2).
The VEGF polyclonal antibody used in our study (1) was the VEGF-A family (VEGF [A-20]: sc-152; Santa Cruz Biotech, Santa Cruz, Calif). Therefore, the extent of its staining might have represented tumor angiogenesis related to VEGF-A (the extent of microvessel density). As we expected, the extent of VEGF staining was higher in malignant nodules and showed significant positive correlation with peak attenuation values at dynamic CT.
The attenuation values of pulmonary nodules at dynamic CT reflect the amount of contrast medium transport within a nodule in the intravascular and interstitial spaces (3). In other words, contrast enhancement values at a given time are a summation of the intra- and extravascular concentrations of contrast medium. The attenuation value of a nodule in the early phase (wash-in phase, usually within 2 minutes) of dynamic study represents the extent of tumor vascularity, whereas that in the late phase (washout phase, usually after 5 minutes) depends on the extent of combination of cells, nonvascular mesenchymal tissue, and fibrosis (4,5). Tumors with high VEGF staining show high enhancement in the early phase of dynamic study. This was proved in our study (1), in which malignant nodules with higher VEGF staining showed higher enhancement, higher maximum relative enhancement ratio, and shorter time to peak enhancement than did benign nodules. However, care should be taken because benign tumors of high vascularity, such as pulmonary sclerosing hemangioma, hemangiopericytoma, leiomyoma, and highly vascular hamartoma, can show high enhancement in the early phase of dynamic study. In these tumors, the morphology at CT usually suggests benignancy with well-defined margins.
As far as we know, there is no single imaging tool that enables the evaluation of exclusive lymphatic vessel growth extent into a nodule. Therefore, it is difficult to measure the extent of VEGF-C (factor involved in lymphatic vessel dilation) family activity in a nodule with an imaging study. Further study on the relationship between in vitro staining extent of lung cancer with the VEGF family (including all members of the family) and presence of hilar or mediastinal lymph node metastasis at imaging, including positron emission tomography (PET) and PET/CT, would be interesting.
References
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