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Magnitude of Stromal Hemangiogenesis Correlates with Histologic Subtype of Non–Hodgkin's Lymphoma

Authors' Affiliations: ¹ Center for Lymphoma and Myeloma, ² Division of Hematology-Oncology, Department of Medicine, ³ Department of Pathology, ⁴ Division of Biostatistics and Epidemiology, Department of Public Health, ⁵ Department of Genetic Medicine, and ⁶ Howard Hughes Medical Institute, Weill Medical College of Cornell University, New York, New York

Requests for reprints: Shahin Rafii, Howard Hughes Medical Institute, Department of Genetic Medicine, Weill Medical College of Cornell University, 1300 York Avenue, Room A-863, New York, NY 10021. Phone: 212-746-2070; Fax: 212-746-8481; E-mail: srafii{at}med.cornell.edu and Jia Ruan, Division of Hematology-Oncology, Department of Medicine, Weill Medical College of Cornell University, 520 East 70th Street, Starr 341, New York, NY 10021. Phone: 212-746-2932; Fax: 212-746-3844; E-mail: jruan{at}med.cornell.edu.

Purpose: Tumor stromal microenvironment promotes neoplastic growth and angiogenesis. We have previously shown that recruitment of marrow-derived vascular endothelial growth factor receptor-1⁺ (VEGFR-1⁺) proangiogenic hematopoietic progenitors contributes instructively and structurally to neoangiogenesis in mouse models. Here, we investigated whether stromal incorporation of CD68⁺ hemangiogenic cells and -smooth muscle actin⁺ (-SMA⁺) stromal cells correlates with neoangiogenesis and progression in human non–Hodgkin's lymphoma subtypes.

Experimental Design: Spatial localizations of vascular and stromal cells expressing CD34, VEGFR-1, -SMA, and CD68 were examined by immunohistochemistry in 42 cases of non–Hodgkin's lymphoma, including diffuse large B-cell lymphoma, Burkitt lymphoma, follicular lymphoma, and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), and compared with benign follicular hyperplasia.

Results: Compared with indolent lymphomas, there was a profound increase in recruitment of CD68⁺ cells and VEGFR-1⁺ neovessels in aggressive subtypes (including those transformed from indolent subtypes), where CD68⁺ cells were localized to the perivascular region of neovessels as well as the stromal compartment. The perivascular CD68⁺ cells expressed VEGFR-1 and VEGF-A. In contrast, there was a diffuse increase in -SMA incorporation throughout the stromal compartment of indolent subtype of CLL/SLL compared with the scant perivascular pattern in aggressive subtypes. Overall, there was no correlation between CD34⁺ microvessel density and lymphoma histologic subtype.

Conclusions: Heightened stromal hemangiogenesis as marked by infiltration of proangiogenic VEGFR-1⁺CD68⁺VEGF-A⁺ cells and their paracrine cross-talk with neovasculature appears to be a distinct feature of aggressive lymphoma, providing novel targets for antiangiogenic therapy, whereas -SMA⁺ stromal vascular network may be differentially targeted in CLL/SLL.

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