title: Spectrum of tumor angiogenesis in the bone marrow of children with acute lymphoblastic leukemia.
abstract: It has been shown that solid tumors progress in concert with an induction of tumor angiogenesis. It is not known, however, whether a similar phenomenon occurs in leukemia. Angiogenesis was characterized immunohistochemically by factor VIII staining of bone marrow biopsies and quantified by assessment of microvessel density using previously described techniques. We evaluated bone marrow biopsies from 40 children with newly diagnosed, untreated acute lymphoblastic leukemia. In 22 of the patients, we also evaluated angiogenesis after the completion of remission induction chemotherapy. Control specimens were obtained from children undergoing staging evaluations at the time of diagnosis of solid tumors and lymphomas. Microvessels were counted throughout the entire core specimen in consecutive x 200 fields, and a median count per field (cpf) was calculated. In addition, the number of microvessels in the single x 200 field with the highest microvessel density was designated as the "hot spot." Biopsies from children with leukemia and from controls showed median microvessel densities of 42 and 6 counts per field, respectively (P < or = 0.0001). Microvessel density of the hot spots of leukemia specimens and controls were also significantly different, 51 and 8, respectively (P < or = 0.0001). A computer-aided three-dimensional reconstruction model of bone marrow vascularity showed a complex, arborizing branching of microvessels in leukemic specimens compared with single, straight microvessels without branching in controls. Urinary basic fibroblast growth factor, a potent angiogenic factor, was measured in 22 of the children with newly diagnosed leukemia and in 39 normal, age-matched controls. Urinary basic fibroblast growth factor levels were increased in all 22 patients before treatment, were variable during induction chemotherapy, and demonstrated statistically insignificant decreases at the time of complete remission. These findings suggest that leukemia cells induce angiogenesis in the bone marrow and that leukemia might be angiogenesis dependent and raise the possibility for a role of antiangiogenic drugs in the treatment of leukemia.
authors.affiliation: Department of Pathology, Children's Hospital, Boston, Massachusetts 02115, USA.
authors.forename: A R
authors.initials: AR
authors.lastname: Perez-Atayde
authors.forename: S E
authors.initials: SE
authors.lastname: Sallan
authors.forename: U
authors.initials: U
authors.lastname: Tedrow
authors.forename: S
authors.initials: S
authors.lastname: Connors
authors.forename: E
authors.initials: E
authors.lastname: Allred
authors.forename: J
authors.initials: J
authors.lastname: Folkman
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use; D001853:Bone Marrow / Q000098:blood supply* / Q000737:chemistry / Q000473:pathology; D002648:Child; D005169:Factor VIII / Q000032:analysis; D016222:Fibroblast Growth Factor 2 / Q000187:drug effects / Q000652:urine; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008833:Microcirculation / Q000187:drug effects; D009389:Neovascularization, Pathologic / Q000209:etiology*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000209:etiology / Q000473:pathology* / Q000652:urine
chemical_list: D000970:Antineoplastic Agents; D016222:Fibroblast Growth Factor 2; D005169:Factor VIII