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CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
From the Division of Hematology and Internal Medicine,
the Division of Hematopathology, and the Cancer Center Statistics Unit,
Mayo Clinic and Mayo Foundation, Rochester, MN.
Recent observations have underscored the biologic relevance of
intratumoral angiogenesis and its potential impact on prognosis. Increased bone marrow angiogenesis has been demonstrated in a variety
of hematologic disorders, including multiple myeloma. The extent and
prognostic significance of bone marrow angiogenesis in 114 patients
with myelofibrosis with myeloid metaplasia (MMM) was investigated. A
control group of 44 patients without bone marrow disease, 15 patients
with polycythemia vera, and 17 patients with essential thrombocythemia
was also studied. Bone marrow microvessel density was assessed by a
semiquantitative method, visual microvessel grading, and 2 separate
quantitative methods, visual count and computerized image analysis.
Angiogenesis estimation by all 3 methods was highly comparable. On
visual microvessel grading, a grade 3 or 4 increase in bone marrow
angiogenesis was demonstrated in 70% of patients with MMM, 33% of
patients with polycythemia vera, 12% of patients with essential
thrombocythemia, and 0% of normal controls. In a multivariate
analysis, increased angiogenesis in MMM correlated significantly with
increased spleen size and was found to be a significant and independent
risk factor for overall survival. Increases in marrow angiogenesis
correlated with hypercellularity and megakaryocyte clumping. In
contrast, these 2 features were inversely proportional to reticulin
fibrosis, whereas increases in marrow angiogenesis were independent of
reticulin fibrosis. These preliminary findings suggest that
neo-angiogenesis is an integral component of the bone marrow stromal
reaction in MMM and may provide useful prognostic information and a
rationale for the therapeutic investigation of anti-angiogenic agents.
(Blood. 2000;96:3374-3380) Angiogenesis, or the formation of new blood
vessels, may be integral to solid tumor growth and
metastasis.1 Quantification and analysis of the degree of
intratumoral angiogenesis may provide prognostic information for
patients with certain solid tumors.2-7 In hematologic
malignancies, the bone marrow is a primary site of disease activity and
a readily accessible tissue for the investigation of angiogenesis.
Under normal conditions, the human bone marrow is supplied by a small
number of blood vessels. The concentration of these vessels, or bone
marrow microvessel density (MVD), has been shown to be increased in
various hematologic disorders, including acute lymphoid8 or
myeloid9 leukemia, myelodysplastic syndrome,10 chronic myeloid leukemia,11 and plasma cell proliferative
disorders.12 Furthermore, increased bone marrow
angiogenesis has been correlated with unfavorable prognosis in
multiple myeloma.13,14
Myelofibrosis with myeloid metaplasia (MMM) is one of the
Philadelphia-negative chronic myeloid disorders and is characterized by
clonal megakaryocytic hyperplasia and secondary bone marrow fibrosis.15 Clinically, patients with MMM manifest
progressive anemia and hepatosplenomegaly that may be associated with
substantial constitutional symptoms. Life expectancy is severely
compromised, and causes of death include progressive cachexia and
transformation of the disease process to acute myeloid
leukemia.16 Several clinical parameters, including
hemoglobin concentration, have been used to develop prognostic models
that help facilitate treatment decisions.17,18 At present,
treatment is primarily palliative and includes the use of androgen
preparations to alleviate anemia19 and chemotherapy,
surgical resection,20 or radiation therapy21 to manage symptomatic splenomegaly. Most recently, both
allogeneic22 and autologous23 hematopoietic
stem cell transplantations have been shown to benefit some patients.
The current pathogenetic hypothesis in MMM is that clonal proliferation
of megakaryocytes or monocytes (or both) is accompanied by an abnormal
cytokine release that mediates a detrimental bone marrow stromal
reaction.24 Implicated cytokines include transforming growth factor-beta (TGF- Patients
For the purposes of this study, the designation MMM was used to include
patients with agnogenic myeloid metaplasia, post-polycythemic myeloid
metaplasia, and post-thrombocythemic myeloid metaplasia. All study
patients had bone marrow fibrosis, atypical megakaryocytic hyperplasia,
and peripheral blood leukoerythroblastosis and
dacryocytosis.28 Patients with the Philadelphia chromosome
(or its molecular equivalent), dyserythropoiesis (myelodysplastic
syndrome with myelofibrosis), or acute myelofibrosis were
excluded. Clinical and laboratory information was obtained at
diagnosis, at the time of bone marrow studies, and during the clinical
course, including last follow-up. The bone marrow MVD estimations in
patients with MMM were compared with those of normal bone marrow
specimens and with specimens from patients with essential
thrombocythemia or polycythemia vera.
Bone marrow: general review
Use of CD34 as the endothelial antigen of choice During the initial stages of the current project, we evaluated the staining performances of commercial antibodies to formalin-resistant endothelial cell antigens, including CD31, CD34, and factor VIII, in 15 patients with MMM. The results demonstrated substantial cross-reactivity of both CD31 and factor VIII with the increased megakaryocyte pool that was expected in this disease. In addition, CD31 staining was comparatively weak and was also present in a broader group of myeloid precursors, compared with CD34 staining. Although the antibody to CD34 stained myeloid progenitors as well, the number of cells stained was sufficiently small as not to interfere with our analysis. Regardless, we were careful in documenting vessel specificity of the CD34-stained stroma that was considered for analysis. In general, CD34 has been found to be a useful antigen for assessing intratumor angiogenesis in various solid tumors.29,30 In one instance, staining for CD34 was directly compared with that for both CD31 and the von Willebrand factor.31 As in our initial observations, staining intensity for CD31 was found to be inferior to that of the other 2 antigens. Similar findings were also reported in a more recent study of the myelodysplastic syndrome in which both CD31 and CD34 were used to target bone marrow vessels.10Bone marrow microvessel staining Bone marrow biopsy slides were prepared from paraffin-embedded blocks. Bone marrow microvessels were visualized by immunohistochemical staining for CD34 with the use of a labeled streptavidin-biotin peroxidase method. After deparaffinization, slides were steam pretreated in 0.01 mol/L EDTA buffer, pH 8, in a Black and Decker Handy Steamer Plus (Black and Decker, Towson, MD) for 30 minutes. After rinsing in cool water, slides were immunostained by a Ventana ES automated stainer (Ventana Systems, Tucson, AZ) using buffers and detection reagents supplied by the manufacturer. The primary antibody (Clone HPCA-1; Becton Dickinson, San Jose, CA) was incubated with tissue sections for 24 minutes in a 1:50 dilution. The AEC (aminoethyl carbazole) detection kit (Ventana Systems) was used for antigen visualization; sections were counterstained with a light hematoxylin, and a coverslip of Kaiseri's glycerol jelly (Mayo Medical Laboratories, Rochester, MN) was applied.Measurement of microvessel density Three separate methods were used to estimate MVD. In the first method, visual microvessel grading, the study slides were visually scanned at 100×, 200×, and 400× magnification and semiquantitatively graded for the extent of CD34 staining (Figure 1). To ensure the accuracy of the grading method, each stained sample was reviewed by 2 of the authors, in a blinded fashion. Morphologic analysis was performed carefully to ensure vessel specificity of the CD 34-stained stroma considered for analysis. The second method, visual count, involved actual counting of microvessels according to previously described methods.2 In performing this visual count, each of the study slides was first scanned at 100× magnification, and 3 areas with abundant microvessels were chosen and defined as "hot spots." The number of microvessels in each of these hot spots was then determined at 400× magnification. The final MVD number (microvessels per high-power [400×] field) was assigned by taking the average of the 3 separate visual counts. During the counting process, large vessels and vessels in the periosteum or bone and open sinusoids were excluded. Areas of staining with no discrete breaks were counted as single vessels, and the presence of a lumen was not required.
In the third and final method, bone marrow MVD was estimated by using computerized image analysis.32 The 3 hot spots used for the visual count were quantified by computer-based image analysis. A PC-compatible computer running the image analysis software (Optimas 6.0 for Windows 95; Optimas, Seattle, WA) was used for analysis of digitally captured images. With computerized pixel counting, microvessel surface area was determined and expressed as the percentage of a bone marrow hot spot occupied by CD34 staining. An optimized microvessel surface area was then determined by eliminating the area occupied by fat and expressing the result as a percentage of cellular area occupied by CD34 staining. Statistical analysis Overall survival was defined as the interval from diagnosis to death or last contact. Survival from the date of bone marrow MVD study was also analyzed. An event was defined as a death from any cause, unless otherwise indicated. The MVD estimation from each of the aforementioned methods was separately studied for possible correlations with various clinical, histologic, or laboratory variables obtained at the time of the bone marrow study. Various univariate techniques were applied, including the Fisher exact test for categorical variables and the Kruskal-Wallis and Wilcoxon rank-sum tests for continuous variables. Results were subsequently evaluated by multivariate analysis. Cox proportional hazards regression analysis was used to assess the prognostic relevance of several clinical parameters, including degree of bone marrow angiogenesis, on survival from the time of diagnosis. All data were analyzed by using SAS software (SAS, Cary, NC).
One hundred fourteen patients with MMM, 15 patients with
polycythemia vera, 17 patients with essential thrombocythemia, and 44 normal controls were studied. MVD was clearly increased compared with
normal controls (Table 1)
(P < .01). Results from the 3 different methods of
estimating angiogenesis showed a significant positive correlation. In
addition, there was excellent interobserver reproducibility of the
qualitative grading system, with more than 95% agreement between
blinded reviewers. Specifically, there was a 1-value discrepancy
(microvessel grade) in 8 patients and a 2-value discrepancy in 3. In
those patients with a discrepancy, consensus was reached after
re-review. With the visual microvessel grading method, approximately
70% of the patients with MMM had a substantial increase (grade 3 or 4)
in bone marrow MVD compared with 33% of those with polycythemia vera
and 12% of those with essential thrombocythemia (Table 1).
Furthermore, none of the patients with either polycythemia vera or
essential thrombocythemia displayed grade 4 bone marrow angiogenesis,
whereas 32.5% of the patients with MMM did. In general, almost all the
patients with MMM had some degree of increase in microvessels.
Increased vascularity was usually appreciable even in the specimens
stained with hematoxylin and eosin (P < .01).
Clinical and laboratory characteristics of the 114 patients with MMM,
obtained at the time of the bone marrow MVD study, are outlined in
Table 2. These characteristics were
investigated for possible correlations with the extent of bone marrow
MVD, as measured by each of the 2 different visual methods of assessing angiogenesis (Table 3). By univariate
analysis, both methods revealed a significant correlation between
increased MVD and increased spleen size.
Various histologic features were quantified from the hematoxylin and eosin preparations, including cellularity, megakaryocyte clumping, reticulin fibrosis, and osteosclerosis. These features were then compared with each another, with bone marrow angiogenesis, and with clinical features (Table 3). Increases in marrow angiogenesis correlated with increases in cellularity (P = .01) and megakaryocyte clumping (P = .01) and were independent of reticulin fibrosis (P = .32) and osteosclerosis (P = .09). In contrast, MVD in the control marrows was independent of either age (P = .66) or cellularity (P = .92). In patients with MMM, increases in cellularity correlated with increases in megakaryocyte clumping (P < .01) and were inversely proportional to osteosclerosis (P < .01). Clinically, hypocellularity was associated with anemia (P = .05), circulating blasts (P < .01), hepatomegaly (P = .06), and weight loss (P = .05). Megakaryocyte clumping was correlated with hypercellularity and increased angiogenesis but was inversely proportional to osteosclerosis (P < .01), thrombocytopenia (P = .04), and weight loss (P = .05). Osteosclerosis and reticulin fibrosis were well correlated (P < .01) and were reflective of hypocellularity (P < .01), anemia (P = .02), thrombocytopenia (P = .03), higher Dupriez score (P < .01), red cell transfusion dependence (P = .05), and hepatomegaly (P = .02). Bone marrow studies of angiogenesis were performed at a median of 2 months (range, 0.2-175 months) from the initial diagnosis of MMM. The median follow-up duration from the time of the marrow study was 31.5 months (range, 0-187 months). During this period, 29 patients (25.4%) required splenectomy and 12 patients (10.5%) experienced leukemic transformation. Increased MVD predicted subsequent splenectomy but not leukemic transformation (Table 3). However, in a multivariate analysis, the significant correlation between MVD and the subsequent need for splenectomy was accounted for by spleen size (Table 3). The prognostic relevance of increased angiogenesis to survival was
investigated by using the MVD values obtained from microvessel visual
grading (Figure 1). Median overall survival from diagnosis in all 114 patients with MMM was 101 months (range, 1.8-187.7 months). Survival
was significantly shorter in patients with a grade 3 or 4 increase in
angiogenesis (median survival, 155 months [range, 10.4-187.7 months]
vs 58.6 months [range, 1.8-174.2 months]; P = .005)
(Figure 2). Although not significant,
survival from the time of the bone marrow MVD study was also shorter in
patients with a grade 3 or 4 marrow angiogenesis (median survival, 69.7 months [range, 3.9-80.6 months] vs 32.1 months [range, 1-79.2 months]; P = .11) (Figure
3). In addition to angiogenesis, various other disease parameters and histologic features, measured at the time
of initial diagnosis, were tested for their prognostic relevance (Table
4). Univariate and multivariate analyses
identified increased angiogenesis, advanced age, and increased
proportion of circulating blasts as risk factors for overall
survival.
The current study clearly demonstrated a substantial increase of marrow vascularity in most patients with MMM compared with normal controls. In addition, the extent of the abnormality was more pronounced in patients with MMM than in those with either polycythemia vera or essential thrombocythemia. Another recent report10 suggests a higher degree of vascular proliferation in chronic myeloproliferative diseases than in other myeloid disorders, including myelodysplastic syndrome and acute myeloid leukemia. Therefore, substantial increased angiogenesis, along with collagen fibrosis and osteosclerosis, may be an integral component of the bone marrow stromal reaction in MMM. In regard to the method of evaluating angiogenesis in MMM, both the semiquantitative and the quantitative methods we used were relatively accurate and showed satisfactory correlation. However, because of an associated architectural disorder of the bone marrow stroma in MMM, the semiquantitative method (visual microvessel grading) may be more suitable for minimizing inaccuracies that may arise from uneven distribution of the lesions. The observation of increased marrow vascularity in MMM is consistent
with our current understanding of the pathogenesis of this disease. The
proliferation of an aberrant clone, most likely of megakaryocytic or of
monocytic origin (or of both), is believed to be the underlying cause
for the induction of an abnormal cytokine milieu that is critical to
the kinetic and synthetic stimulation of polyclonal fibroblasts
(causing collagen fibrosis) and osteoblasts (causing
osteosclerosis).33-36 The 2 primary cytokines that have been implicated in this pathogenetic process are
TGF- VEGF is the most potent endothelial cell mitogen whose mechanism of action may involve the stimulation of tyrosine kinase receptors (flt-1/KDR).49 Increased constitutive expression and secretion of VEGF has been demonstrated in human megakaryocytes, and such VEGF expression may be inducible by either a paracrine or an autocrine mechanism.50,51 Prominent megakaryocyte VEGF expression has also been shown in the chronic myeloid disorders.10 Furthermore, a recent study26 has demonstrated increased serum levels of VEGF in most patients with MMM, and the concentration of the cytokine was significantly higher in platelet-rich than in platelet-poor plasma. These observations suggest that the cytokine-mediated bone marrow stromal reaction in MMM includes angiogenesis and that clonally expanded megakaryocytes and related cells are also capable of secreting angiogenic cytokines. An increase in either intratumoral angiogenesis or serum levels of VEGF has been associated with poor prognosis in a variety of solid malignancies.3,52-55 The possible prognostic relevance of these measurements in hematologic malignancies has so far been appreciated in acute myeloid leukemia,56,57 multiple myeloma,13,14 and non-Hodgkin lymphoma.58 In the current study, we show that the degree of increased angiogenesis in patients with MMM may have an independent prognostic value and could serve as an additional variable in clinical prognostic models. In most studies of patients with MMM, anemia, advanced age, and increased percentage of circulating blasts have been independently correlated with poor survival.15 In the current study, univariate analysis revealed that increased angiogenesis, along with advanced age and increased percentage of circulating blasts, was a highly significant risk factor for survival. Furthermore, all 3 variables maintained their prognostic relevance in a subsequent multivariate analysis. Although a correlation existed among angiogenesis, cellularity, and megakaryocyte clumping, the different relationship these features exhibit with osteosclerosis, reticulin fibrosis, and survival suggests that angiogenesis may have an independent and biologically more important role in disease progression. Neither the extent of bone marrow collagen fibrosis nor the degree of osteosclerosis has been shown to have consistent prognostic value in MMM.17,59,60 It is emphasized, however, that the currently observed prognostic value of bone marrow angiogenesis in MMM should be confirmed by well-designed prospective studies. Increased marrow angiogenesis in MMM was also associated with marked
splenomegaly and a subsequent need for splenectomy (a surrogate for
symptomatic splenomegaly). Because splenomegaly in MMM is primarily a
result of extramedullary hematopoiesis,61 it is possible
that increased marrow vascularity either facilitates splenic
extramedullary hematopoiesis or shares a common pathogenetic cytokine
that is responsible for both pathologic processes. The former
possibility is consistent with the view that splenic extramedullary hematopoiesis arises from the migration of bone marrow hematologic precursor cells that enter the systemic circulation through the marrow
sinusoids and are filtered in the spleen, where they undergo further
progenitor cell expansion.62,63 Such a process may further
be enhanced by the presence of increased intravascular hematopoiesis in
MMM.64 There is limited information regarding the
potential for VEGF, TGF- The preliminary findings in the current study suggest that microvessel proliferation is a major component of the mixed stromal reaction in MMM and that it may be a marker of disease activity and progressive extramedullary hematopoiesis. Possible prognostic significance was demonstrated and supports the investigation of anti-angiogenic agents in the treatment of patients with MMM. Accordingly, we have initiated a phase 2 study using thalidomide, a drug with anti-angiogenic properties.65 Thalidomide has been successfully used in patients with multiple myeloma,66 and it may also have therapeutic activity in patients with chronic myeloproliferative diseases, including some with MMM.67 However, it is unknown whether the therapeutic benefit of thalidomide is related to its anti-angiogenic, immunomodulatory, or cytokine regulatory properties. Nevertheless, it is reasonable to consider the investigative use of more potent anti-angiogenic agents in patients with MMM.
Submitted April 17, 2000; accepted July 25, 2000.
Supported in part by National Cancer Institute grant CA85818. S.V.R. is a Leukemia and Lymphoma Society Translational Research Awardee.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Ayalew Tefferi, Division of Hematology and Internal Medicine, Mayo Clinic, 200 First St SW, Rochester, MN 55905.
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Abstract
Introduction
), basic fibroblast growth factor (bFGF), and platelet-derived growth factor (PDGF). The resultant secondary processes include polyclonal proliferation of fibroblasts and osteoblasts, which is associated with collagen fibrosis and new bone
formation, respectively.
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