Blood, 1 March 2003, Vol. 101, No. 5, pp. 1715-1717
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
Brief report
Prognostic value of angiogenesis in solitary bone
plasmacytoma
Shaji Kumar,
Rafael Fonseca,
Angela Dispenzieri,
Martha Q. Lacy,
John A. Lust,
Linda Wellik,
Thomas E. Witzig,
Morie A. Gertz,
Robert A. Kyle,
Philip R. Greipp, and
S. Vincent Rajkumar
From the Division of Hematology and Internal Medicine,
Mayo Clinic, Rochester, MN.
 |
Abstract |
Angiogenesis plays an important role in the biology of
multiple myeloma (MM) and has prognostic importance in this disease. Solitary plasmacytoma is a localized plasma cell malignancy that progresses to MM in a significant number of patients. We examined if
angiogenesis is increased in solitary plasmacytoma and if it can help
identify patients likely to progress to myeloma. We studied angiogenesis in plasmacytoma biopsy samples and bone marrow
biopsies from 25 patients. High-grade angiogenesis was present in 64%
of plasmacytomas. In contrast, bone marrow angiogenesis was low in all
patients. Patients with high-grade angiogenesis in the plasmacytoma sample were more likely to progress to myeloma and had a shorter progression-free survival compared with patients with low-grade angiogenesis (P = .02). Angiogenesis is increased in
solitary plasmacytoma and is a significant predictor of progression to myeloma and provides further evidence of its importance in the pathogenesis of myeloma.
(Blood. 2003;101:1715-1717)
© 2003 by The American Society of Hematology.
| |
Introduction |
Solitary plasmacytomas are characterized by a
localized collection of malignant plasma cells without evidence of a
systemic plasma cell proliferative disorder. It accounts for 5% to
10% of all plasma cell neoplasms and may present with a single bone lesion (solitary bone plasmacytoma, or SBP) or as a single
extramedullary or extraosseous lesion.1-3 Despite local
radiation with curative intent, the median time to progression to
multiple myeloma (MM) is 2 to 3 years.1,2,4-7
Angiogenesis is critical to the growth and spread of
tumors.8-10 As in solid tumors, angiogenesis has an
integral role in the pathophysiology of hematologic malignancies,
including leukemias,11 myeloma,12-14 and
myelofibrosis.15 Increased angiogenesis in bone marrow
(BM) is associated with a poor prognosis in MM.13,16 The
purpose of this study was to determine if increased angiogenesis was a
feature of SBP and whether it was predictive of progression to MM.
| |
Study design |
Twenty-five patients seen at the Mayo Clinic with SBP in whom
adequate plasmacytoma and BM samples were available were studied. SBP
was defined as the presence of biopsy-proven osseous lesion, a negative
BM biopsy for MM, absence of any other lesions on skeletal survey, and
absence of anemia, renal failure, or hypercalcemia.
Methods used to estimate angiogenesis have been previously published
and validated.13,15,17,18 Immunohistochemical staining for
CD34 was performed on sections from paraffin-embedded BM and tissue
blocks by a labeled streptavidin-biotin-peroxidase method. Slides were
first scanned under low power (× 100) to identify 3 areas with the
greatest number of microvessels. These areas then were evaluated at
× 400 magnification; the number of vessels in the entire field was
determined for each, and the average was expressed as microvessel
density (MVD). Large vessels, vessels within bony spicules, and those
under the periosteum were excluded. Areas of staining without discrete
breaks were counted as single vessels. The presence of a lumen or red
cells was not required; any highlighted endothelial cell or cell
cluster separate from the adjacent microvessels was counted as a
distinct vessel. The slides were independently read by 2 of the authors
(S.K. and S.V.R.). Two grades of angiogenesis were established: low
(MVD lower than 20) and high (MVD 20 or higher). A cutoff of 20 was
used based on our previous studies on BM angiogenesis in myeloma.
Progression-free survival (PFS) was estimated as time from diagnosis of
plasmacytoma to development of MM or last follow-up using the
Kaplan-Meier method; survival curves were compared using the log-rank
test. The Fisher exact test was used to compare differences in nominal
variables. The Cox proportional hazards model was used evaluate the
prognostic value of different factors in a multivariate analysis. The
study was approved by the Mayo Foundation Institutional Review Board.
| |
Results and discussion |
The study group consisted of 25 patients, including 17 men (68%),
with a median age of 62 years (range, 31-94 years) (Table 1). Nineteen patients (76%) had a
detectable M protein or light chain in their serum or urine at
diagnosis. Twenty-three patients received radiation therapy with
curative intent to the lesion, and 2 patients had primary surgical
intervention. Patients were followed for a median period of 75 months
(range, 11.5-364.5 months) during which 10 patients (38.5%) progressed
to MM.
Based on the MVD, 16 patients (64%) had high-grade angiogenesis in the
plasmacytoma and the rest had low-grade angiogenesis. The median MVD
for the entire group was 26 (range, 2-50), for the high-grade group
(n = 16) was 30 (range, 20-50), and for the low-grade group was 11 (range, 2-16). There was no increase in BM MVD in any patient.
Nine patients (56%) with high-grade angiogenesis progressed to MM
after a median of 32 months, compared with 1 (11%) with low-grade
angiogenesis (P = .02). PFS was significantly shorter in
those with high-grade angiogenesis (Figure
1); P = .02. Of the 7 patients with disappearance of M protein after therapy, only 1 developed myeloma (14%), compared with 2 (33%) of the 6 with
nonsecretory disease and 7 (70%) of the 10 with persistent M protein
(P = .06). The median PFS among those with persistent M
protein was 17 months, compared with "not reached" for the other 2 groups; P = .04. Follow-up M protein data were unavailable
for 2 patients.
The median PFS for the 2 groups (high MVD with or without persistent M
protein) was 17.5 months and 57 months, respectively. There was no
correlation between MVD and age, M protein level, urinary light chain,
2 microglobulin (2M), or tumor location. In a
multivariate Cox analysis including the persistence of M protein,
angiogenesis grade, and spinal versus nonspinal tumor location, none of
the factors were independently prognostic for progression. Patients who
had both a persistent M spike and high-grade angiogenesis (6 patients)
were 5 times more likely to progress compared with the rest of the
group (P = .01). Disappearance of M protein following
local radiation therapy has been associated with reduced risk of
progression.1,7,19 Although significant in univariate
analysis, an independent prognostic effect could not be demonstrated
for MVD or other factors previously described
probably a reflection of
small patient numbers.
We also evaluated the expression of vascular endothelial growth factor
(VEGF) and basic fibroblast growth (bFGF) by immunohistochemistry. Expression of VEGF and bFGF could be demonstrated in 7 patients and
bFGF alone in 2 additional patients.
Unlike in solid tumors, the role of angiogenesis in MM and other
hematologic malignancies continues to be debated.12-14
This study strengthens the argument for a role for angiogenesis in the
biology of plasma cell malignancies, because SBP is the closest approximation to a solid tumor in this group of diseases. It
demonstrates the markedly increased angiogenesis seen in SBP and its
prognostic value. The degree of angiogenesis seen is higher than newly
diagnosed MM and comparable to that seen in patients with relapsed MM.
In a large study evaluating BM angiogenesis, the median MVD was 11 (range, 1-48) in newly diagnosed MM and 20 (range, 6-47) in relapsed MM.14
In MM, the malignant plasma cells can secrete various angiogenic
cytokines, including VEGF,20,21 bFGF,21,22
and hepatocyte growth factor.21 VEGF induces vascular
permeability and is an endothelial cell mitogen.20
Stimulation of endothelial cells and marrow stromal cells with VEGF
results in increased interleukin-6 (IL-6) secretion.20,23
IL-6 is a potent growth factor for myeloma cells and can stimulate VEGF
secretion by myeloma cell lines and plasma cells from patients with
MM.23 Increased levels of VEGF have recently been
demonstrated in plasmacytoma samples by
immunohistochemistry.24 However, this study also included
a significant number of patients with myeloma and may explain the
difference in our findings. VEGF may also promote myeloma cell
migration and proliferation.25
The prognostic value of increased angiogenesis in SBP is intriguing.
The higher vascularity in the tumors may predispose to systemic
dissemination of the tumor. It is possible that the increased vascularity leads to increased concentration of the local stimulatory factors secreted by the endothelial cells, allowing a more rapid proliferation of the plasma cells.23,25 Another
possibility is that plasmacytomas likely to progress to myeloma are
capable of recruiting more tumor-associated blood vessels, explaining the association between increased angiogenesis and progression.
Demonstration of increased angiogenesis raises the possibility of
clinical trials using antiangiogenic agents as adjuvant therapies
for high-risk patients with SBP to prevent or delay progression. The
presence of increased angiogenesis in SBP can be combined with
persistence of M protein for identifying those at high risk for progression.
| |
Footnotes |
Submitted August 22, 2002; accepted October 3, 2002.
Prepublished
online as Blood First Edition Paper, October 17, 2002; DOI
10.1182/blood-2002-08-2441.
Supported in part by the Judith and George Goldman Foundation
Fighting Catastrophic Diseases, Deerfield, IL, and grants CA 93842, CA 85818, and CA62242, National Cancer Institute, Bethesda, MD. S.V.R. is a Leukemia and Lymphoma Society of America
Translational Research Awardee and is also supported by the Multiple
Myeloma Research Foundation.
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: S. V. Rajkumar, Mayo Clinic, 200 First
St SW, Rochester, MN 55905; e-mail:
rajks.shaji{at}mayo.edu.
| |
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Abstract
Introduction
