Blood, 1 June 2001, Vol. 97, No. 11, pp. 3665-3667
BRIEF REPORT
Clinical correlates of splenic histopathology and splenic
karyotype in myelofibrosis with myeloid metaplasia
Ruben A. Mesa,
Chin-Yang Li,
Georgene Schroeder, and
Ayalew Tefferi
From the Division of Hematology and Internal Medicine,
the Division of Hematopathology, and the Cancer Center Statistics Unit,
Mayo Clinic, Rochester, MN.
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Abstract |
Splenic extramedullary hematopoiesis is an integral component
of myelofibrosis with myeloid metaplasia (MMM) and may be classified into 3 distinct histologic patterns of infiltration by myeloid precursors: diffuse, nodular, and a predominance of immature
granulocytes. These 3 histologic patterns occurred in 121 (56.8%), 75 (35.2%), and 17 (8%), respectively, of 213 patients with MMM who
underwent splenectomy at a single institution. In general, karyotypic
findings in splenic tissue (n = 92) were similar to those seen in the
bone marrow. The histologic pattern of immature granulocyte
predominance, the presence of microscopic splenic infarcts (26 patients), or the detection of an abnormal splenic karyotype (52 patients) was significantly associated with decreased postsplenectomy
survival. These adverse features were also associated with
characteristics of advanced disease. These observations support the
bone marrow origin of the myeloid progenitor pool in the spleen of
patients with MMM and suggest a prognostic value for splenic
histopathology and karyotype.
(Blood. 2001;97:3665-3667)
© 2001 by The American Society of Hematology.
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Introduction |
Specific extramedullary hematopoiesis (EMH) in
myelofibrosis with myeloid metaplasia (MMM) was originally believed to
arise from reactivation of fetal hematopoietic elements.1
Current evidence suggests that splenic EMH in MMM results from
sequestration, accumulation, and proliferation of circulating myeloid
progenitors in splenic cords.2 Immunohistochemical
analysis of splenic tissue has revealed that EMH in MMM is primarily
granulocytic3 as compared with the fetal spleen, which is
mainly a site for erythroid differentiation.4 The bone
marrow origin of EMH precursors in MMM has further been suggested by
immunohistologic and morphometric studies of
megakaryocytes5 and the in vitro demonstration of committed, but not pluripotent, myeloid progenitors in splenic tissue.6 Splenectomy may be necessary to palliate symptoms and improve the quality of life in patients with MMM.7 It
was recently reported that splenic pathology in MMM may undergo a prognostically relevant progression from an erythroid to a pan-myeloid composition.8 Accordingly, and to provide complementary
information in a recently described series of patients with MMM who
underwent splenectomy,7 we investigated the prognostic
value of splenic histopathology and karyotype.
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Study design |
Archived splenic tissue obtained from splenectomized
patients with MMM (n = 213) was stained with hematoxylin and eosin
and examined under light microscopy by one of the authors (C.-Y.L.), who was blinded to the clinical characteristics and the outcomes of the
study patients. All cases were histologically categorized according to
the pattern of myeloid precursor infiltration in the spleen. The 3 categories recognized were diffuse (diffuse pattern of EMH with
trilineage myeloid involvement), nodular (macronodular proliferation of
EMH), and a predominance of immature granulocytes (immature granulocyte
predominance) (Figure 1). In addition,
the presence or absence of microscopic splenic infarctions was noted (Figure 1), and the results of karyotypic studies in the splenic tissue
and bone marrow were recorded.
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| Figure 1.
Splenic histologic findings in patients with
myelofibrosis with myeloid metaplasia.
(A) Normal spleen (× 128). (B) Diffuse splenic EMH (× 128). (C)
Nodular splenic EMH (× 80). (D) Immature granulocytic predominant EMH
(× 128). (E) Splenic microinfarction (× 51).
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Correlations among clinical, histologic, and cytogenetic parameters
were studied by nonparametric statistical techniques. The relations
between categorical variables were studied with the Fisher exact test.
When a continuous variable was divided into 2 categories, the Wilcoxon
rank sum test was used to compare the medians of the continuous
variable between the 2 categories. When a continuous variable was
divided into 3 or more categories, medians of the continuous variable
in each of the 3 or more categories were compared by means of a
Kruskal-Wallis test. Kaplan-Meier9 methodology was used to
estimate the distributions of survival from diagnosis and survival from
splenectomy. The log-rank test was used to assess whether survival from
diagnosis and survival from splenectomy differed between various
categories. Multivariate analysis was performed using logistic regression.
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Results and discussion |
One hundred twenty-one (56.8%) of the 213 splenectomized patients
with MMM had a diffuse infiltrative pattern of EMH that was composed of
granulocytic, erythroid, and megakaryocytic precursors (diffuse). In
another 75 patients (35.2%), this trilineage infiltration of
precursors formed a macronodular pattern (nodular). The histologic pattern in the remaining 17 patients (8.0%) consisted almost
exclusively of immature granulocyte precursors (immature granulocyte
predominance). In none of the patients was the EMH composed strictly of
erythroid elements. Results of our histologic review of MMM splenic
tissue are consistent with those of previous reports.3,10
Patients with immature granulocyte predominance had unfavorable
prognostic scores11 (P = .04) and a higher
incidence of cytopenias (erythrocyte transfusion dependence,
P < .01; and platelet count less than 50 × 109/L, P < .01) compared with those
with more balanced trilineage EMH (nodular or diffuse) (Table
1). In addition, independent of blastic
transformation, the particular histologic pattern was associated with
decreased overall survival (Figure 2A).
The respective median survival times from diagnosis were 49.4, 64.5, and 90.8 months for immature granulocyte predominance, diffuse, and
nodular EMH histology. Although direct comparison of the 2 most common histologic patterns revealed no survival difference, patients with
diffuse EMH had significantly worse prognostic scores11 and a higher incidence of cytopenias (Table 1). Collectively, these
observations suggest that splenic EMH in MMM may initially follow a
nodular pattern and then undergo a prognostically relevant histologic
transformation into a diffuse pattern first and granulocyte predominance second.
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Table 1.
Results of statistical analysis among splenic histologic
subgroups in 213 splenectomized patients with myelofibrosis with
myeloid metaplasia
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| Figure 2.
Histologic prognostic factors from splenic tissue in 213 patients with myelofibrosis with myeloid metaplasia.
(A) Survival from diagnosis according to splenic EMH. (B) Survival from
splenectomy according to the presence of microinfarctions. (C) Survival
from splenectomy according to splenic karyotype. PPIG indicates
predominance of immature granulocytes.
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Microscopic splenic infarcts were observed in 26 patients and were not
associated with a particular histologic pattern or with the occurrence
of postsplenectomy thrombocytosis or vascular events. In contrast,
their presence was significantly associated with an adverse prognostic
score,11 thrombocytopenia, and the presence of circulating
blasts. In addition, patients with splenic infarcts weremore
likely to have their disease transform into acute leukemia
(P = .08) and to have worse overall and postsplenectomy survival (Figure 2). Splenic cytogenetic studies were performed in 92 patients, and 52 (56.5%) had an abnormal karyotype (29 single and 23 multiple karyotypic lesions). Specific abnormalities included 20q
(n = 15), 13q (n = 11), +9 (n = 5), abnormalities of
chromosome 5 or 7 (n = 5), 12p (n = 4), abnormal chromosome 1 (n = 4), isochromosome 17q (n = 3), and +8 (n = 2). Of the 92 patients who had splenic karyotype analysis, 68 had information on bone
marrow karyotype that was performed either before (n = 60) or after
(n = 8) splenectomy. The karyotypic findings in the 2 tissues were
concordant in more than 85% of cases. Among 9 of the 10 patients who
had karyotype discordance between spleen and bone marrow, the splenic
karyotype showed the same clone as in the bone marrow but with
additional chromosomal lesions. Only one patient had an abnormal
karyotype that was found in the bone marrow but not in the spleen. The
presence of an abnormal splenic karyotype was associated with decreased postsplenectomy survival (P = .03) (Figure 2), but
not with other clinicopathologic variables.
The excellent concordance between bone marrow and splenic cytogenetic
clones, as well as our histologic observations, strengthens the
hypothesis12 that splenic EMH in MMM arises from
filtration of the clonally involved circulating progenitor cells.
Splenic EMH arising in other conditions, such as myelophthisis from
metastatic cancer or marrow stimulation by granulocyte
colony-stimulating factor,13 has also been shown to arise
from filtration of circulating progenitors.14,15 The
peripheral blood progenitor pool in MMM is markedly
elevated,16 and its preferential localization and proliferation in the spleen and liver suggest that these organs provide
an environment conducive to progenitor growth and differentiation. Our
observation concerning the detrimental prognostic significance of
immature granulocyte predominance of splenic EMH may therefore reflect
a changing circulating progenitor pool in advanced MMM.
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Footnotes |
Submitted November 6, 2000; accepted February 6, 2001.
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
