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Blood, Vol. 93 No. 6 (March 15), 1999:
pp. 2132-2134
CORRESPONDENCE
Splenectomy in Agnogenic Myeloid Metaplasia
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LETTER |
To the Editor:
Agnogenic myeloid metaplasia (AMM) is a clonal myeloproliferative
disorder characterized by progressive bone marrow fibrosis and
extramedullary hematopoiesis.1 Because of the lack of
curative options, treatment is mostly palliative and is essentially
aimed at improving severe cytopenia and at relieving symptomatic
organomegaly.2 In a substantial number of patients
this can only be achieved with splenectomy.3 It was
therefore with the greatest interest that we read the report by Barosi
et al4 reporting the association of splenectomy with a
higher than expected incidence of acute leukemic transformation in
patients with AMM. Although the observations and the conclusions
reported in the study are interesting, we believe that alternative
explanations should also be considered. This has important clinical
implications, because the hypothesis proposed by Barosi et
al,4 by potentially discouraging the use of splenectomy,
may in fact be detrimental for the optimal management of some patients
with AMM. Indeed, the hypothesis that splenectomy directly affects the
rate or the frequency of leukemic transformation in AMM remains
speculative and, in our view, should not influence at this time the
physician's decision to consider splenectomy in selected cases.
Drawing from other case-control studies of secondary malignancies after
splenectomy in Hodgkin's disease5 and aplastic
anemia,6 Barosi et al4 imply that the effect of
splenectomy may result from a disruption of the host-tumor
relationship. However, convincing experimental or clinicopathological evidence is lacking. Furthermore, despite a sophisticated statistical analysis aimed at retrospectively adjusting for selection bias, risk-time dependency, and bias related to splenectomy indications, the
confounding effect of many of these factors cannot be entirely eliminated. Specifically, the possibility that the need for splenectomy identifies a group of AMM patients who are undergoing subclinical blastic transformation, either in the bone marrow or in sites of
extramedullary hematopoiesis (EMH), was not considered by Barosi et
al,4 and potentially informative data on the histopathology of bone marrow and spleen in these patients were not provided.
We recently reported preliminary clinicopathological observations
in a small number of patients with primary myelofibrosis and prominent
splenic EMH, correlating the histopathological findings in the spleen
with clinical course and survival.7 We believe that our
data not only are of general relevance to the issue raised by Barosi et
al,4 but also may provide an alternative explanation for
the high incidence of leukemic transformation after splenectomy. We
studied surgically removed spleens from 8 patients with advanced stage
AMM. For all patients, a bone marrow biopsy was available demonstrating
no evidence of acute leukemia around the time (±2 weeks) of
splenectomy. Splenectomy was performed in an attempt to ameliorate
severe pancytopenia (n = 2), to palliate severe abdominal pain
(n = 2), or for both reasons (n = 4). Median time from diagnosis to
splenectomy was 4.5 years (range, 2 to 7 years). Seven of eight
patients developed overt acute myeloid leukemia (>20% circulating
blasts or >30% marrow blasts) within 1 to 10 months (median, 4 months) from the time of splenectomy, and 1 patient developed
refractory anemia with excess of blasts in transformation (RAEB-t) 4 months after splenectomy. Median survival from the time of
blastic transformation was 13 months (range, 8 to 25 months). At the
time of last follow-up, 4 patients were dead of disease at a median of
9 months (range, 8 to 15 months) from transformation. In all cases,
histological examination of the spleen sections showed trilineage
hematopoiesis with a significant predominance of myeloid cells,
clusters of immature mononuclear cells, and a large number of cells
staining for myeloperoxidase (MPO) and lysozime (LY). As controls, we
examined the spleens of 5 patients with early stage AMM who underwent
splenectomy for reasons unrelated to their primary hematological
condition (eg, motor vehicle accidents). The median time from diagnosis
to splenectomy for these patients was 12 months (range, 3 to 14 months). Control spleens showed a predominance of erythroid cells; less
numerous MPO+, LY+ cells; and the absence of
clustering of immature mononuclear cells. When the proliferation rate
of splenic hematopoietic cells was examined by staining for
proliferating cell nuclear antigen (PCNA), significant differences were
found between the splenectomy specimens of early stage AMM and late
stage AMM (32.3% v 59.7%, respectively;
P < .001). These data suggest that late stage AMM patients
who require splenectomy for symptom control may be undergoing acute
leukemic transformation in areas of splenic EMH, often without overt
marrow transformation. This accelerated phase of extramedullary myeloid
proliferation may be responsible for the symptom escalation that
eventually leads to splenectomy and, ultimately, for the development of
acute leukemic transformation. Splenectomy, therefore, may not promote
blastic transformation, as suggested by Barosi et al,4 but
the need for splenectomy may identify patients who are already
developing it. Conversely, it is not surprising that the removal of
spleens harboring EMH in blastic transformation does not prevent the
development of acute leukemia, because it is likely that a significant
number of circulating malignant myeloid progenitor cells remain
unaffected by the splenectomy. Although based on very preliminary data,
our model of a predominant extramedullary (splenic) blastic
transformation in AMM, predating overt acute leukemia, provides a
plausible explanation for the observations of Barosi et al4
and deserves further investigation. A histopathological review of a
large number of splenectomy specimens could show whether leukemic
evolution occurs only or predominantly in patients who have areas of
splenic myeloid metaplasia in transformation. Specifically, the
relationship between the number of blasts or the expression of
proliferative markers and the time to develop acute leukemia should be
studied. Furthermore, sensitive cytogenetic and molecular data
simultaneously obtained on the spleen, peripheral blood, and bone
marrow could indicate if any other anatomic compartment is affected at
the time of splenectomy.
Pierluigi Porcu
Department of Medicine (Hematology/Oncology)
Richard S. Neiman
Department of Pathology (Hematopathology)
Indiana
University
Indianapolis, IN
Attilio Orazi
Department
of Pathology (Hematopathology)
Columbia University College of
Physicians and Surgeons
New York, NY
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REFERENCES |
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4.
Barosi G, Ambrosetti A, Centra A, Falcone A, Finelli C, Foa P, Grossi A, Guarnone R, Rupoli S, Luciano L, Petti MC, Pogliani E, Russo D, Ruggeri M, Quaglini S:
Splenectomy and risk of blastic transformation in myelofibrosis with myeloid metaplasia.
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Tura S, Fiacchini M, Zinzani PL, Brusamolino E, Gobbi PG:
Splenectomy and the increasing risk of second acute leukemia in Hodgkin's disease.
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Splenic myeloid metaplasia with increased blast percentage: A frequent occurrence in patients with advanced stage primary myelofibrosis and postpolycythemic myeloid metaplasia.IX Meeting European Association for Haematopathology, Leiden, The Netherlands, April 26-29, 1998 (abstr P68)
Response
We read with interest the comments of Porcu et al to our study about
the influence splenectomy has on the development of blast transformation in MMM. The interest derives from the data they offered
as a possible alternative explanation of our results. First, they
documented a progressive shift of splenic metaplasia from mostly
erythroid to mostly myeloid and from mostly mature to mostly immature
cells during the progression of the disease. These data are consistent
with the previously reported findings of a progressively
increasing number of promegakaryocytes in the spleen as opposed to the
bone marrow1 and support a model of the disease in which
splenic hematopoiesis originates by displacement of the most immature
precursor myeloid cells from the bone marrow. Second, they reported a
high number of splenic mononuclear cells positive for lisozyme
staining. This stands for the monocytic nature of the cells and
confirms the hypothesis2 that in MMM, a progressively
increasing population of monocyte-macrophages both produces fibrogenic
growth factors (as transforming growth factor- and
bFGF), and participates in myeloid metaplasia under the
regulation of macrophage colony-stimulating
factor.3
However, these data disclose only small hints about the influence of
splenectomy on blast transformation. Porcu et al suggested that the
development of acute leukemia in patients who had been splenectomized
could be coincidental to the propensity to develop acute leukemia in
those patients for whom splenectomy was advocated. However, this was
the fundamental issue of our report, ie, to distinguish the factors
that induce blast transformation from confounding factors. For this
purpose, we used two different and complementary approaches:
multivariate analysis (Cox model) and propensity score. When corrected
for other covariates, splenectomy remained an independent factor for
blast transformation. The hypothesis that an occult splenic blast
transformation could modify the picture of the disease to advocate
splenectomy might justify our results only by assuming that our study
did not retrieve all the clinical features leading to splenectomy. In
particular, the propensity score we identified included age, appearance
of anemia, and increase in spleen volume.
Histological examination of the removed spleens was performed in our
collection of cases, and no accumulation of blasts in this organ was
reported by our pathologists. However, our study did not specifically
address the accumulation of blasts, and, in absence of any standardized
method of research, it might have been overlooked.
Splenectomy increases blast transformation in MMM in every setting
of care, as also supported by a recent report from the Mayo
Clinic.4 Discerning the reasons of this phenomenon is, in
our opinion, of primary importance for understanding the biology of the
disease.
Giovanni Barosi
Roberta Guarnone
Laboratory of Medical Informatics
IRCCS Policlinico S. Matteo
Pavia, Italy
| |
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J Immunol
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Increased circulating CSF-1 (M-CSF) in myeloproliferative disease: Association with myeloid metaplasia and peripheral bone marrow extension.
Blood
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Mesa RA, Nagomey DM, Silverstein MN, Schroeder G, Tefferi A:
Splenectomy in myelofibrosis with myeloid metaplasia (MMM): A single institution experience with 223 patients.
Blood
92:489a, 1998 (abstr, suppl 1)
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