Diffuse osteolytic lesions in leukemic transformation of myelofibrosis
ABSTRACT Myelofibrosis is a clonal myeloproliferative disorder characterized by splenomegaly, abnormal deposition of reticulin and collagen in the bone marrow, extramedullary hematopoiesis, dacryocytosis and leukoerythroblastic blood smear. Development and sustainment of fibrosis are mediated by complex network of several cytokines. Osteosclerosis is the most frequently observed bone change in myelofibrosis. We present an atypical case of leukemic transformation in myelofibrosis associated with diffuse osteolytic lesions and extremely elevated lactate dehydrogenase in serum, which indicates high bone turnover during leukemic infiltration and bone destruction.
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ABSTRACT: Tumor necrosis factor-alpha (TNF-alpha) is important for function, differentiation, and transformation of B-lymphocytes in multiple myeloma (MM) but can also induce apoptosis of myeloma cells. Based on this opposite effect, it is very crucial to analyze the correlation of the serum level of TNF-alpha with clinical parameters of the patients. In this article, we analyzed 18 MM patients, 48% male and 52% female, with a mean age of 52 yr (range: 35-81 yr), clinical stage I in 21.4%, stage II in 26.4%, and stage III in 52.2% of patients. Patients with advanced clinical stage, presence of osteolysis, and elevated lactate dehydrogenase (LDH) had a significant difference (Mann-Whitney U-test, p < 0.05) in the serum level of TNF-alpha in comparison with those in the early stage, without osteolysis, and normal LDH. The correlation of individual values of TNF-alpha with the percentage of plasma cells in the bone marrow, LDH, beta2-microglobulin, fibrinogen, and sedimentation rate was significant (p < 0.05). However, we have not found a significant correlation between TNF-alpha and concentration of hemoglobin, the number of white blood cells or platelets (p > 0.05). We concluded that our data indicate determination of TNF-alpha as a good parameter for estimation of tumor mass presence, among individual patients with MM, and may by used for monitoring during application of different therapy protocols.Medical Oncology 01/2002; 19(3):133-9. · 2.06 Impact Factor
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ABSTRACT: An 80-year-old man presented to the internist with fever, fatigue and leukocytosis up to 66.8 x 10(3)/microl. Although a chronic myelogenous leukemia was initially suspected, he was diagnosed as metastatic bone marrow tumor with bone marrow necrosis from primary prostate cancer on the basis of the clinical and pathological findings. The serum concentrations of IL-6 and TNF-alpha were mildly elevated to 65.0 pg/ml and, 54.0 pg/ml respectively. It is probable that these humoral factors were partially responsible for the leukemoid reaction although other factors induced by the bone marrow necrosis with bone marrow metastasis of prostate cancer are also likely involved.Internal Medicine 11/2005; 44(10):1093-6. · 0.97 Impact Factor
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ABSTRACT: Patients with myelofibrosis with myeloid metaplasia (MMM) often experience debilitating constitutional symptoms such as drenching night sweats, profound fatigue, unexplained fevers, and unintentional weight loss. Tumor necrosis factor (TNF) contributes to organ fibrosis and hypercatabolic symptoms in a variety of disease states. We conducted an open-label pilot study of etanercept, a soluble TNF receptor, administered at a dose of 25 mg subcutaneously twice weekly for up to 24 weeks in 22 patients with MMM. Of 20 evaluable patients, 12 (60%) experienced an improvement in constitutional symptoms, and 4 (20%) had an objective response (improvement in peripheral cytopenias or spleen size). The degree of marrow fibrosis was unchanged, and only minor changes in overall marrow cellularity were observed. Toxicity was mild, with injection site reactions (20%) and minor infections (10%) as the most common side effects. One patient developed reversible pancytopenia. Etanercept may be useful for palliation of constitutional symptoms in MMM.Blood 04/2002; 99(6):2252-4. · 9.78 Impact Factor
www.onk.ns.ac.yu/Archive Vol 15, no 1-2, July 2007
Arch Oncol 2007;15(1-2):45-7.
1Institute of Hematology, University
Clinical Center, Belgrade, Serbia,
2School of Medicine University of
Kragujevac, Serbia, 3Institute for
Molecular Biology and Genetic
Engineering, Belgrade, Serbia
Vladimir Jurišić, MD PhD, University of
Kragujevac, School of Medicine,
PO Box 124, 34 000 Kragujevac, Serbia
Provisionally accepted: 17.07.2007
© 2007, Oncology Institute of
Vojvodina, Sremska Kamenica
Primary myelofibrosis is a chronic clonal myeloproliferative disorder char-
acterized by splenomegaly, bone marrow fibrosis and extramedullary hema-
topoiesis, dacryocytosis, and leukoblastic blood smear (1-4). Between 5%
and 20% of patients with myelofibrosis terminate with acute leukemia that
can display certain morphological or immunophenotypic subtype. Secondary
leukemia in myelofibrosis complicates natural course of disease due to
chemotherapy or irradiation treatment (4).
The precise mechanism leading to bone marrow fibrosis remains unclear,
but there are suggestions that reactive proliferation of fibroblasts and clonal
process exists. Development and sustainment of fibrosis are mediated by
complex network of several cytokines. These cytokines mainly include tumor
necrosis factor-α (TNF-α) as well as other: transforming growth factor β
(TGF-β), basic fibroblast growth factor (FGF), vascular endothelial growth
factor (VEGF), platelet factor 4, and calmodulin (5,6).
TNF-α has the influence on proliferation of both normal and malignant cells,
stimulates fibroblastic proliferation and it is a key mediator of fever and
cachexia (6-9). For better explanation of the role of TNF-α in pathogenesis of
leukemic transformation in myelofibrosis we determined TNF-α values in sera
of the patients with acute myeloid leukemia (AML) developed from myeloi-
brosis. To exclude other reasons for diffuse osteolytic lesions, we additionally
analyzed serum level of parathormone and its production from cultured bone
marrow cell and peripheral blood cells.
A 49-year-old female developed malaise and abdominal pain in 1991. Physical
examination disclosed splenomegaly. Laboratory analyses showed hemoglo-
bin (Hb) 102 g/l, platelets 158 x109/l, white blood cell (WBC) count of 8.7
x109/l, erythroblast in peripheral blood of 12/100 WBC, and dacryocytes. In
differential leukocyte formula there was 3% myeloblasts, 6% myelocytes, 10%
metamyelocytes, 7% bands, 32% segmented neutrophils, 13% monocytes,
and 29% lymphocytes. Cytogenetic analyses showed normal female karyotype
(46, XX). The first bone marrow biopsy disclosed hypocellularity, presence of
all cell lineages with relatively normal maturation, and marked reticulin fibrosis
(grade 3). The prominent proliferation, clustering and pleomorphism of mega-
karyocytes suggested the diagnosis of cellular phase of primary myelofibrosis.
Immunohistohemical staining with CD34 did not review any increase of blast
cells. In vitro culture studies of peripheral and bone marrow progenitor cells
showed spontaneous growth of erythroid and granulocyte cells colonies. Based
on the presence of splenomegaly, leukoerythroblastosis and dacryocytosis in
peripheral blood, bone marrow fibrosis and cytogenetic finding a diagnosis of
myelofibrosis was established. The patient was treated symptomatically.
After 4 years, patient's condition deteriorated with malaise and bone pains.
The physical examination at that time showed pale skin and mucous
membranes with enlarged spleen that packed the entire abdominal cavity,
270 mm in diameter. The laboratory analyses showed Hb of 54 g/l, WBC of
8.0 x 109/l, platelets of 122 x 109/l, with myeloblasts 39%, myelocytes 7%,
metamyelocytes 1%, bands 6%, segmented neutrophils 18%, eosinophils
1%, lymphocytes 22%, monocytes 6%, and 13 erythroblasts/100 leukocytes.
Concentrations of immunoglobulines were IgA of 1.88 g/l, IgM of 1.23 g/l,
and IgG of 11.27 g/l. The biochemical analyses were normal except extremely
elevated sera LDH activity (1339 U/l). The parathormone determined in sera
and from in vitro cultured leukemic cells were in reference values. Serum cal-
cium is without changes in comparison to reference values. The serum TNF-α
determined by bioassay, previously reported (7,8) was extremely increased
(1421 pg/ml) in comparison to healthy controls (700 pg/ml).
Bone marrow aspirate was hypocellular with 72% of blasts mostly with charac-
teristics of myeloblasts and more than 20% of monoblastic type. Cytochemical
staining with myeloperoxidase showed that 30% of blasts were positive, and
25% of blasts were alpha-naphthol-esterase positive. The cytological finding
was in accordance with FAB-M4 type of acute leukemia. Bone marrow biopsy,
showed hypocellular bone marrow with collagen fibrosis and increasing
numbers of blasts. The blast cells were CD34+, CD13+ and MPO+. The
diagnosis of leukemic transformation of myelofibrosis was established.
The immunophenotyping of the peripheral blood cells obtained after cell
separation on gradient were analyzed by Flow cytometry (Becton Dickinson,
San Jose, USA). These analyses revealed clone which expressed HLA-DR
(74.96%), CD34 (77.99%), CD13 (60.36%), CD33 (42.60%), CD14 (39.89%),
CD4 (42.40%). Other immunophenotypic lymphoid and myeloid markers have
been negative. The diagnosis of AML, FAB type M4 was confirmed.
Cytogenetic examination of bone marrow cells showed inversion of chro-
mosome 16 [46,XX, inv(16)(p13q22)]. Molecular analyses studied by
Diffuse osteolytic lesions in leukemic transformation of
Vladimir Jurišić1,2, Nataša Čolović1 Sonja Pavlović3, Milica Čolović1
Myelofibrosis is a clonal myeloproliferative disorder characterized by splenomegaly, abnormal deposition of reticulin and colla-
gen in the bone marrow, extramedullary hematopoiesis, dacryocytosis and leukoerythroblastic blood smear. Development and
sustainment of fibrosis are mediated by complex network of several cytokines. Osteosclerosis is the most frequently observed
bone change in myelofibrosis. We present an atypical case of leukemic transformation in myelofibrosis associated with diffuse
osteolytic lesions and extremely elevated lactate dehydrogenase in serum, which indicates high bone turnover during leukemic
infiltration and bone destruction.
Key words: Myelofibrosis; Osteolysis; Lactate dehydrogenases; Parathyroid Hormone; Cell Transformation, Neoplastic;
www.onk.ns.ac.yu/Archive Vol 15, no 1-2, July 2007
RT-PCR confirmed cytogenetic finding and revealed the CBFβ/MYH11 fusion
gene transcript. PCR disclosed the presence of FLT3 Asp835 mutation.
Retrospective analyses of extracted DNA from bone marrow histological
specimen at the time of diagnosis, showed that there no presence of FLT3
mutations before leukemic transformation.
X-ray showed the presence of diffuse osteolytic lesions in the pelvis and
long bones (Figure 1). Multiple osteolyses were also present in the bodies
of vertebra. The global skeletal scintigraphy documented diffuse increase of
accumulation of the radiopharmaceuticals.
The patient was treated with cytosine-arabinoside, IV. She developed pancy-
topenia with high fever and hemorrhagic syndrome for which she received
pooled platelets and antibiotics. After chemotherapy, leukemic infiltration of
the bone marrow was again documented. She is not in remission, but she is
alive and on supportive therapy with blood transfusion ever since.
We report an unusual case of spontaneously developed acute myeloid
leukemia FAB M4 type in a patient with myelofibrosis associated with diffuse
osteolytic lesions. These osteolytic lesions were accompanied with extremely
elevated TNF-α and LDH but no disturbance in parathormone determined in
sera and in the supernates of cultured leukemic cells were evident.
Osteosclerosis is the most frequently observed bone change in myelofibrosis
mostly mediated by elevated TGF in irradiated patients or experimental animal
models (6,7). In this case we found diffuse osteolytic bone lesions that are
rarely reported in literature (10,11).
In our patient the presence of diffuse osteolytic lesions can be related to the
leukemic transformation per se by means of enhanced secretion of cytokines,
or ectopic secretion of the parathormone, parathormone-like mediators or
vitamin D3 (10-13). Ectopic secretion of parathormone is usually associ-
ated with hypercalcemia, which is not case in this patient. We did not find
elevated parathormone in sera or supernates from separated and cultured
We postulated that extremely elevated TNF-α could be reason for lytic bone
lesions in this patient, accompanied with high sera LDH activity indicating
high bone turnover.
Osteolytic bone lesions could be also a consequence of leukemic bone
infiltration or focal bone destruction by TNF-α locally released by leukemic
cells (7,8). We previously reported that TNF-α can induce apoptosis in
leukemic cell lines in vitro (9,14) and can stimulate osteoclast activation
with subsequent development of bone degradation. Osteolytic lesions in
myelofibrosis have been described but rarely and only in irradiated patients
(1,11). Association of bone marrow necrosis and elevated TNF-α was
described in leukemoid reaction in patients with metastatic prostate cancer
(15). Proliferation of the stromal cells, which produce marrow fibrosis may
also induce TNF-mediated bone destruction.
Based on significant and permanently increased concentration of serum TNF-
α and LDH in myelofibrosis in our patient we postulated that this cytokine
might have important role in bone destructions.
Figure 1 a, b. X-ray showing multiple osteolytic lesions in humerus and pelvis.
www.onk.ns.ac.yu/Archive Vol 15, no 1-2, July 2007
This study is partly supported by the grant 145 061 of the Serbian Ministry
Conflict of interest
We declare no conflicts of interest.
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