Acute (Malignant) Myelosclerosis/Acute Panmyelosis with Myelofibrosis (APMF) is a rare form of acute myeloid leukemia and is characterized by acute panmyeloid proliferation with increased blasts and accompanying fibrosis of the bone marrow that does not meet the criteria for AML with myelodysplasia related changes.[rx]
APMF is classified under acute myeloid leukemia not otherwise specified by WHO 2008. This entity is distinct and needs to be distinguished from acute megakaryoblastic leukemia (AML-M7), myelodysplastic syndrome – refractory anemia with excess blast II ( MDS-RAEB-II) with fibrosis, primary myelofibrosis (PMF) and AML with myelodysplasia related changes.[rx] The clinical course of this entity is rapidly progressive and fatal, therefore, it is essential to be aware of this entity and distinguish it from its mimickers.[rx,rx] Though it may be extremely difficult to differentiate APMF from its mimickers in some cases, detailed clinical history and hematological workup can be helpful in such cases. Many consider, as evidenced by many published articles, that APMF is a variant of MDS.[rx,rx,rx,rx] Since the outcome of these patients is poor therefore it is important to aggressively manage these patients with timely diagnosis as it can reduce morbidity and prolong life. In this case report, other differential diagnoses considered are highlighted.
- Acute myelodysplasia with myelofibrosis, Acute myelofibrosis, Acute myelosclerosis
- Also called acute (malignant) myelofibrosis, acute (malignant) myelosclerosis, acute myelodysplasia with myelofibrosis
- Now a distinct entity in WHO (2008) but not previously (Ann Hematol 2004;83:513, Leuk Lymphoma 2004;45:681)
- Rare, rapid onset, aggressive, usually adults
- Weakness, fatigue, fever, bone pain, pancytopenia; usually no marked splenomegaly
- Median survival is 2 – 9 months
Acute panmyelosis with myelofibrosis (APMF) is an ill-defined disorder that may either evolve as a clonal hematopoietic condition or as a sequel of toxic exposure to the bone marrow (BM). Therefore, controversy and discussion continue as to whether APMF may be considered as a hyperfibrotic (de novo) myelodysplastic syndrome (MDS), as acute myeloid leukemia (AML), or as severe toxic myelopathy with accompanying myelofibrosis. In this context, scant knowledge exists about BM findings, but especially the evolution of this disorder according to sequential examinations. Clinically patients present with pancytopenia, a very few blasts in the peripheral blood, and no or little splenomegaly. Initially, BM histopathology is characterized by different degrees of reticulin-collagen fibrosis and wide ranges of cellularity with a prominent left-shifted and often macrocytic erythropoiesis associated with a reduction and maturation defects of the neutrophil series. Most conspicuous are abnormalities of the megakaryocytes including loose clustering, dislocation towards the endosteal border, and appearance of atypical microforms with compact nuclei. Moreover, besides myelofibrosis in a number of patients the interstitial compartment displays a remarkable inflammatory reaction with lymphoid nodules, abundant iron-laden macrophages, perivascular plasmacytosis, and an increase in microvessels. Repeatedly performed BM biopsies reveal an accumulation of dispersed or clustered CD34+ and lysozyme-expressing blasts in keeping with the insidious transformation into acute leukemia. Prognosis is unfavorable with a median survival of less than 1 year. In conclusion, APMF has to be regarded as a condition that shows considerable overlappings with primary hyperfibrotic MDS, AML, and toxic myelopathy (secondary MDS) with accompanying myelofibrosis and therefore can not be considered as a definite clinical entity.
Symptoms of Acute (Malignant) Myelosclerosis
Bone marrow biopsy shows abnormal megakaryocytes, macrocytic erythropoiesis, and defects in neutrophil production and fibrosis of the marrow (myelofibrosis).
- Bone pain
- Easy bruising or bleeding
- Shortness of breath
- Weight loss or loss of appetite
Clinically patients present with a reduction in the count of all blood cells (pancytopenia), a very few blasts in the peripheral blood and no or little spleen enlargement (splenomegaly). Cells are usually CD34 positive.[rx]
Diagnosis of Acute (Malignant) Myelosclerosis
- Bone marrow aspiration and biopsy
- Complete blood count (CBC)
- CT (CAT) scan
- Cytogenetic analysis
- Lumbar puncture
- Peripheral blood smear
- Physical exam and history (H&P)
- Reverse transcription-polymerase chain reaction test (RT-PCR)
i) Clinical characteristics
28 patients were studied which included 8 with APMF (median age 63 years) and 20 with AMKL (median age 65 years). Splenomegaly was commonly seen in AMKL (40%) as opposed to APMF (12.5%) (P=0.21). None of the APMF patients had an antecedent hematologic malignancy, compared to 50% of AMKL patients (p=0.02). Accordingly, APMF patients had a lower incidence of the JAK2V617F mutation compared to AMKL (14% vs. 78%, p=0.04).
ii) Pathological features
Patients with APMF had a hypercellular marrow with increased erythropoiesis (87% vs. 10%, p<0.01) and granulopoiesis (100% vs. 25%, p<0.01), with lower bone marrow blast percentage (14% vs. 33%, p<0.01), with all blasts staining positive for CD34 (p=0.23) compared with AMKL. In AMKL, the majority of blasts stain positive for anti-megakaryocytic antibodies CD61 (100% vs. 30%, p=0.02), CD41 (75% vs. 20%, p=0.10), and factor VIII (50% vs. 20%, p=0.02). On flow cytometry, all cases of APMF demonstrated multilineage proliferation with subsets of blasts positive for CD61, CD117, and MPO. In comparison, all cases of AMKL expressed a megakaryocytic marker CD61.
Core biopsies were reviewed for the following characteristics: cellularity, blast count, and the presence and quality of trilineage hematopoietic elements. The percentage of blasts was determined in each case by a careful analysis of H&E- and/or Giemsa-stained bone marrow biopsy sections which were cut at 3 μm. A 500-cell differential count was performed in each case. APMF blasts were defined as cells with high nuclear: cytoplasmic ratio, dispersed nuclear chromatin, and scanty cytoplasm. A comparison ‘side by side’ with a corresponding section stained with CD34 (see below) was particularly helpful in confirming the marrow blast percentage. In AMKL, blasts were identified on the basis of their cytologic characteristics, which included, in poorly differentiated cases, a lymphoblast-like appearance with coarse to variably dispersed chromatin and scanty cytoplasms. In more differentiated cases, megakaryoblasts with a lower nuclear: cytoplasmic ratio and more abundant cytoplasm were observed. Similarly to APMF, a comparison with sections immunostained with CD42b and CD34 (see below) was also performed in these cases. This was helpful in confirming the estimated marrow blast cell percentage.
Bone marrow aspirates or minced bone marrow core biopsy material was analyzed using three-color flow cytometry. After red blood cell depletion with ammonium chloride and subsequent washes, a total cell count was determined using an automated cell counter. The viability of the sample was analyzed with propidium iodide staining. Following these initial steps, cell suspensions were incubated with antibody cocktails. Antibodies used were specific to CD14, CD5, CD19, CD10, CD2, CD7, CD3, HLA-DR, CD61, glycophorin, CD33, CD34, CD16, CD56, CD64, CD41, CD22, CD117, CD13, CD15, myeloperoxidase, TdT, and kappa and lambda light chains. The antibodies were directly conjugated with fluorescein isothiocyanate (FITC), phycoerythrin (PE), or rhodamine (RD). Flow cytometric analysis was performed using a COULTER® EPICS XL™ flow cytometer (Beckman Coulter, Miami, FL, USA). Cells of interest were gated on right angle scatter vs CD45 display. An antigen was considered positive if 20% or more cells in the blast gate stained with a specific antibody.
The following immunoperoxidase stains were performed using an automated immunostainer (DAKO, Carpinteria, CA, USA) and a standard streptavidin-biotin–peroxidase complex technique. The progenitor/early precursor associated antibody (Ab) CD34 (QBEND10) and the following anti-Mk Abs: CD31 (JC70A), CD42b (MM2/174), vWF (polyclonal factor VIII), and anti-LAT (linker for activation of T cells; antibody kindly provided by Professor George Delsol, see Acknowledgments). Myeloid and erythroid differentiation was assessed by using polyclonal anti myeloperoxidase and antihemoglobin antibodies (both obtained from DAKO). Briefly, endogenous peroxidase activity was blocked with 3% hydrogen peroxide in methanol, and endogenous biotin activity was blocked using avidin and biotin. The peroxidase activity was developed with 3,3-diaminobenzidine (DAB), and counterstained with hematoxylin. Controls stained appropriately. The immunohistochemical results were expressed as the mean (±s.d.) percentage of marrow blasts reactive with the given antibody.
For bone marrow aspirate specimens, the cell culture, harvesting, and GTG-banded karyotype methods were performed as previously described.[rx]In one case, a bone core biopsy specimen was first minced with dissecting scissors and then cultured similar to bone marrow aspirate specimens (patient 13).
|Age in years (median)||63||65||0.11|
|Splenomegaly at diagnosis, n (%)||1 (12.5)||8 (40)||0.21|
|Antecedent hematological malignancy||8- myeloproliferative neoplasm
2- myelodysplastic syndromes
|Hgb [median] g/dl||9.6||8.7||0.73|
|WBC [median] x 109/L||1.1||4.4||0.15|
|Platelets [median ] X 109/L||28||36||0.29|
|Blast % [median]||2||13||0.47|
|JAK2V617F mutation, n (%)||1/7 (14)||7/9 (78)||0.04|
|Bone marrow Cellularity, n (%):
|8 (100)||13 (65)
|↑erythropoiesis, n (%)||7 (87)||2 (10)||<0.01|
|Left shift, n (%)||5 (62)||6 (30)||0.20|
|↑granulopoiesis, n (%)||8 (100)||5 (25)||<0.01|
|Left shift, n (%)||8 (100)||9 (55)||0.01|
|↑megakaryopoiesis, n (%)||7 (87)||16 (80)||1.00|
|Micromegakaryocytes, n (%)||7 (87)||18 (90)||1.00|
|↓megakaryocyte nuclear lobulation, n(%)||7 (87)||12 (60)||0.21|
|Clustering of megakaryocytes, n (%)||5 (62)||13 (65)||1.00|
|BM blast % [median]||33||14||<0.01|
|% of blasts CD34 + [median]||100||30||0.23|
|% of blasts + for megakaryocyte markers [median]
– Factor VIII+
|Reticulin fibrosis ≥ 3+, n (%)||5 (62)||9 (45)||0.67|
|Complex karyotype, n (%)||4(50)||10(50)||1.00|
|Treatment, n (%)
– Induction chemotherapy
– Hypomethylating agent
– Clinical trial
– Supportive care
|Allogeneic bone marrow transplant, n (%)||3 (38)||3 (15)|
|Overall survival in months (median)||8.67||7.61||0.82|
Treatment of Acute (Malignant) Myelosclerosis
Median survival is about 9 months. Autologous stem cell transplantation has been used in treatment.[rx]