At a glance......
- 1 Types of Acute Monoblastic Leukemia
- 2 Causes of Acute Monoblastic Leukemia
- 3 Symptoms of Acute Monoblastic Leukemia
- 4 Diagnosis of Acute Monoblastic Leukemia
- 5 Treatments of Acute Monoblastic Leukemia
- 5.0.1 The following article may help you
- 5.0.2 Cytochemistry
- 5.0.3 Flow cytometry
- 5.0.4 Patient characteristics, cytochemistry, and a tentative diagnosis of AML subtype
- 5.0.5 Phenotypes of the leukemic cells
- 5.0.6 Expression of monocyte-related antigens in AML-M1, -M2, and -M3
- 5.0.7 Relationship between the expression of monocyte-related antigens and positive or weakly positive α-NB staining
- 5.0.8 Discussion
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Acute monoblastic leukemia (AML-M5), is one of the most common subtypes of acute myeloid leukemia (AML; see this term) that is either comprised of more than 80% of monoblasts (AML-M5a) or 30-80% monoblasts with (pro)monocytic differentiation (AML-M5b). AML-M5 presents with asthenia, pallor, fever, and dizziness. Specific features of AML-M5 include hyperleukocytosis, propensity for extramedullary infiltrates, coagulation abnormalities including disseminated intravascular coagulation, and neurological disorders. Leukemia cutis and gingival infiltration can also be seen. A characteristic translocation observed in AML-M5.
Acute monocytic leukemia is a subtype of acute myeloid leukemia (AML) and is denoted as AML-5 or M5. This subtype of AML has distinct clinical and biological characteristics and is associated with hyperleukocytosis, coagulation abnormalities, and extramedullary involvement.
AML M5 represents an immunologically heterogeneous population similar to non-M5 AML with a prognosis that is not dependent on morphology. The disease-free survival and overall survival of patients with M5a, M5b, and non-M5 appear not to differ with currently available therapy.
Types of Acute Monoblastic Leukemia
Classification of AML M5
AML M5 is further classified into M5a and M5b.
- AML M5a accounts for 5-8% of AML and is usually seen in children and young adults. In this subtype, the hypercellular marrow contains a high number of large monoblasts, which have highly basophilic cytoplasm and delicate azurophilic granules but very few or no Auer rods. The monoblasts also have round nuclei, vacuoles, and lacy chromatin with multiple nucleoli. A bone marrow biopsy in patients with this type of AML shows the marrow partially or completely replaced by monoblasts. About 75% of M5a patients have cytogenetic abnormalities and about 7% have FLT3 mutations.
Diagnosis criteria: >80% of monocyte lineage cells should be monoblasts (hence the name “acute monoblastic leukemia”).
- AML M5b accounts for 3-6% of AML and is seen in people of all ages. Leukemic cells in this subtype are often promonocytes having less basophilic cytoplasm and more of azurophilic granules. These cells have folded nuclei which contains fine chromatin, and erythrophagocytosis is often present. Electron microscopy images of promonocytes show cytoplasm with several tiny cisternae of endoplasmic reticulum and a few dense granules. The nucleus is seen with multiple lobes and marginated chromatin. About 30% of patients with this subtype have cytogenetic abnormalities and nearly 30% have FLT3 mutations. AML M5b treatment may often lead to tumor lysis syndrome and false elevated platelet counts.
Causes of Acute Monoblastic Leukemia
- M5 is associated with characteristic chromosomal abnormalities, often involving chromosome 11, such as affecting the MLL (KMTA2) locus however, MLL translocations are also found in other leukemia subtypes. The translocation in Amol is associated with hemophagocytosis.
- Secondary leukemia, which may include AML-M5, has been associated with exposure to epipodophyllotoxins, such as etoposide.[rx]
Symptoms of Acute Monoblastic Leukemia
This table lists symptoms that people with this disease may have. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. This information comes from a database called the Human Phenotype Ontology (HPO). The HPO collects information on symptoms that have been described in medical resources. The HPO is updated regularly. Use the HPO ID to access more in-depth information about a symptom.
|Medical Terms||Other Names||
|100% of people have these symptoms|
|Acute monocytic leukemia||0004845|
|30%-79% of people have these symptoms|
|Bone marrow hypercellularity||0031020|
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High lymphocyte count
|5%-29% of people have these symptoms|
Swollen lymph nodes in the neck
|Increased lactate dehydrogenase level||0025435|
|Progressive hearing impairment||0001730|
Firm lump under the skin
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Skin manifestations are most frequent in acute monocytic leukemia and acute myelomonocytic leukemia. The skin lesions may be widespread and are often accompanied by gingival hyperplasia. Rarely, the leukemic skin infiltrates precede the development of bone marrow involvement by several months. A dense perivascular or diffuse dermal infiltrate characterizes the lesions histologically. The infiltrate is composed of a monotonous population of neoplastic cells with large folded or kidney-shaped nuclei and a thin rim of basophilic cytoplasm. The neoplastic cells often adopt a linear arrangement, resembling the “single-file” pattern of invasive lobular carcinoma of the breast (Fig. 49-78). The leukemic cells generally stain positively with antilysozyme and CD43 and can also be positive for CD45 and CD15. Myelomonocytic leukemia is characterized by both monocytic and granulocytic precursors. The dermal infiltrate is thus composed of an admixture of monocytoid and immature myeloid cells. The immunohistochemical staining pattern is similar to that of acute monocytic leukemia.
Diagnosis of Acute Monoblastic Leukemia
In order to fulfill World Health Organization (WHO) criteria for AML-5, a patient must have greater than 20% blasts in the bone marrow, and of these, greater than 80% must be of the monocytic lineage. A further subclassification (M5a versus M5b) is made depending on whether the monocytic cells are predominantly monoblasts (>80%) (acute monoblastic leukemia) or a mixture of monoblasts and promonocytes (<80% blasts). Monoblasts can be distinguished by having a roughly circular nucleus, delicate lacy chromatin, and abundant, often basophilic cytoplasm. These cells may also have pseudopods. By contrast, promonocytes have a more convoluted nucleus, and their cytoplasm may contain metachromatic granules. Monoblasts are typically MPO-negative and promonocytes are MPO variables. Both monoblasts and promonocytes stain positive for non-specific esterase (NSE), however, NSE may often be negative.
Common Test Are
- Bone marrow biopsy
- Flow cytometry
- Genetic testing
- Histologic confirmation
Immunophenotypically, M5-AML variably express myeloid (CD13, CD33) and monocytic (CD11b, CD11c) markers. Cells may aberrantly express B-cell marker CD20 and the NK marker CD56. Monoblasts may be positive for CD34.
A diagnosis of acute monocytic leukemia (AML-M5) based on α-naphthyl butyrate esterase (α-NB) staining has some problems because AML-M5 leukemic cells often show weak or faint positivity on α-NB staining. In these situations, some cases of AML-M5 tend to be misdiagnosed as AML-M0. Therefore, we evaluated the significance of weak or faint α-NB staining in AML-M5 diagnosed by flow cytometry (FCM). Nineteen AML cases in which leukemic cells were negative for naphthol AS-D chloroacetate esterase staining were studied. For FCM, we defined leukemic cells as having a monocytic nature when more than 10% of the leukemic cells were positive for at least one of the following antigens: CD4, CD11c, CD14, and CD64. The monocytic nature determined by FCM was consistent with positive or weak positivity on α-NB staining. Five of 6 cases in which leukemic cells exhibited faint positivity for α-NB staining could be diagnosed as AML-M5 by FCM, while negative α-NB staining was consistent with a diagnosis of AML-M0. These results suggest that AML-M5 should be taken into consideration even when leukemic cells are faintly positive for α-NB staining.
Treatments of Acute Monoblastic Leukemia
- Hematologic Transplant and/or Endocrine Procedures
The following article may help you
It is sometimes difficult to make a differential diagnosis of acute monocytic leukemia (AML-M5 by FAB Classification) from AML-M0 (FAB Classification), which shows poor differentiation in morphological and cytochemical examinations because leukemic cells from AML-M5 are often negative for myeloperoxidase (MPO) staining. These cells also frequently show weak or faint positivity on α-naphthyl butyrate esterase (α-NB) staining, which is a specific tool to determine if leukemic cells have a monocytic nature.[rx-rx] Furthermore, AMLM5 cells are sometimes negative for cytoplasmic MPO (cyMPO) on flow cytometric (FCM) analysis.[rx-rx] Weak or faint positivity often causes a diagnostic problem in which AML M5 is misdiagnosed as AML-M0 because of the controversial interpretation regarding the weak or faint positivity of α- NB staining. Therefore, we conducted a study to evaluate the significance of weak or faint α-NB staining in patients diagnosed with AML-M5 by FCM.
Surface antigens that indicate leukemic cells to be of a monocytic nature include CD4, CD11c, CD14, and CD64. Immature and mature monocytes express CD64,[rx-rx] CD4,[rx,rx] and CD11c[rx,,rx], antigens on their surface membranes, whereas CD14[rx-rx, rx-rx] is mostly expressed on mature monocytes. However, all of these antigens are not simultaneously expressed on leukemic cells in a single AML-M5 case; sole or dual expression of these antigens appears to be common. Therefore, in this study, we considered that single, as well as multiple expressions of these antigens, is sufficient to make a diagnosis of AML-M5 by FCM. Thus, in this study, we examined the relationship between the expression of these antigens and α-NB staining.
Marrow or peripheral blood samples were evaluated with a kit for double esterase staining (Muto Pure Chemicals, Tokyo, Japan). All patients with AML were included in this study regardless of the positive or negative MPO staining of leukemic cells. On the other hand, patients in whom leukemic cells were positive for naphthol AS-D chloroacetate esterase staining, which is specific for the neutrophilic cell lineage,[rx] were excluded from this study. Also, patients with AML-M6 or AML-M7 were excluded. To the best of our knowledge, no study has defined the α-NB activity required to make a diagnosis of monocytic leukemia. We did, however, find the diagnostic criteria for α-NB staining on the website for Beckman Coulter, Inc. (Tokyo, Japan). We show the criteria, which were originally written in Japanese, as [rx]. According to the criteria, leukemic cells with more than 6 dots in their cytoplasm are considered to show positive staining (+), but when the dot number is less than 5, it is considered weak or faint staining (±) [rx]. However, from our preliminary observations, we thought that the weak or faint criteria (1 to 5 dots) were ambiguous, leading to diagnostic confusion as to whether it was AML-M5 or AML-M0. Therefore, in the present study, we defined the positivity of α-NB staining as follows [rx]: positive staining (++): more than 3% of leukemic cells contain more than 6 dots in the cytoplasm; weakly positive (+): leukemic cells with 3 to 5 dots [rx]; faintly positive (±): those with 1 or 2 dots [rx]; negative (-): those without cytoplasmic dots. We excluded small cells with round nuclei in the evaluation of the α- NB staining because normal T lymphocytes show weak positivity on α-NB staining.[rx]
Flow cytometry was performed using FACS Cant II (Nippon Becton Dickinson Company, Ltd. (Tokyo, Japan) according to the manufacturer’s instructions. All marrow and blood samples were analyzed by CD45- positive mononuclear cell (MNC) gating as the first step. In this study, we diagnosed the leukemic cells as having a monocytic nature when the cells expressed either CD4, CD11c, CD14, or CD64 in more than 10% of the analyzed cells in addition to an AML pattern (positive for CD13, CD33, and CD34). We also defined acute leukemias as AML-M0 on flow cytometric analysis when leukemic cells showed the AML but not lymphoid pattern with or without cyMPO and without antigens related to monocytic, erythroid, or megakaryocytic lineages. Monoclonal antibodies employed in this study were as follows: CD45 (PerCP), CD4 (FITC), CD11b (PE), CD11c (FITC), CD13 (PE), CD14 (FITC), CD19 (APC), CD33 (PE), CD34 (APC), CD56 (APC), CD64 (FITC), and MPO (FITC). The MPO antibody was purchased from Beckman Coulter Co., Inc. (Tokyo, Japan) and the others were from Nippon Becton Dickinson Company, Ltd. The time of incubation with each antibody was 15 min at room temperature, then red blood cells were lysed in phosphate buffer solution (PBS) containing 0.5% paraformaldehyde and 0.5% saponin for 5 min, at 4°C. After washing twice with PBS cells were subjected for flow cytometric analysis.
Patient characteristics, cytochemistry, and a tentative diagnosis of AML subtype
In clinical data and cytochemistry of 19 AML patients included in this study are shown.MPO staining was negative in 4 of the 19 patients examined. As for the α-NB staining, 5, 8, 6, and 1 of the 19 patients showed positive, weakly positive, faintly positive, and negative staining, respectively. Patients in whom leukemic cells showed positive or weakly positive α- NB staining could be diagnosed with AMLM5 because blast cells in individual patients showed morphologically monocytic differentiation. On the other hand, patients in whom leukemic cells showed faintly positive or negative α-NB staining were tentatively diagnosed with AML-M5a or undifferentiated leukemia (Patient No.7, 9, 10, 13, and 14), indicating diagnostic difficulty with only morphological and cytochemical examinations for this group of patients. However, AML-M1, AML-M2, AML-M3, AML-M6, and AML-M7 could be ruled out from their characteristic morphology or negative naphthol AS-D chloroacetate esterase staining (for AML-M1, AML-M2, and AML-M3) in these 5 patients. In addition, positive α-NB staining was diminished by the treatment with sodium fluoride (NaF) in all cases.
Phenotypes of the leukemic cells
Surface antigens and cytoplasmic MPO (campo) expressed in leukemic cells from the 19 AML patients are shown in. In all patients, leukemic cells showed the AML phenotype, that is, the concomitant expression of CD34, CD33, and CD13, although these cells lacked CD34 expression. HLA-DR was positive in all but Patient 7 (data not shown). Leukemic cells were weakly positive for α-NB staining with monocytic morphology. In-Patient 10 whose leukemic cells exhibited CD19 positivity, these cells were positive for MPO staining. CD14 expression was observed in only 9 of all 19 patients. These results indicated that CD11c was the most frequently expressed (84.2%), followed by CD64 (56.3%), CD4 (47.4%), and CD14 (31.6%). Representative flow cytometry of bone marrow cells from Patient 10 is shown, in which leukemic cells expressed both CD11c and CD64.
We analyzed whether CD4, CD11c, CD14, or CD64 was expressed in AML in the neutrophil lineage. Leukemic cells were analyzed with the same antibody panel during the same period as in the present study in a total of 11 AML patients (2 AML-M1, 5 AML-M2, and 4 AML-M3 patients). Leukemic cells were positive for naphthol AS-D chloroacetate esterase staining in all these patients. CD11c was expressed in an AML-M1 patient at a level of 11%, and CD64 was expressed in 2 AML-M2 patients (28 and 30%) and one AML-M3 patient (30%).
In the relationship between the expression of monocyte-related antigens and positive or weakly positive α-NB staining is shown. Positive α-NB staining was observed in 5 of the 19 patients (Patients 1, 3, 11, 16, and 18). In these patients, leukemic cells from 3 patients expressed all 4, Patient 2 expressed 2, and Patient 1 expressed one of the 4 monocyte-related antigens, respectively. Weakly positive α- NB staining was observed in 8 of the 19 patients, and in all these 8 patients, the leukemic cells expressed one to 4 monocyte- related antigens. Collectively, leukemic cells that showed positive or weakly positive α-NB staining mostly expressed more than 2 monocyte-related antigens, being consistent with the results of FCM and α-NB staining.
To make a differential diagnosis of the AML subtype, double esterase staining is a useful tool. Naphthol AS-D chloroacetate esterase staining is specific for the granulocyte lineage and its sensitivity is excellent. [rx,rx] While α-NB staining is specific for the monocytic lineage, its sensitivity is too low for leukemic monocytes.[rx,rx] Therefore, α-NB staining often shows weakly or faintly positive results, even when leukemic cells are strongly suspected to be of a monocytic nature upon morphological examination. Indeed, in this study, positive or weakly positive α-NB staining, which is usually accepted as diagnostic for AML-M5, was observed in only 13 of the 19 patients. We first confirmed whether positive or weakly positive α-NB is sufficient for the diagnosis of AML-M5 with the expression of monocyte- related antigens with the use of FCM. As a result, the leukemic cells from these 13 patients expressed more than 2 monocyterelated antigens, except for 2 patients (Patients 7 and 14; CD11c only), indicating that positive or weakly positive α-NB staining is sufficient to make a diagnosis of AML-M5.
The problem to be addressed in this study was the diagnostic value of faintly positive α-NB staining for AML-M5. Faintly positive α-NB staining was observed in 6 of the 19 patients in this study, and FCM analysis showed that leukemic cells from 5 of these 6 patients expressed one to 2 monocyte-related antigens, indicating that the majority of patients in whom leukemic cells showed faintly positive α-NB staining could be diagnosed with AML-M5. Aberrant expression of monocyte- related antigen in these patients may be unlikely because other subtype AML except for AML-M5 and AML-M0 could be ruled out. In the present study, negative α- NB staining was observed in only one patient. An early study described the presence of α-NB staining-negative AML-5 or AML-M4; however, the diagnosis of these types of AML was performed based on morphologic and cytochemical methods at this time period.[rx] Thus, the relationship between the antigen profile of the leukemic cells and negative α-NB staining should be examined in a larger number of patients in the future.
We employed CD4,[rx,rx] CD11c,[rx,rx,rx] CD14, and CD64 antigens as monocyte-related antigens, and diagnosed a patient with AML-M5 when the leukemic cells expressed at least one of these antigens at the level of 10% in the present study. Of these antigens, CD4, CD14, and CD64 may have been established as monocyte-related antigens.[rx-rx] CD11c is expressed on immature monocytes[rx,rx,rx] like CD4. CD11c is also expressed on granulocytes, but mainly on mature granulocytes.[rx] Therefore, it may reasonable to conclude that leukemic cells are an immature monocytic lineage based on the expression of CD11c. Furthermore, in the present study, AML in the granulocytic lineage was excluded by the use of naphthol AS-D chloroacetate esterase staining; therefore, CD11c may have been a valuable tool to determine if the leukemic cells were of monocytic lineage. Indeed, CD11c was weakly positive in only one patient among 11 patients with AML in the neutrophil-lineage (AML-M1-3), as described above.