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Role Of Laboratory Tests In The Diagnosis Of Myelodysplastic Syndrome

Overview

Myelodysplastic syndrome or MDS is a heterogenous group of clonal hematopoietic disorders characterized by “a hypercellular or hypocellular marrow with impaired morphology and maturation (dysmyelopoiesis) and peripheral blood cytopenias, resulting from ineffective blood cell production” (Emmanuel and Woermann, 2009). The condition can involve any of the lineages of the myeloid system, including megakaryotic, granulocytic and erythrocytic hematopoiesis and is considered to be a premalignant condition with the potential to progress to acute myeloid leukemia. The main pathophysiology in this condition is that the hematopoietic stem cells do not mature in a proper fashion to healthy erythrocytes, leukocytes and platelets resulting in low counts of mature cells and abnormal morphology. Thus there are many immature cells which do not function in a proper manner leading to several complications.

MDS an be primary or secondary. Secondary MDS can occur due to several causes like exposure to radiotherapy or cytotoxic chemotherapy for another cancer, intensive pretreatment for patients with autologous bone marrow transplants, viral infection, genetic predisposition or exposure to chemicals like benzene (Emmanuel and Woermann, 2009, Nguyen, 2009). Exposure to heavy metals like lead and mercury can also result in this condition (National Cancer Institute, 2010).

80-90 percent of cases occur in those who are above 60 years of age (American Cancer Society, 2010). The incidence is men in at least 2 times more than in women (Emmanuel and Woermann, 2009). The condition is found worldwide and affects all races and ethnic groups (Emmanuel and Woermann, 2009).

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The condition is associated with significant morbidity and mortality. More than 30 percent cases of MDS transform in acute leukemia (National Cancer Institute, 2010). Survival following the diagnosis of MDS is variable and dependent on the prognostic factors (Stone, 2009). The survival can occur from months to years (National Cancer Institute, 2010). In children, the course of the disease is more aggressive and the mean survival is less than 10 months (Tilak et al, 2008).
Figure-1. Hematopoiesis (National Cancer Institute, 2010).

Diagnostic criteria

In many patients, MDS is often detected late due to absence of early symptoms. In some others, routine hematological examination may reveal the condition. Those who have advanced disease present with signs and symptoms related to the cytopenias like shortness of breath, pallor, easy fatigability, easy bruising, uncontrollable bleeding, frequent petechiae, fever and frequent infections (National Cancer Institute, 2010). In about 18 percent cases,
autoimmune manifestations in the form of arthralgias can occur (Giannouli et al, 2004). Hepatomegaly can occur in 10- 15 percent cases (Shah et al, 2009).
Investigations which help in the arrival of the diagnosis are complete blood count, peripheral smear, bone marrow aspiration and biopsy and cytogenetic analysis (National Cancer Institute, 2010). Based on these tests, MDS can be classified as described in the sections below.

1. Peripheral blood tests
Peripheral blood tests may reveal anemia, thrombocytopenia or neutropenia or a combination of these. In most of the cases, all the 3 cell lineages are affected. Anemia may be mild to severe and is usually macrocytic with mean cell volume of more than 100fl. The red blood cells appear as macro-ovalocytes and have punctate basophilia. In many cases macro-ovalocytes are associated with microcytes. When neutropenia is present, it may be mild or severe. The granulocytes often have abnormalities like bilobes, unsegmented nuclei or hypersegmented nuclei, resembling megaloblastic disease. Granules may either be absent or present in abnormal proportions in the cytoplasm, when they are called Dohle bodies. When platelets cell lineage is affected, decrease in the number of platelets occurs and abnormalities of the morphologic size and cytoplasm occur. Some such abnormalities are megakaryocyte fragments and hypogranular platelets (Emmanuel and Woermann, 2009).

2. Bone marrow aspiration studies
In most patients, there is hypercellularity of the marrow. However, in some cases, hypocellular marrow can occur resembling aplastic anemia. In some patients, myelofibrosis may be present, creating a confusion with mucopolysaccharidoses. In RBC lineage, dyserythropoiesis occurs leading to characteristic dysplastic changes. The changes are similar to those in megaloblastic anemias. The erythroid precursor cells may exhibit binuclearity or multinuclearity. Ringed sideroblasts due to accumulation of iron in the mitochondria may be seen. In the WBC lineage, dysmyelopoiesis occurs leading to dysplastic changes. Myeloid hyperplasia occurs with expanded metamyelocyte and myelocyte population. This is known as midstage bulge. This is one of the differentiating aspects from acute leukemia in which there is characteristic absence of mid stage. FAB classification is based on the percentage of myeloblasts. In matured WBCs, there is characteristic nuclear-cytoplasm dissociation. When platelet lineage is involved, dysthrombopoiesis occurs, resulting in micromegakaryocytes. These cells have poor nuclei lobulation and possess giant buds (Emmanuel and Woermann, 2009).
Figure-2. Blasts, promyelocytes, abnormal promyelocytes (Mufti et al, 2008).

3. Cytogenetic studies
Mutations in the clonal cell lines are seen. In 48- 64 percent cases, abnormal chromosomes are seen in different series. However, some researchers claim that up to 79 percent of patients with MDS have chromosomal abnormalities. Higher resolution techniques like hybridization using fluorescent in situ or color coding techniques are useful tests to detect chromosomal abnormalities. These cells help in the observation of non-mitotic intact cells. The most commonly detected chromosomal anomalies are monosomy 7, trisomy 8 and 5q-. Most of the chromosomal anomalies are clonal. Multiple chromosomal anomalies is suggestive of poor prognosis. Single abnormality involving chromosome 7 indicates good prognosis (Emmanuel and Woermann, 2009).

4. Histopathological studies on bone marrow biopsy
Features on histological examination which are diagnostic of myelodysplastic syndrome are trilineage dysplasia, dysplastic changes on peripheral blood smear and hypercellular features in bone marrow aspiration sample. Detection of chromosomal abnormalities supports the diagnosis and gives inference for prognosis (Emmanuel and Woermann, 2009).

Staging

Once a patient is diagnosed to have myelodysplastic syndrome, staging of the disease is very important because of varying clinical outcomes. Staging is based on prognosis and treatment is based on staging. Staging is based on International Prognostic Scoring System or IPPS (Emmanuel and Woermann, 2009). Scoring is done as follows:
The percentage of myeloblasts is the bone marrow aspiration of the patient is the first prognostic factor in MDS. When myeloblasts are less than 5 percent, the score located is zero. For 5- 10 percent presence in myeloblasts, the score is 0.5, for 11- 20 percent presence of myeloblast, the score is 1.5 points and for more than 20 percent of myeloblasts, the score is 2 points. The next prognostic factor is karyotype. Prognosis in those with no chromosomal abnormality, or -Y, del (20q), del(5q) is good and hence the score allotted is 0 point. In those with trisomy 8(+8), the prognosis is intermediate and the score is 0.5 point. In those with other chromosomal abnormalities like 7q- or -7, the prognosis is guarded and the score allotted is 1 (Emmanuel and Woermann, 2009).

The last prognostic factor is the number of cell lineages involved, i.e., the number of cytopenias. Thus, for only anemia, the score is 1, for anemia with neutropenia or thrombocytopenia, the score is 2, and for those with all the 3 cytopenias, the score is 3.

There are five stages as follows:

1. Low stage- 0
2. Intermediate stage 1- 0.5- 1
3. Intermediate stage 2- 1.5- 2
4. High stage- 2.5 or beyond

Classification

The current classification for MDS is based on certain morphological criteria as identified in the peripheral smear and bone marrow aspiration study. The criteria are proposed by the French-American-British or the FAB classification and the WHO groups.

FAB classification (Bennett et al, 1982)

1. Refractory anemia or RA: The patient has only anemia. The count and morphology of white blood cells and platelets is normal. The myeloblast count in bone marrow is less than 5 percent.
2. Refractory anemia with ringed sideroblasts or RARS: There is anemia along with presence of excess iron manifesting as ringed sideroblsts on peripheral smear. In the bone marrow study, the myeloblast count is less than 5 percent. The percentage of ringed sideroblasts that is significant is mre than 15 percent.
3. Refractory anemia with excess blasts or RAEB: The peripheral smear is suggestive of anemia and the bone marrow study is indicative of increased number of myeloblasts. There are 2 stages her. In RAEB stage-1, the bone marrowmyeloblast cells are more than 5 percent , but less than 10 percent. In stage-2, the myeloblast count is between 21- 30 percent.
4. RAEB-T: Blast cells more than 20 percent in transformation is suggestive of acute myeloid leukemia.
5. Chronic myelomonocytic leukemia or CMML: The criteira for classifying the disease under this stage is based not only the myeloblasts, but on the monocyte count. Monocytosis of more than 1000 per micriliter fall under this classification. This group is now considered under myeloproliferative disorder.
Currently, the WHO classification, which is an improvement of the FAB classification is in vogue (Vardiman et al, 2002) as illustrated in table-1.

FAB

WHO
RA (<5% blasts)
RA

Refractory cytopenia with multilineage dysplasia

MDS-unclassified
MDS with isolated del (5q)

RARS

Refractory cytopenias with multilineage dysplasia and ringed sideroblasts
RAEB (5-20% blasts)
RAEB-1 (5-9% blasts)
RAEB-2 (10-19% blasts)
RAEB-T (21-30% blasts)
Acute myeloid leukemia (>20% blasts)
FAB
WHO
RA (<5% blasts)
RA

Refractory cytopenia with multilineage dysplasia

MDS-unclassified
MDS with isolated del (5q)

RARS

Refractory cytopenias with multilineage dysplasia and ringed sideroblasts
RAEB (5-20% blasts)
RAEB-1 (5-9% blasts)
RAEB-2 (10-19% blasts)
RAEB-T (21-30% blasts)
Acute myeloid leukemia (>20% blasts)
Current trends
For appropriate classification, accurate enumeration of blast cells in the bone marrow aspiration sample is critical. However, due to lack of precise criteria for proper morphological identification and definition of metamyeloytes and myeloblasts, proper enumeration of myeloblasts is very difficult (Mufti et al, 2008).
According to the International Working Group on Morphology of Myelodysplastic Syndrome (IWGM-MDS), “(1) agranular or granular blast cells be defined (replacing the previous type I, II and III blasts), (2) dysplastic promyelocytes be distinguished from cytologically normal promyelocytes and from granular blast cells, (3) sufficient cells be counted to give a precise blast percentage, particularly at thresholds that are important for diagnosis or prognosis and (4) ring sideroblasts be defined as erythroblasts in which there are a minimum of 5 siderotic granules covering at least a third of the nuclear circumference” (Mufti et al, 2008).

References

American Cancer Society. (2010). Detailed Guide: Myelodysplastic Syndrome. http://www.cancer.org/docroot/CRI/CRI_2_3x.asp?dt=65
Bennett, J.M., Catovsky, D., Daniel, M.T., Flandrin, G., Galton, D.A., Gralnick, H.R., et al. (1982). Proposals for the classification of the myelodysplastic syndromes. Br J Haematol., 51, 189-99.
Emmanuel, C.B., and Woermann, U. (2009). Myelodysplastic Syndrome. Emedicine from WebMD. Retrieved on 21st April, 2010 from http://emedicine.medscape.com/article/207347-overview
Mufti, G.J., Bennettt, J.M., Goasguen, J. (2008). Diagnosis and classification of myelodysplastic syndrome: International Working Group on Morphology of myelodysplastic syndrome (IWGM-MDS) consensus proposals for the definition and enumeration of myeloblasts and ring sideroblasts. Hematologica, 93(11), 1712- 1717.
National Cancer Institute. (2010). Myelodysplastic Syndrome. Retrieved on 21st April, 2010 from http://www.cancer.gov/cancertopics/pdq/treatment/myelodysplastic/Patient/page1
Nguyen, P.L. (2009). The myelodysplastic syndromes. Hematology/Oncology Clinics of North America., 23, 675.
Shah, N.M., Prajapati, S.G., Adesara, R.P., and Patel, A.P. (2009). An analysis of 30 cases of myelodysplastic syndrome. Indian Journal of Pathology and Microbiology, 52(2), 206- 209.
Stone, R.M. (2009). How I treat patients with myelodysplastic syndromes. Blood, 113, 6296.
Tilak, V., Sookmane, D.D., Gupta, V., and Shukla, J. (2008). Myelodysplastic Syndrome. Indian Journal of Pediatrics, 75(7), 729- 732.
Vardiman, J.W., Harris, N.L., Brunnig, R.D. (2002). The World Health Organization (WHO) classification of the myeloid neoplasms. Blood, 100, 2292-302.

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