Morphological features

Morphological features

Patient A:

A 52 year old man presented to his general practitioner complaining of weight-loss, anorexia, and abdominal discomfort. On clinical examination marked splenomegaly and pallor were noted with. Blood was taken for analysis and the results are given below.

Table 1: Full Blood count

Red blood cell indices

Value

Normal values (male)

WBC (L)

100 x 109 ↑

4.0-11.0 x 109

RBC (L)

3.45 x 1012 ↓

4.5-6.5

HGB (g/dl)

11.6 ↓

13.5-17.5

HCT (%)

34.1 ↓

40-52

MCV (fL)

98.7 ↑

80-95

MCHC (g/dl)

34.1 ↔

30.0-35.0

RDW

21.6 ↑

11.5-14.5

Table 2: Manual differential count of Cells

Cells

Manual differential count (%)

Normal values (%)

Neutrophil

48 ↓

50-70

Lymphocytes

6 ↓

15-45

Monocytes

3 ↔

0-10

Basophils

3 ↑

0-2

Metamyelocytes

13 ↑

3-5

Myelocytes

20

Promyelocytes

5

Blasts

2

Morphological features: Cytogenetic t (9q+; 22q-) present.

From the Cytogenetic test we can confirm the presence of the Ph chromosome in all dividing cells. The Philadelphia chromosome is an acquired cytogenetic abnormality that characterizes all leukemic cells in CML (Goldman, 1997). It is formed as a result of a reciprocal translocation of chromosomal material between the long arm of one chromosome 22 and one chromosome 9, t (9: 22) (q34: q11) (Goldman and Preisler, 1984). The (9:22) translocation generated the BCR-ABL fusion gene on the Ph chromosome and also a reciprocal fusion gene that designated ABL-BCR on the derivative 9q+ chromosome. Such translocation involving just two chromosome are described as simple, whereas about 10% of patients have complex translocation involving chromosome 9, 22 and one or sometimes two other chromosomes (Spurr et al. 1982).

BCR- ABL is transcribed as an 8.5 kb mRNA and encodes a protein with a molecular weight of 210 kda. This p210 oncoprotein has far greater tyrosine kinase activity than normal ABL gene product. The BCR/ABL fusion protein activates signal transduction pathways leading to uncontrolled kinase activity, therefore uncontrolled cell growth (Frazer et al, 2006).

Chronic Myeloid Leukaemia (CML) is also known as chronic granulocytic leukaemia, is a blood cancer that grows gradually to become worse. CML initiates from the presences of Philadelphia chromosome, an acquired abnormality of pluripotent stem cell (Canaani et al. 1984). CML disorder is a least (15%) common form of Leukaemia, with its high incidence in either sex, at middle to old age individuals. This patient's age is 54, and hence he falls within the set category of CML. Patients with CML can show clinical features over 3 phase's i.e. chronic phase: during this phase the ratio of myeloblasts and promyelocytes is low whereas the count for basophil and monocyte may be increased which is seen in table 2. The unstable accelerated phase is due to increased cytogenetic abnormalities and the last is the terminal blastic phase (Frazer et al, 2006).

A typical feature of CML is the abnormally increased white blood cell count; which is 10 times higher than the upper limit of the reference range within this patient. This is due to the uncontrollable proliferation of cells resulting of fused bcr/abl protein on chromosome 22 that interacts with interleukin-3 receptor subunit. This in turn accelerates cell division, as bcr/abl tends to promote enzymes and cell-controlling proteins. The bcr promoter is always switched on therefore influencing tyrosine kinase to repeatedly and spinning the production of cells out of control (Konopka et al 1985). This result in an overproduction of granulocytic white blood cells and therefore both mature and immature cells can be present in the bloodstream. In addition, the increased number of granulocytes is also an indicative of CML disease. This is because the Philadelphia chromosome abnormality in the cloned granulocytes allows them to be preferentially replicated and ultimately substitutes the myeloid precursor cells therefore the bone marrow becomes hypercellular. The cells with the Philadelphia chromosome have an elevated rate of cytoplasmic maturation in comparison to nuclear maturation. This can be observed in the CML promyelocytes which contain increased number of cytoplasmic granules. In addition, the DNA repair is inhibited by the genetic abnormality (Ph) which causes genomic instability which in turn results in blast crisis as demonstrated by CML (Kantarjian et al 2006).

On medical examination, this patient presented with marked splenomegaly, which could result from increased destructions of erythrocytes in the spleen. Hence this explains the low level of RBC. The irregular pattern of erythrocytes maturation and survival often results in patient experiencing anaemia (Hoffbrand et al, 2006). In addition, an abnormal white blood cell (WBC) continuously replicates itself. They do not function normally i.e. they do not fight infection as suppose to, and also importantly they do not die at the same rate as seen in the normal WBCs. This is due to their impaired apoptosis resulting from the Philadelphia chromosome and therefore they accumulate in the marrow which inhibits the production of the other blood cells. This can in turn lead to anaemia. Ultimately, the leukemic cells spread through bloodstream where they continue to multiply, at times forming tumours and damaging other organs. Since, filtration of blood and destruction of old cells take place in spleen, the spleen is predisposed to become swollen and enlarged with the abnormal cells (Goldman and Preisler, 1984). Therefore the spleen is continuously working to remove abnormal cells whilst producing normal erythrocytes through the process of haemopoiesis. This possibly could give an impression to the individual that they are full; despite they have not consumed any food.

The microscopic blood film of patients with CML often present a norm chromic, normocytic anaemia, which is also seen in this patient blood film this is due to erythroid precursors being suppressed in the bone marrow and decreased erythrocyte life span in the peripheral blood. The increase in MCV and RDW are characteristics of anaemia, and thus indicating early stage of CML (Hoffbrand et al, 2006). The low level of RBC is a result of breakdown of erythrocytes in the spleen. This could also provide an explanation for low level of HGB. The low level of HGB would mean reduced capacity of erythrocyte to carry oxygen, resulting in less oxygen delivered to the epithelial cells which leads to pallor and could be the explanation for patient undergoing moderate pallor.

The patient also emphasised on weight loss and anorexia, this could be down to hypermetabolism which is common in CML patients due to increased requirement of proliferating cancerous blood cells in marrow, large amounts of energy is required for the DNA replication (Goldman, 1997).

The treatment in the initial phase could involve Allopurinol, which can prevent from hyperuricaemia and gout (Roger and Clive, 1999). However the treatment of the chronic phase involves Imatinib mesylate, a drug that functions to inhibit tyrosine kinase specifically by inhibiting the fusion protein bcr-abl. Imatinib mesylate stops tyrosine kinase activity by competing with adenosine triphosphate (ATP) (Russell and Norman, 2008).

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