Oncology & Palliative Care
A 4 year old boy is brought to the Emergency Department with a persistent sore throat and malaise. Examination reveals multiple bruises and splenomegaly. A full blood count shows:
- Haemoglobin: 8.7 g/dL
- White cell count: 5 x 109/L
- Platelets: 43 x 109/L
- MCV: 85 fl
Which of the following is the most likely diagnosis?
Answer:
Acute lymphoblastic leukaemia (ALL) is caused by an accumulation of lymphoblasts in the bone marrow and is the most common malignancy of childhood. The incidence of ALL is highest at 3 - 7 years, with 75% of cases occurring before the age of 6. Clinical features include feeling generally unwell, perhaps with a sore mouth or throat, features of anaemia, neutropaenia, thrombocytopaenia (bruising) and organ infiltration (splenomegaly). Haematological investigations reveal a normochromic normocytic anaemia with thrombocytopenia in most cases.Leukaemia
Haematology / Oncology & Palliative Care
Last Updated: 30th March 2023
The leukaemias are a group of disorders characterised by the accumulation of malignant clonal white cells in the bone marrow and blood.
Acute leukaemias are usually aggressive diseases in which malignant transformation occurs in the haemopoietic stem cell or early progenitors. Genetic damage is believed to involve several key biochemical steps resulting in:
- An increased rate of proliferation
- Reduced apoptosis
- A block in cellular differentiation
Together, these events cause accumulation in the bone marrow of early haemopoietic cells called blast cells. The dominant clinical feature of acute leukaemia is usually bone marrow failure caused by accumulation of blast cells, although organ infiltration also occurs.
Acute leukaemia is normally defined as the presence of over 20% of blast cells in the bone marrow at clinical presentation (although it can be diagnosed with less than 20% blasts if specific leukaemia-associated cytogenetic or molecular genetic abnormalities are present). The lineage of the blast cells is defined by microscopic examination (morphology), immunophenotypic (flow cytometry), cytogenetic and molecular analysis. This will define whether the blasts are of myeloid or lymphoid lineage and also localise the stage of cellular differentiation.
The chronic leukaemias are distinguished from acute leukaemias from their slower progression. Chronic leukaemias can be broadly subdivided into myeloid and lymphoid groups.
Acute Myeloid Leukaemia
Incidence:
Acute myeloid leukaemia (AML) is the most common form of acute leukaemia in adults and becomes increasingly common with age, with a median onset of 65 years. It forms only a minor fraction (10 - 15%) of childhood leukaemia.
Clinical Features:
The clinical features of AML are dominated by the pattern of bone marrow failure caused by the accumulation of malignant cells within marrow. Infections are frequent and anaemia and thrombocytopaenia are often profound. Tumour cells can infiltrate a variety of tissues.
Investigations:
Haematological investigations reveal a normochromic normocytic anaemia with thrombocytopenia in most cases. The total white cell count is usually increased and blood film examination typically shows a variable number of blast cells. The bone marrow is hypercellular and typically contains many blast cells.
Management:
- General supportive therapy for bone marrow failure
- Insertion of central venous cannula, blood product support, prevention of tumour lysis syndrome, prompt treatment of fever
- Specific therapy of AML
- Determined by age and performance status of patient as well as the genetic lesions within the tumour; aim of treatment in acute leukaemia is to induce complete remission (less than 5% blasts in the bone marrow, normal peripheral blood counts and normal clinical status) and then to consolidate this with intensive therapy, hopefully eliminating the disease; allogeneic stem cell transplantation is considered in poor prognosis cases or for patients who have relapsed
Prognosis:
The outcome for an individual patient with AML will depend on a number of factors including age and white cell count at presentation. However, the genetic abnormalities in the tumour are the most important determinant. The prognosis for patients with AML has been improving steadily, particularly for those under 60 years of age, and approximately one-third of patients of this group can expect to achieve long-term cure. For the elderly, the situation is poor and less than 10% of those over 70 years of age achieve long-term remission.
Acute Lymphoblastic Leukaemia
Incidence:
Acute lymphoblastic leukaemia (ALL) is caused by an accumulation of lymphoblasts in the bone marrow and is the most common malignancy of childhood. The incidence of ALL is highest at 3 - 7 years, with 75% of cases occurring before the age of 6. There is a secondary rise after the age of 40 years. 85% of cases are of B-cell lineage and have an equal sex incidence; there is a male predominance for the 15% of T-cell lineage.
Clinical features:
- Bone marrow failure
- Anaemia
- pallor
- lethargy
- dyspnoea
- Neutropaenia
- fever
- malaise
- recurrent infections (mouth, throat, skin, respiratory, perianal or other)
- Thrombocytopaenia
- spontaneous bruising
- purpura
- bleeding gums
- menorrhagia
- Anaemia
- Organ infiltration
- Tender bones
- Lymphadenopathy
- Splenomegaly
- Hepatomegaly
- Meningeal syndrome (headache, nausea and vomiting, blurred vision and diplopia)
- Testicular swelling or signs of mediastinal compression
Investigations:
Haematological investigations reveal a normochromic normocytic anaemia with thrombocytopenia in most cases. The total white cell count may be decreased, normal or increased. The blood film typically shows a variable number of blast cells. The bone marrow is hypercellular with >20% blast cells. Lumbar puncture for CSF examination is not generally performed as it may promote the spread of tumour cells to the CNS. Initial assessment of the CSF should always be combined with the concurrent administration of intrathecal chemotherapy. Biochemical tests may reveal a raised serum uric acid, serum lactate dehydrogenase or, less commonly, hypercalcaemia, Liver and renal functions tests are performed as a baseline before treatment begins. Radiography may reveal lytic bone lesions and a mediastinal mass caused by enlargement of the thymus and/or mediastinal lymph nodes.
Management:
- General supportive therapy for bone marrow failure
- Insertion of central venous cannula, blood product support, prevention of tumour lysis syndrome, prompt treatment of fever
- Specific therapy of ALL
- Chemotherapy +/- radiotherapy; treatment is guided by age, gender and white cell count at presentation; aim of treatment in acute leukaemia is to induce complete remission (less than 5% blasts in the bone marrow, normal peripheral blood counts and normal clinical status) and then to consolidate this with intensive therapy, reducing the tumour burden to very low levels or hopefully eliminating the disease
Prognosis:
There is great variation in the chance of individual patients achieving a long-term cure based on a number of biological variables. Approximately 25% of children relapse after first-line therapy and need further treatment but overall 90% of children can expect to be cured. The cure rate in adults drops significantly to less than 5% over the age of 70 years.
Chronic Myeloid Leukaemia
Incidence:
Chronic myeloid leukaemia (CML) is a clonal disorder of a pluripotent stem cell. The disease accounts for around 15% of leukaemias and may occur at any age. The diagnosis of CML is rarely difficult and is assisted by the characteristic presence of the Philadelphia (ph) chromosome. This disease occurs in either sex, most frequently between the ages of 40 and 60 years. However, it may occur in children and neonates, and in the very elderly. There is a genetic predisposition to development of the disease.
Clinical Features:
In up to 50% of cases the diagnosis is made incidentally from a routine blood count. In those cases where the disease presents clinically, the following features may be seen:
- Symptoms related to hypermetabolism
- weight loss
- lethargy
- anorexia
- night sweats
- Splenomegaly
- Features of anaemia
- pallor
- dyspnoea
- tachycardia
- Features of abnormal platelet function
- bruising
- epistaxis
- menorrhagia
- haemorrhage
- Gout or renal impairment caused by hyperuricaemia from excessive purine breakdown
- Visual disturbance and priapism (rare)
Investigations:
- Leucocytosis is the main feature, with a complete spectrum of myeloid cells seen in the peripheral blood. The levels of neutrophils and myelocytes exceed those of blast cells and promyelocytes.
- Increased circulating basophils are a characteristic feature.
- Normochromic normocytic anaemia is usual.
- Platelet count may be increased (most frequently), normal or decreased.
- Bone marrow is hypercellular with granulopoietic predominance.
- Serum uric acid is usually raised.
- Ph chromosome on cytogenetic analysis (98% of cases)
Management:
- Tyrosine kinase inhibitors (TKI) are the mainstay of treatment and several different drugs are now available, largely replacing chemotherapy treatment
- Allogeneic stem cell transplantation is a potentially curative treatment for CML but because of the risks associated with the procedure, it is usually reserved for TKI failures or patient's presenting in accelerated phases.
Prognosis:
The clinical outlook is very good and 90% of patients can expect long-term control of disease.
Chronic Lymphocytic Leukaemia
Incidence:
Chronic lymphocytic leukaemia (CLL) is the most common of the chronic lymphoid leukaemias and has a peak incidence between 60 and 80 years of age. It is the most common form of leukaemia within Europe and the USA but less frequent elsewhere. The CLL tumour cell is a mature B-cell with weak surface expression of immunoglobulin (IgM or IgD). CLL cells typically exhibit impaired apoptosis and a prolonged lifespan, and this is reflected in their accumulation in the blood, bone marrow, liver, spleen and lymph nodes. The mean age at diagnosis is 72 years, with only 15% of cases before 50 years of age. The male: female ratio is approximately 2:1.
Clinical Features:
- Over 80% of cases are diagnosed from the results of a routine blood test, usually taken for another reason.
- Enlargement of cervical, axillary or inguinal lymph nodes is the most frequent clinical sign.
- Features of anaemia and thrombocytopenia may be present
- Splenomegaly and, less commonly, hepatomegaly are common in later stages
- Immunosuppression is often a significant problem with recurrent infection
Investigations:
- Lymphocytosis
- CLL tumour cells
- Normochromic normocytic anaemia
- Thrombocytopenia
- Bone marrow aspiration shows up to 95% lymphocytic replacement of normal marrow elements
- Reduced concentrations of serum immunoglobulins are found
- Autoimmunity directed against cells of the haemopoietic system is common
Management:
It is very difficult to cure CLL and so the approach to therapy is generally conservative, aiming for symptom control rather than a normal blood count. Indeed, chemotherapy given too early in the disease can shorten rather than prolong life expectancy. Many patients never need treatment but treatment may be given for troublesome symptoms or if the lymphocyte count rises rapidly. Use of chemotherapy and an anti-CD20 monoclonal antibody establishes disease remission but is not curative.
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- Biochemistry
- Blood Gases
- Haematology
| Biochemistry | Normal Value |
|---|---|
| Sodium | 135 – 145 mmol/l |
| Potassium | 3.0 – 4.5 mmol/l |
| Urea | 2.5 – 7.5 mmol/l |
| Glucose | 3.5 – 5.0 mmol/l |
| Creatinine | 35 – 135 μmol/l |
| Alanine Aminotransferase (ALT) | 5 – 35 U/l |
| Gamma-glutamyl Transferase (GGT) | < 65 U/l |
| Alkaline Phosphatase (ALP) | 30 – 135 U/l |
| Aspartate Aminotransferase (AST) | < 40 U/l |
| Total Protein | 60 – 80 g/l |
| Albumin | 35 – 50 g/l |
| Globulin | 2.4 – 3.5 g/dl |
| Amylase | < 70 U/l |
| Total Bilirubin | 3 – 17 μmol/l |
| Calcium | 2.1 – 2.5 mmol/l |
| Chloride | 95 – 105 mmol/l |
| Phosphate | 0.8 – 1.4 mmol/l |
| Haematology | Normal Value |
|---|---|
| Haemoglobin | 11.5 – 16.6 g/dl |
| White Blood Cells | 4.0 – 11.0 x 109/l |
| Platelets | 150 – 450 x 109/l |
| MCV | 80 – 96 fl |
| MCHC | 32 – 36 g/dl |
| Neutrophils | 2.0 – 7.5 x 109/l |
| Lymphocytes | 1.5 – 4.0 x 109/l |
| Monocytes | 0.3 – 1.0 x 109/l |
| Eosinophils | 0.1 – 0.5 x 109/l |
| Basophils | < 0.2 x 109/l |
| Reticulocytes | < 2% |
| Haematocrit | 0.35 – 0.49 |
| Red Cell Distribution Width | 11 – 15% |
| Blood Gases | Normal Value |
|---|---|
| pH | 7.35 – 7.45 |
| pO2 | 11 – 14 kPa |
| pCO2 | 4.5 – 6.0 kPa |
| Base Excess | -2 – +2 mmol/l |
| Bicarbonate | 24 – 30 mmol/l |
| Lactate | < 2 mmol/l |
