Pathology
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Haematology
A 4 year old boy presents to his GP with a persistent sore throat and malaise. Examination reveals bruising and splenomegaly. A full blood count demonstrates a normochromic normocytic anaemia with thrombocytopaenia. 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.Acute Leukaemia
Pathology / Haematology / Malignancy
Last Updated: 3rd June 2020
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.
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.
Investigation:
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 in children
- 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
- Specific therapy of ALL in adults
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.
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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 |
