Leukaemia – How is it diagnosed?

There are four categories of leukaemia: acute myeloid leukaemia (AML), chronic myeloid leukaemia (CML), chronic lymphocytic leukaemia (CLL) found more commonly in adults, and acute lymphoblastic leukaemia (ALL) more commonly presenting in childhood. 

Symptoms

The diagnosis is heralded by several clinical characteristics, such as bone pain, bleeding and bruising, fatigue, shortness of breath, and recurrent infections.

In cases of ALL, patients may present with lymph node enlargement and abdominal distention owing to an enlarged liver and/or spleen. 

In CML, early satiety and abdominal distention, features of a high white cell count, such as tinnitus, blurred vision, and headaches may potentiate the need for further investigation. 

Clinical presentation

The clinical presentation is variable between patients and prior to further investigations the initial clinician (GP or a casualty officer in hospital) will conduct a thorough clinical examination. 

Diagnostic investigations

A full blood count (FBC) with a differential count and peripheral blood smear (PBS) is required to make the diagnosis. This entails samples of your blood being drawn and sent for testing. 

The peripheral blood is examined, by a haematopathologist, in the laboratory using a microscope to identify and enumerate the presence of immature cells, termed blasts, in cases of acute leukaemia. Chronic leukaemia usually will have increased number of mature lymphoid cells in CLL, and in CML will show immature white blood cells in different stages of maturation. 

The anticipated FBC findings include a high white cell count coupled with an anaemia and low platelet count. Referral to a specialist haematologist is advised to facilitate the performance of a bone marrow aspirate and trephine (BMAT) biopsy with supporting investigations, such as flow cytometry and molecular analysis for confirmation and prognostication of the leukaemia. 

BMAT

This procedure, performed by a doctor, is done under sedation with local anaesthetic and involves using a needle to retrieve a sample of a bone marrow aspirate at sites, such as the pelvic or hip bone and occasionally the sternum. 

Bone marrow aspirate is spread on glass slides and some of the aspirate may be sent for other forms of test, including flow cytometry and genetic testing.

Flow cytometry 

This procedure involves enumerating and identification of the leukaemic cells by accessing the presence of cell surface markers, termed cluster of differentiation (CD) markers or immunophenotypic expression. These markers are located on the surface of blasts and assist in describing, classifying, and prognosticating the type of leukaemia. 

This highly-sensitive test is performed in specialised haematology laboratory centres and can be performed on either a peripheral blood or bone marrow aspirate sample with an expected turnaround time within 48 hours. 

Determining the genetics

Some tests used to determine the genetics of the leukaemia include cytogenetics or fluorescence in situ hybridisation (FISH) analysis and molecular methods like polymerase chain reaction (PCR) and next-generation sequencing (NGS). 

The molecular analysis is the most sensitive and specific test in diagnosing leukaemia. The role of molecular testing is diagnostic, confirmatory, and prognostic, and is furthermore performed at a haematology laboratory on request by a specialist clinical haematologist or haematopathologist. 

These tests are expensive and require the expertise of medical technologists, scientists, and haematopathologists. The clinical haematologist and haematopathologists will make judicious usage of these testing platforms given the circumstances and clinical indications.

Chronic myeloid leukaemia (CML)

CML involves the white blood precursors and granulocytes. There are two phases within the disease: chronic and blast phase, with the chronic phase being the most common presentation. 

Often this disease is incidentally found on routine clinical examination, however, recognisable symptoms include early satiety due to a massive spleen, symptoms of the high white cell count, such as chest pain, claudication, bleeding, tinnitus, headaches, hearing loss, or visual disturbances. 

The diagnosis is confirmed on a molecular blood test; either a PCR or FISH analysis demonstrating the Philadelphia chromosome which is a translocation between chromosome 9 and chromosome 22. This genetic abnormality drives and proliferates the malignant process. 

The routine investigations in CML include an FBC and PBS, BMAT, flow cytometry and molecular analysis which includes conventional cytogenetics, PCR or FISH analysis. 

Clinical scoring (Sokal and Hasford scores) assist in prognosticating patients into good and poor risk groups depending on the results of a formula encompassing the following clinical and laboratory criteria: age, spleen size, blast percentage, number of platelets, basophils, and eosinophils. 

Chronic lymphocytic leukaemia (CLL)

CLL is an indolent lymphoid leukaemia. The leukaemic counterpart involves the developed B-cells or B-lymphocytes. 

The normal function of B-lymphocytes is to produce protective antibodies which become dysfunctional in CLL.

Expected clinical manifestations include recurrent infections, progressively enlarging lymph nodes, abdominal distention, night sweats, bruises, weight loss, difficulty breathing, and tiredness. 

An FBC and differential count will demonstrate a high white cell count owing to an increase in lymphocytes. 

The peripheral blood smear demonstrates an increase in mature lymphocytes with a classic description of a cobble stone appearance. 

A BMAT may be indicated in cases of diagnostic challenges or when blood levels are low, however, may not be routine in all cases. 

Conventional cytogenetics and FISH analysis to investigate for specific chromosomal aberrations are mandatory for prognostication and guidance of therapy.

Radiological evidence through a CT scan may be indicated to identify occult presenting lymph node enlargement and for staging purposes and a lymph node biopsy may be indicated in certain cases to confirm diagnosis. The biopsy is usually performed under general anaesthesia.

CLL is staged according to the Rai and Bennet classification according to several clinical, radiological, and laboratory parameters. 

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