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Do you know which disease fits this month’s case? Then test your knowledge in the quiz below!

1.What is making this girl ill? B lymphoblastic leukaemia (B-ALL)
Pelger-Huet anomaly
Burkitt’s lymphoma
Mononucleosis

Online version of this month`s case:

The correct answer to March's quiz is:

Acute B lymphoblastic leukaemia (B-ALL)

Scattergrams and microscopy

The lymphocyte population in the WDF scattergram showed an increased fluorescence signal, which could be caused by blasts, abnormal lymphocytes or atypical lymphocytes. However, after a reflex analysis in the WPC channel only the ‘Blasts?’ flag was displayed.
Abnormal lymphocytes were not detected in the SSC-SFL scattergram of the WPC channel.
The SSC-FSC scattergram of the WPC channel showed an increase in lymphocytes with high lipid content, which have a low side scatter (SSC) and a low forward scatter (FSC).
Analysis of the PLT-F channel showed a thrombocytopenia with an increased immature platelet fraction (IPF).
Peripheral blood smear
 

 

 

Table

Interpretation and differential diagnosis

The answer can be inferred from...

  • Anaemia and thrombocytopenia: (low HGB, low PLT)
  • Normal leukocyte count and no                                    
    increase of reactive lymphocytes: (HFLC = 0)
  • The presence of blasts: ('Blasts?' flag and smear morphology)

Case history

A 14-year old girl was brought to her physician with a suspected infection. She was in poor overall condition: Feverish, tired and sweaty. The physician sent a blood sample to the hospital where a differential blood count revealed thrombocytopenia and anaemia combined with relative lymphocytosis. The 'Blasts?' flag was triggered but an 'Atypical Lympho?' flag was not generated, suggesting the absence of reactive lymphocytes. Small blast-like cells and the absence of heterogeneous atypical lymphocytes were confirmed by a peripheral blood smear analysis.


Case results

Although the girl's poor overall condition suggested an infection, no other clinical signs of infection were observed, such as activated lymphocytes (high HFLC, presence of 'Atypical Lympho?' flag) or activated neutrophils (high NEUT-SFL, presence of neutrophilia). Indeed, the anaemia and thrombocytopenia pointed to a different cause. Furthermore, the presence of small cells resembling blasts (28%, morphologically like L1 blasts) made an acute lymphoblastic leukaemia probable. The immunophenotype (CD34+, TDT+, CD19+, CD10+, CD79a+, negative for surface or cytoplasmic immunoglobulins) and genetic examination confirmed the diagnosis of acute B lymphoblastic leukaemia harbouring a translocation between the TEL (ETV6) and AML1 (RUNX1) genes on chromosomes 12 and 21 (formerly known as common precursor B-ALL). Acute B lymphoblastic leukaemias are typically associated with bone marrow infiltration, resulting in low platelet counts and a large immature platelet fraction. Childhood Acute Lymphoblastic Leukaemia Treatment was started.


Explanation of the 'Blasts?' flag

Measurement in the WPC channel was triggered because abnormal populations of lymphocytes (increased mean fluorescence intensity) and neutrophils (low NEUT-SSC) were detected in the WDF channel. After labelling with WPC reagents, lymphocytes in samples from healthy individuals are visible as two populations in the WPC (SSC-FSC) scattergram caused by a difference in lipid composition: A population with reduced cell size after treatment with WPC reagents and a population containing larger cells. In this B-ALL sample, the flagging algorithm recognized an abnormally large population of lymphocytes of reduced size and this triggered the 'Blasts?' flag.

 

The following answers are incorrect for the described reasons.

 

Pelger-Huet anomaly

Pelger-Huet anomaly is an autosomal-dominantly inherited genetic disorder characterized by neutrophils with hyposegmented nuclei. Homozygotes suffer from developmental delay, epilepsy and skeletal abnormalities. A pseudo-Pelger-Huet cell was found in the peripheral blood smear of the presented patient. Such cells are sometimes found in patients with chronic myelogenous leukaemia (CML), juvenile myelomonocytic leukaemia (JMML), myelodysplastic syndrome (MDS) or acute myelogenous leukaemia (AML). In rare cases, they are also observed in patients with acute lymphoblastic leukaemia (ALL). However, Pelger-Huet patients have normal blood counts and no blasts in the peripheral blood so this condition is unlikely.


Mononucleosis

Infectious mononucleosis (‘kissing disease’) is caused by an infection with the Epstein-Barr virus, a DNA virus of the herpes group. It is characterized by lymphocytosis, fever, sore throat and lymphadenopathy. The peripheral blood smear of mononucleosis patients shows a wide range of different developmental stages of atypical, reactive lymphocytes (heterogeneous lymphocyte morphology). In contrast, no absolute lymphocytosis was observed here, the lymphocyte population seen in the WDF scattergram was contained within a compact ‘cloud’ and reactive lymphocytes were absent. Extreme thrombocytopenia is not observed in patients with infectious mononucleosis.


Burkitt’s lymphoma/leukaemia

Burkitt’s disease mostly affects children and massive lymphadenopathy as well as bone marrow infiltration is commonly observed, sometimes resulting in anaemia and thrombocytopenia. The lymphocytes observed in Burkitt’s disease are uniformly large and have a low N/C ratio. Their cytoplasm is intensely basophilic with a higher degree of vacuolization than observed here. Burkitt blasts have a very high fluorescence intensity in the WDF channel, which was not the case here. The peripheral blood smear shown here contained smaller blasts (L1, L2 type) without intensive basophilic staining or vacuolization. It is important to differentiate acute B lymphoblastic leukaemia from Burkitt’s disease because the treatment is completely different (Burkitt’s patients need a mature lymphoma treatment strategy).

Underlying disease

Acute lymphoblastic leukaemia in children

Acute lymphoblastic leukaemia (ALL) is a malignant, clonal disease of the bone marrow in which early lymphoid precursors proliferate and replace normal haematopoietic cells. Leukaemic blasts may be present systemically at the time of presentation and may not be restricted to the bone marrow. Extramedullary involvement is especially observed in thymus, liver, spleen, lymph nodes, testes and central nervous system (CNS). ALL is the most common malignancy occurring in childhood with a peak incidence between the ages of three and five years, and accounts for nearly one-third of all paediatric cancers. Prior to 1948, the median survival of children with ALL was two months from diagnosis but the cure rate has improved dramatically and today approaches 80%.

While a few cases are linked to inherited genetic syndromes, such as Down syndrome or Fanconi anaemia, environmental factors such as ionising radiation, chemicals, viruses and bacteria have all been investigated as possible causes. It is now recognised that childhood ALL is not a single disease but is biologically diverse with an increasingly well-defined number of subgroups based on genetic abnormalities. For example, chromosome translocations result in chimeric fusion genes that act as stable, sensitive markers for diagnosis, therapy design and monitoring of treatment response. These translocations may occur prenatally and are therefore believed to be the primary initiating event of ALL1.The resulting clinically silent preleukaemic clone may evolve into an acute leukaemia up to 14 years later following a ‘second hit’, such as an infection or chemical exposure.

The distribution of molecular subsets of ALL varies with age. Three broad age categories are recognised namely (a) less than 1-year old, (b) 2- to 10-years old, and (c) adults. Each subset has its own distinct clinical characteristics and prognosis pattern. One of the reasons for successful modern survival outcomes in ALL has been the utilisation of risk-adapted treatment schedules to optimise cure rates for high-risk patients while at the same time limiting toxicity for lower-risk patients.

The clinical history of ALL is typically short with symptoms resulting from bone marrow failure (less common in children). Anaemia may lead to paleness, fatigue, tachycardia and dyspnoea; reduced granulopoiesis may result in fever and predispose patients to infection; diminished platelet production may lead to purpura, easy bruising and bleeding. Bone pain is present in at least 50% of children and is due to leukaemic invasion of the bones. Leukaemic infiltration of joints may occur and produce arthralgia similar to that occurring in juvenile rheumatoid arthritis. Meningeal leukaemia may lead to headache, vomiting, signs of meningeal irritation, raised intracranial pressure and cranial nerve palsies. Superior vena caval obstruction due to infiltrated anterior mediastinal lymph nodes commonly occurs in association with T-ALL and results in a widening of the mediastinum visible on X-ray. Physical signs may be absent or limited to lymph node enlargement. The liver and spleen may also be enlarged.

The initial diagnosis of ALL results from a complete medical history, physical examination and morphological examination of the blood and bone marrow followed by cytochemical, biochemical, immunological, chromosomal, molecular genetics and cytokinetic studies.

Typical laboratory findings at diagnosis include leukocytosis of up to 100 x (109/L). In all multivariate analyses of blood count parameters, the initial white blood cell count has been found to be the most powerful predictor of outcome. Often a normochromic, normocytic anaemia is observed with a haemoglobin concentration of less than 100 g/L. The platelet count may be less than 50 x (109/L) and there is some evidence that this indicates a poor prognosis. However, the white cell count is normal or reduced in about one-third of paediatric patients and the platelet count is normal in 15% of cases. Peripheral blood smears nearly always reveal some lymphoblasts and the number of blasts cells relates directly to the prognosis.

Literature

Literature acute lymphoblastic leukaemia

 

1.    Greaves MF (2002): Childhood Leukaemia. British Medical Journal 324: 283-287

2.    Friedmann AM, Weinstein HJ (2000): The role of prognostic features in the treatment of childhood acute lymphoblastic leukaemia. The Oncologist 5: 321-328

3.    Greaves MF (1997): Aetiology of acute leukaemia. Lancet 349: 344-349

Advanced clinical parameters

Reference ranges

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