Fatigue and bruising in a teenager

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Problem 47 Fatigue and bruising in a teenager

Charles G. Mullighan

A usually fit and active 13-year-old boy complains of gradually worsening tiredness for a month. In the last few days, he has noticed bruises, both after minor trauma and without any obvious trauma, to his arms and legs. His past medical history includes a tonsillectomy, adenoidectomy and appendicectomy. He does not take any regular medication, and denies using alcohol, over-the-counter or non-prescription drugs. He has a low-grade fever, is pale and has moderate cervical lymphadenopathy. There are multiple small to moderate bruises in dependent areas, and small haemorrhages at the bite line of the buccal mucosa. The spleen is palpable 5 cm below the left costal margin.

Q.1

What are the possible causes of this boy’s signs and symptoms? What investigations should be performed?

The following investigations become available.

Investigation 47.1 Summary of results

Blood film (Figure 47.1) comment:

Figure 47.1

Macrocytic anaemia. Anisocytosis and poikilocytosis. Abnormal lymphoctes present; possibly atypical, possibly blasts.

Infectious mononucleosis screen (IM): Negative. EBV IgM: Negative.

Q.2

Interpret the blood test results. What further investigations and management should be arranged?

While awaiting transfer to the haematology ward, he develops rigors and is noted to have a temperature of 39°C.

Q.3

What investigations should be performed immediately, and what treatment would you like to start?

An urgent bone marrow aspirate is performed (Figure 47.2). Microscopic examination of the aspirate smears shows over 90% blasts, immature chromatin, few nucleoli, scant cytoplasm and few granules. Immunophenotyping of the bone marrow aspirate shows the presence of a lymphoblast populations staining for CD45, CD5, CD7, and cytoplasmic CD3, but negative for cell surface CD3, negative for the B lymphoid markers CD19 and CD79a, and negative for the granulocytic markers CD13 and CD33.

Figure 47.2

Immunophenotyping of peripheral blood yields similar results. Subsequent examination of bone marrow trephine sections shows complete replacement with a homogeneous infiltrate of lymphoblasts.

Q.4

What is the diagnosis?

While the patient awaits further investigations, including a lumbar puncture, and prepares for initial treatment, the ward nursing staff are concerned that the he has become short of breath, with a dry cough and difficulty swallowing. You are asked to review him urgently.

Q.5

What are the possible diagnoses? What do you look for on examination and what investigations should be performed?

He is sitting on the edge of his bed with respiratory rate of 25, a peripheral oxygen saturation of 94% on air and mild facial swelling. Chest examination reveals dullness to percussion at the right lung field base, with reduced breath sounds on the right side. You repeat the chest X-ray (Figure 47.3).

Figure 47.3

Q.6

What does the chest X-ray show, and what is the diagnosis? What additional management is appropriate?

Soon after commencing chemotherapy the patient becomes confused and is noted to have reduced urine output.

Q.7

What complication is likely to have developed? What investigations should be ordered, and what are they likely to show?

Q.8

How should this complication be prevented and managed?

Following stabilization and a good initial response to treatment, the patient and his family enquire as to the prognosis of his disease.

Q.9

What do you tell them?

Answers

A.1 Fatigue, pallor, spontaneous/easy bruising and enlargement of the spleen and lymphoid organs strongly suggests a serious haematological disorder or malignancy. However, primary viral infections such as Epstein–Barr virus (EBV), causing infectious mononucleosis or glandular fever, can also present in this way and must be considered in the differential.

An acute leukaemia or lymphoma should be considered. Aplastic anaemia is less likely given the presence of lymphadenopathy. Appropriate investigations include a full blood count with examination of the peripheral blood film, serum biochemistry and serology for EBV infection (Paul Bunnell/monospot tests and/or EBV antibodies/PCR).

A.2 He has pancytopenia, i.e. all three cell lineages, red cells, platelets and white cells, are abnormally low. There are abnormal lymphocytes seen on examination on the blood film. The blood film raises the possibility of an acute leukaemia, and a bone marrow biopsy is required.

Poikilocytosis simply means abnormally shaped red blood cells and is seen in a wide range of conditions. It is therefore fairly non-specific.

Anisocytosis, as its name suggests, means there are red cells of different sizes. Again, this can occur in many conditions including those in which folate and ferritin deficiency occur, producing macrocytes and microcytes. Coeliac disease would be one example of a condition in which this phenomenon occurs.

The EBV serology results are against a diagnosis of acute infectious mononucleosis. Review by a haematologist should be arranged urgently and admission arranged. The creatinine is high for his age and, taken with the elevated LDH and biochemistry results, suggests a degree of spontaneous tumour lysis.

A.3 Fever in a patient with pancytopenia is a potentially life-threatening medical emergency. Clinical re-examination and investigations should be performed quickly and antibiotics commenced without delay. The patient should be examined for any site of infection, including the skin, mouth, teeth, chest, urinary tract and perianal region. At least one set of blood cultures should be taken, urine collected and sputum, if available, sent for culture. Broad-spectrum antibiotics should be commenced according to local haematology unit protocols – this usually consists of a third-generation cephalosporin and aminoglycoside (e.g. gentamicin) but the choice of antibiotics varies widely according to local sensitivities. The combination chosen should cover both Gram-positive and Gram-negative bacteria as well as Pseudomonas spp. A chest X-ray should be performed for occult infection.

A.4 Acute lymphoblastic leukaemia, T-lineage.

We know you may consider this an unfair question as the interpretation of immunophenotyping is an area of expertise only to be expected from haematology specialists. The key features of the bone marrow exam are, however, the presence of a large population of lymphoblasts. Abnormalities within the nuclear material of these cells suggests that they may be neoplastic in nature. While the total blood count is elevated, there are very few normally functioning white cells, meaning that this young man is very susceptible to infection.

A.5 He may have pneumonia or a mediastinal mass due to lymph node enlargement from leukaemic involvement. A detailed respiratory examination should be performed, and the initial chest X-ray reviewed. A further X-ray may be needed if the initial film was normal.

A.6 The chest X-ray shows gross mediastinal widening with compression of the right lung field. This is consistent with a mediastinal mass from involvement by leukaemia. The facial swelling raises the possibility of superior vena cava obstruction. This is a medical emergency.

The haematologist should be notified and intensive care should be called to assess the patient immediately. A CT is required to evaluate the degree of tracheal compression. The lumbar puncture will require anaesthetic support. The patient should receive a platelet transfusion prior to the lumbar puncture to minimize the risk of a traumatic lumbar puncture (bleeding into the CSF).

A.7 In view of the diagnosis and mediastinal involvement, the patient is at high risk of tumour lysis syndrome after commencement of chemotherapy. Urgent measurement of electrolyte levels and ECG are required. These may show hyperkalaemia, hypocalcaemia, hyperphosphataemia, hyperuricaemia and renal impairment.

A.8 All patients at risk of tumour lysis should receive vigorous intravenous hydration with potassium-free fluids, supplemental sodium bicarbonate and close monitoring of fluid balance. Allopurinol should be given. Treatment of established tumour lysis will depend on the severity of electrolyte disturbance and renal dysfunction, but may require intensive care management, continuous cardiac monitoring for arrhythmias, and more aggressive therapy to correct electrolyte imbalances, hyperuricaemia, and preserve renal function. All nephrotoxic agents (aminoglycosides, non-steroidal anti-inflammatory drugs and intravenous contrast, etc.) should be avoided if at all possible.

A.9 ALL is the commonest childhood cancer and over 80% of children are cured. The prognosis declines in adolescence, and is less favourable in older males with T-lineage ALL. Accurate prediction of outcome will depend on close monitoring of the early response to therapy (for example, by flow cytometry of bone marrow or blood samples to measure levels of minimal residual disease). Treatment usually consists of combination multi-agent chemotherapy and CNS prophylaxis (with intrathecal chemotherapy), and is commonly prolonged, lasting up to 2 years. Strict compliance with therapy is essential to maximize the chance of cure.

Revision Points

• Acute leukaemia is a malignancy of leucocyte precursors. Acute lymphoblastic leukaemia (ALL) is the commonest childhood cancer. Acute myeloid leukaemia is less common in children, but more common in adults. There is a bimodal peak in the incidence of leukaemia – young children and older adults. Acute leukaemia is characterized by recurring chromosomal alterations including aneuploidy (abnormal number of chromosomes) and translocations, but the aetiology in most cases is unknown.

• Acute leukaemia results in proliferation of leukaemic cells (blasts) that fill the bone marrow and suppress growth of non-leukaemic blood cells, resulting in anaemia, thrombocytopenia and neutropenia.

• Appropriate investigations to distinguish acute leukaemia from other disorders resulting in pancytopenia, such as viral infections, severe vitamin deficiencies and drug/toxin effects, are required. A bone marrow biopsy is usually required.

• Acute leukaemia is fatal if untreated, but over 80% of children with ALL are cured. Prognosis is worse for adolescents and adults.

• ALL may arise from B or T lymphocytes. T-lineage ALL more commonly occurs in older males, and is associated with higher-presentation leucocyte counts and solid tumour (most commonly mediastinal) masses.

• The mainstay of ALL treatment is intensive multi-agent chemotherapy, intrathecal chemotherapy to prevent CNS relapse, and careful supportive care. Clinical and genetic features are used to stratify risk and guide the intensity of treatment (including the use of bone marrow transplantation).

• Patients presenting with and undergoing therapy for acute leukaemia are extremely vulnerable to infection, bleeding, and tumour lysis. These require specialized care but awareness of these potential problems is important.

Issues to Consider

• What are the implications of successful treatment of childhood leukaemia when the patient enters adulthood?

• What are the different types of ‘bone-marrow transplant’?

• What is red cell distribution width (RDW) and how is it interpreted?

Further Information

Acute leukemia. In Hoffbrand A.V., Moss P.A.H., Pettit J.E., editors: Essential haematology, 5th edn, Oxford: Blackwell, 2006. ch 12. This is an excellent book covering normal and malignant disorders aimed at medical students

Acute lymphoblastic leukemia. In Pui C.H., editor: Childhood leukemias, 2nd edn, Cambridge: Cambridge University Press, 2006. ch 16. A detailed textbook covering all aspects of the biology and management of ALL

www www.leukaemia.org. A UK-based web resource for parents and sufferers

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