Examination Medicine: A Guide to Physician Training, 7th Edition

CHAPTER 8. The haematological long case

The modern haematologist, instead of describing in English what he can see, prefers to describe in Greek what he can’t.

Richard Allan John Asher (1912–69)

Haemolytic anaemia

This is an uncommon but important long case. It is usually a diagnostic problem. Coombs’ positive haemolytic anaemia is most often encountered in the examination.

The history

1. Ask about the symptoms of anaemia (e.g. fatigue, shortness of breath on exertion) and whether the patient has noticed or been told about jaundice.

2. Determine whether there is a history of known haemolytic episodes. Onset at an early age or a family history suggests an intrinsic red cell defect (e.g. hereditary spherocytosis or elliptocytosis (both autosomal dominant), sickle cell anaemia).

3. Ask about symptoms of connective tissue disease. Joint pain or swelling may also occur in acute sickle cell crisis and especially affect the knees and elbows. Refractory leg ulcers occur in hereditary spherocytosis and sickle cell syndromes. Systemic lupus erythematosus (SLE) and other connective tissue disorders may be associated with warm antibody immunohaemolytic anaemia. Lymphoma is associated with both warm and cold antibodies and anaemia.

4. A history of pain in the abdomen, back and elsewhere suggests sickle cell anaemia or paroxysmal nocturnal haemoglobinuria. Congenital haemolytic anaemias can result in pigment gallstones that can cause symptomatic cholelithiasis and even acute cholecystitis; these episodes can be confused with acute crises.

5. Ask about neurological problems. Spinal cord lesions can occur with hereditary spherocytosis. Paraspinal masses (extramedullary haemopoiesis) are a rare complication of any hereditary haemolytic anaemia or lymphoma. Acute sickle cell crisis can also result in neurological impairment, particularly stroke. Tertiary syphilis may cause paroxysmal cold haemoglobinuria. In thrombotic thrombocytopenic purpura (TTP) there are often fluctuating neurological abnormalities. For other features of TTP, remember the mnemonic FAT RN:

  Fever

  Anaemia (microangiopathic haemolytic)

  Thrombocytopenia

  Renal failure

  Neurological abnormalities

6. List all drugs that have been taken. For example, methyldopa, penicillin and quinidine can cause warm antibody immunohaemolytic anaemia, and antimalarials, sulfonamides and nitrofurantoin cause haemolysis in subjects deficient in glucose-6-phosphate dehydrogenase (G6PD). Note: Between 10% and 20% of people taking methyldopa have a positive direct Coombs’ test, but only a small minority of these develop haemolysis. The drug alters Rh antigens so that antibodies are produced against them, which then cross-react with normal Rh antigens. The indirect Coombs’ test is therefore positive, even when the drug is not added to the test. The other drugs produce an indirect Coombs’ test result only when the drug is added to the mixture, because in that case the antibodies are directed against a combination of drug and cell membrane. Fludarabine, which is increasingly used as first-line treatment of chronic lymphatic leukaemia in patients under the age of 65 and non-Hodgkin’s lymphoma, may cause exacerbation of warm autoimmune haemolytic anaemia. When fludarabine is combined with the anti-CD20 monoclonal rituximab, AIHA is mitigated.

7. Enquire about any operations, particularly mechanical heart valve replacement (10% of those with aortic valve prostheses have significant haemolysis; this percentage is lower with mitral valve prostheses unless a paravalvular leak is present, as the pressure gradient is lower). Severe haemolysis in these patients suggests a paravalvular leak. Consider the other occasional cause of haemolysis within the circulation – external trauma, such as occurs in joggers who wear thin-soled shoes, and the traditional group, bongo drummers. In these cases, haemolysis is intravascular and haemosiderinuria is characteristic.

8. Determine the patient’s ethnic background (e.g. Greeks or Italians may inherit the beta-thalassaemia trait; both thalassemias are common on the subcontinent and alpha thalassaemia is common in China and Southeast Asia; black men may have G6PD deficiency).

9. The patient may have an underlying medical problem associated with the risk of developing microvascular fragmentation of red cells. These conditions include: disseminated intravascular coagulation (DIC), which is usually caused by vessel wall changes related to an underlying disease, such as disseminated malignancy, renal graft rejection or malignant hypertension; TTP, which is of unknown aetiology; and haemolytic uraemic syndrome (HUS, with similar features to TTP), which can follow gastroenteritis caused by E. coli 0157:H7 infection (do not treat these cases with an antibiotic, since this increases the risk of HUS!).

The examination

1. A careful haematopoietic system examination is required. The characteristic ‘chipmunk’ facies in a young person with thalassaemia is caused by maxillary marrow hyperplasia and frontal bossing.

2. Look for pallor and icterus.

3. Examine the heart for a valve prosthesis or severe aortic stenosis (traumatic haemolysis). Profound anaemia may be associated with high-output cardiac failure. An iron overload state in thalassaemia major from repeated transfusions may cause skin pigmentation, cardiac failure and hepatomegaly.

4. Carefully palpate for the spleen; splenomegaly from any cause (see Table 16.21) may result in haemolysis. Lymphadenopathy may indicate lymphoma (associated with warm or cold antibody haemolysis), chronic lymphocytic leukaemia or in practice glandular fever (cold agglutinin haemolysis).

5. Signs of chronic liver disease should be noted – in severe cirrhosis spur-cell (acanthocyte) anaemia is occasionally observed.

6. Examine for focal neurological signs. Look in the fundi – retinal detachment, retinal infarcts and vitreous haemorrhages can be manifestations of sickle cell anaemia; Kayser-Fleischer rings may be present in the cornea when haemolysis is caused by Wilson’s disease.

7. Joint swelling and tenderness, and occasionally aseptic necrosis of bone (e.g. neck of femur), also occur in sickle cell anaemia; bony infarcts may become infected (e.g. Salmonella osteomyelitis).

8. Look for leg ulceration. Note any signs of connective tissue disease.

9. Test the urine – urobilinogen may be present with haemolysis; it may be dark from haemoglobin in intravascular haemolysis and the sediment may be abnormal (e.g. TTP).

10. Fever may occur with septicaemia or malaria-associated haemolysis, with acute crises in sickle cell anaemia and in TTP.

Investigations

It is important to confirm that haemolysis is present, exclude intravascular haemolysis and perform tests to determine the aetiology. The history and physical examination may have provided hints about the likely aetiology.

1. Ask for the results of a blood count, reticulocyte count, serum bilirubin and lactate dehydrogenase. Haemolysis is likely to be present if there is a normochromic normocytic anaemia with an increased reticulocyte count (but reticulocytosis also occurs with blood loss or partially treated anaemia) and release of red blood cell components (increased unconjugated bilirubin and, more variably, lactate dehydrogenase).

2. Usually serum haptoglobin is absent and haemosiderin is present in the urine. Intravascular haemolysis is documented by the presence of methaemalbumin in the plasma (Schumm’s test) and, less often, of haemoglobin in the urine.

3. The presence of fragmented red cells (schistocytes) suggests valve haemolysis, DIC and TTP (or HUS). TTP (or HUS) is very likely when fragmented red cells occur in association with thrombocytopenia and normal coagulation studies; look for renal and neurological impairment.

4. The blood film usually shows polychromasia; it may show other red cell changes (Tables 8.1 and 8.2). In thalassaemia, the anaemia is often hypochromic and always significantly microcytic.

Table 8.1

Full blood count and liver function tests from a female patient with autoimmune haemolytic anaemia (AIHA)

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Table 8.2

Haemolytic anaemia

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DAF = decay accelerating factors; DIC = disseminated intravascular coagulation; G6PD = glucose-6-phosphate dehydrogenase; Hb = haemoglobin; HbH = haemoglobin H; TTP = thrombotic thrombocytopenic purpura.

5. If a congenital intracorpuscular defect seems unlikely, ask for a Coombs’ test to determine whether the anaemia is immunohaemolytic. The polyspecific direct Coombs’ test measures the ability of anti-IgG and anti-C3 to agglutinate the patient’s red blood cells. Warm antibodies (80% of cases) react at body temperature and may occur with lymphoma (usually non-Hodgkin’s), chronic lymphocytic leukaemia, solid tumours (lung, colon, kidney and ovary), SLE and drugs, or may be idiopathic. They are usually IgG antibodies directed at the Rh antigens. Cold reactive antibodies are precipitated by exposure to room temperature (‘cold’) – cold agglutinin disease (IgM antibodies) may occur acutely with glandular fever, mycoplasma infection or hepatitis C, and chronically may be caused by lymphoma or may be idiopathic; paroxysmal cold haemoglobinuria (IgG antibodies) is rare.

6. If the haemoglobinuria occurs usually at night and there is pancytopenia and venous thrombosis, paroxysmal nocturnal haemoglobinuria (PNH) should be strongly suspected (an acquired stem cell disease secondary to a defective PIG-A gene). The disease may also be associated with aplastic anaemia, in which the neutrophil alkaline phosphatase score is low (but this test is now rarely performed). The sucrose lysis and acid haemolysis (Ham’s) test used to be performed. The most reliable test now is analysis by flow cytometry for glycosylphosphatidylinositol (GPI)-linked proteins (e.g. CD55 or decay-accelerating factors (DAF) on the red cell surface, and CD59 or homologous restriction factor). PNH, which is an acquired clonal disease, is a result of a mutation that causes faulty or absent production of the GPI anchor molecule. Various linked proteins are missing from the red cell surface and, as a result, the cells are not protected from lysis by complement.

  Tests for other causes of haemolysis are presented in Table 8.2.

Treatment

This depends on the underlying disease process, which should be reversed if possible (e.g. drug withdrawal, treatment of transplant rejection, adoption of another musical instrument) (see Table 8.2).

1. Steroids are useful in immunohaemolytic anaemia caused by warm-reactive antibodies. The usual approach is to commence at a starting dose of 1 mg/kg/day of prednisolone. The haemoglobin level will usually rise within the first week. Concurrent use of folate is often recommended. Once a normal haemoglobin level has been achieved, the steroid dose must be tapered slowly. Splenectomy works as well as steroids, and is indicated in poorly responsive or resistant disease. Immunosuppressive treatment is reserved for those who do not respond to steroids and splenectomy. Azathioprine and cyclophosphamide have each been used with some benefit. Response takes 2 to 3 months. Normal human immunoglobulin is often effective. There is increasing evidence of the efficacy of rituximab in very refractory cases, but AIHA remains an ‘off label’ indication.

2. Transfusion is not usually indicated unless there is symptomatic anaemia with a haemoglobin level <90 g/L; it may exacerbate haemolysis. The antibody in immunohaemolytic anaemia is likely to react with all normal donor cells so that standard cross-matching is not possible.

  Laboratory testing in such cases most often reveals a ‘pan agglutining’ autoantibody. Occasionally the autoantibody has Rh antigen specificity and donor red cells lacking the antigen can be safely transfused under close observation.

3. When cold-reactive antibodies are responsible, steroid treatment is less effective. Avoidance of cold can be helpful. The disease tends to progress unless the underlying malignancy can be treated.

4. The chimeric antibody, rituximab, which attaches to the CD20 binding site on B lymphocytes and induces their destruction, may be useful in severe cases of resistant autoimmune haemolytic anaemia.

5. The acute haemolytic episodes of patients with G6PD deficiency are self-limiting (only older red blood cells are affected) and require no specific treatment. Hydration should be maintained to protect renal function. Patients should be warned to avoid precipitating factors (e.g. broad beans, antimalarials and sulfonamides).

6. Valve haemolysis may be improved by iron supplements and an increase in haemoglobin (reduced cardiac output). Paravalvular leaks often need to be repaired and occasionally the prosthetic valve may have to be replaced with a larger one.

7. TTP is now treated with plasmapheresis, which improves the mortality rate from almost 100% to 10%. Twice-daily treatment is combined at first with high-dose steroids. Even severe neurological deficit, including coma, may be reversible. Anti-platelet drugs are of uncertain benefit. Cyclophosphamide and vincristine are used when plasmapheresis has been unsuccessful. Relapse (10%) can usually be treated successfully. Platelet transfusions must be avoided as they exacerbate thrombosis. The preferred replacement solution is cryosupernatent or fresh frozen plasma (FFP).

8. Splenectomy is virtually curative for patients with hereditary spherocytosis and elliptocytosis (only 10% have severe haemolysis), and may be useful in selected patients with massive splenomegaly, immunohaemolytic anaemia, certain haemoglobinopathies and enzymopathies. All patients undergoing splenectomy should receive pneumococcal vaccine preoperatively if possible. Sometimes, prophylactic treatment with penicillin is recommended for 2 years following splenectomy (Table 8.3). Failure of splenectomy to control haemolysis may be caused by an accessory spleen (which can be detected by a liver–spleen scan).

Table 8.3

Treatment advice for patients having a splenectomy

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9. PNH can be treated with washed red cell transfusions and steroids. Heparin and warfarin should be used for thrombotic episodes. Bone marrow transplant may be curative. Trials of the monoclonal antibody eculizimab, which blocks the complement cascade below C5, have shown major benefits with a reduction in transfusion requirements and reduced incidence of thrombosis; the drug prevents the complement-driven haemolysis in PNH. The Commonwealth Department of Health has a specific program to fund the administration of eculizimab for Australian patients on a PNH registry.

Thrombophilia

The discovery of new thrombophilic factors has made the patient with recurrent or even a single thrombotic episode a very suitable long case. Suspect this possibility if the patient is under 50 or has a family history of recurrent thromboses (Table 8.4).

Table 8.4

Occurrence of and risk associated with the thrombophilic factors

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APC = activated protein C; AT = antithrombin.

The history

1. Ask about the reasons for any recent admissions to hospital. There may have been a recent episode of venous or arterial thrombosis or the patient may have been admitted for a procedure that has a high risk of thrombosis.

2. Ask about the nature of thrombotic episodes. These may have been arterial or venous, or both. Find out how often the problem has occurred and what part of the body was involved.

3. Ask whether a thrombotic tendency has been identified and how this was done (the patient may know).

4. Ask what anticoagulation therapy is currently being used. The possibilities include intravenous unfractionated heparin, fractionated heparin given subcutaneously, low-molecular-weight heparin, warfarin, aspirin or (less likely) clopidogrel or dipyridamole. Since 2010, a number of novel oral anti-coagulants (NOACs) have become available, including the anti Xa agents apixaban, rivaroxaban and the direct thrombin inhibitor dabigitran. None of these appears superior to warfarin in terms of recurrent thrombosis, but there is the major benefit of the lack of need for monitoring. None is reversible in the setting of severe trauma or haemorrhage.

5. If the patient is or has been on treatment with warfarin, find out how much he or she understands about the drug, including the importance and necessary frequency of international normalised ratio (INR) testing and the target INR. The patient should probably know the most recent INR result and have some understanding of food and drug interactions with warfarin. For a patient on warfarin, ask about the usual frequency of blood tests and whether practical difficulties have been encountered in getting to the pathology laboratory. Ask who usually relays INR results and dose changes to the patient, and whether the patient has ever used a home INR tester.

6. Enquire about a family history of thrombosis and whether the patient’s own problem has led to the testing of other family members. In general, 50% of first-degree relatives will inherit the mutation if there is an identified autosomal dominant hereditary factor (e.g. protein C, protein S and antithrombin deficiency). Remember, a family history of thrombosis greatly increases a patient’s risk. Patients with a thrombophilic defect, but without a family history of thrombosis, have only a slightly increased risk. The absence of a family history may make thrombophilia testing irrelevant, as positive tests will not likely change management.

7. Ask about other factors that may increase thrombotic risk, including smoking, oestrogen-containing oral contraceptives, pregnancy, malignancy, recent surgery and immobility. Long aeroplane flights are controversial as a risk factor, but have received extensive discussion in the popular press.

8. If the event has followed a surgical operation, ask what prophylaxis was used to try to prevent thrombosis.

9. In women, ask about previous unexplained miscarriages. This can be associated with the presence of antiphospholipid antibodies, which are autoantibodies against various platelet surface molecules, including phospholipids. These include lupus anticoagulant (which prolongs the aPTT), anticardiolipin and anti-β2 glycoprotein antibodies. Consider this possibility too if there is a history of unusual thromboses or eclampsia and pre-eclampsia.

10. Specifically ask about previous myocardial infarction. The occurrence of myocardial infarction in young women with normal coronary arteries has been associated with factor V Leiden mutation.

11. Ask whether there have been chronic venous problems in the legs. Damage to the venous system can cause chronic oedema and ulceration that can be quite disabling (post-thrombotic syndrome). If there have been chronic problems, asking detailed questions about their effect on the patient’s life is essential.

12. Ask about the congenital abnormality, homocysteinuria, which is associated with a Marfanoid habitus and premature strokes and coronary artery disease. Homocysteine is a thrombophilic agent.

13. Ask about features of PNH – recurrent episodes of dark urine, anaemia and pancytopenia.

The examination

1. Note the presence or absence of an intravenous heparin infusion. If present, look at the infusion rate.

2. Note the presence of obesity and look for signs of venous insufficiency from previous venous thromboses.

3. Examine the legs for oedema, venous ulceration and venous valvular insufficiency.

4. Check the peripheral pulses for evidence of arterial obstruction.

5. Note the presence of abdominal wall bruising from subcutaneous low-molecular weight heparin injections.

6. There may be evidence of a myeloproliferative disorder, SLE, nephrotic syndrome (oedema) or a malignancy.

Investigations

There is a case now for testing anyone with a significant arterial or venous thrombosis for thrombophilic factors (Tables 8.4 and 8.5), especially those with a family history of thromboembolic disease. Certainly, unusual or repeated thromboses should be investigated, as set out below. The currently available routine screening tests are listed in Table 8.6.

Table 8.5

Indications for thrombophilia investigations

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Table 8.6

Tests for thrombophilia

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1. Factor V Leiden is an abnormal factor V molecule. The abnormality is caused by a point mutation that affects the cleavage site on the activated molecule. The abnormal factor V is resistant to neutralisation by activated protein C (APC), which forms part of the natural anticoagulation pathway. The condition is also called APC resistance. The mutation occurs in 4% of the general population in Australia and in up to 50% of people with a family history of recurrent venous thrombosis. The condition is autosomal dominant. The heterozygous state is associated with an eightfold increase in venous thrombotic risk; the homozygous state also occurs and these people have 100 times the average risk.

  The thrombotic risk is higher for women with this condition because of the additional risk associated with pregnancy and the use of oral contraceptives containing oestrogen. Use of these drugs causes a 35 times increased risk of a thrombotic event (approximately a 3% risk over 10 years). The mechanism is probably that of lowering antithrombin III levels.

2. Antithrombin III deficiency is present in a mild form in about 1 in 2000 of the population. The thrombotic risk is somewhat unpredictable, but the occurrence of a first thrombotic event in these patients is a relative indication for lifelong anticoagulation therapy with warfarin.

3. Proteins C and S are natural anticoagulants. Their deficiency is associated with recurrent venous thrombosis and pulmonary embolism, but the level of increased risk is less clear than that for the abnormalities above. There is overlap between the serum levels in people with, and apparently without, an increased risk of thrombosis. Testing must occur after at least 2 weeks without warfarin treatment. In homozygotes with protein C deficiency, warfarin may induce skin necrosis.

4. Prothrombin gene mutation is present in about 3% of the Australian population. This point mutation leads to an increased plasma level of prothrombin. Its detection requires DNA PCR analysis. It is an autosomal dominant trait and leads to a fourfold increase in the risk of venous thrombosis.

5. Homocysteine levels are increased in patients with venous thrombosis and are also an independent risk factor for coronary artery disease. The test is now widely available.

6. Combined thrombophilic abnormalities are relatively common and further increase the thrombotic risk.

7. Antiphospholipid syndrome is diagnosed if there is clinical evidence of thrombosis or a suggestive history of miscarriage plus an abnormal anti phospholipid antibody test on two occasions. Anticardiolipinantibodies and lupus anticoagulant (IgG or IgM antiphospholipid) antibodies are associated with an increased risk of venous thrombus and arterial embolus. In most cases, both are abnormal. The transient presence of these antibodies at low titres is common, is often associated with infection and is probably not of clinical significance. They may be present as part of SLE or occur alone (primary antiphospholipid syndrome).

8. Consider investigations for other illnesses that are ‘prothrombotic’. These include malignancy, cardiac failure, nephrotic syndrome and haematological conditions such as PNH, polycythaemia rubra vera and thrombocythaemia.

Management

Try to identify transient and continuing risk factors.

1. In general, an initial episode of thrombosis is treated in the usual way, with low molecular-weight heparin or intravenous non-fractionated heparin. This should be followed by at least 6 months of treatment with warfarin for idiopathic above-knee DVTs or for pulmonary embolism. Patients with antithrombin III deficiency will still respond to treatment with heparin because of the presence of small amounts of antithrombin III. Tests for the vitamin K-dependent proteins C and S should be performed before the patient is begun on warfarin.

2. Patients with protein C and S deficiency or heterozygous APC resistance do not need long-term anticoagulation until after their second thrombotic event. Homozygous APC deficiency is an indication for long-term warfarin treatment.

3. All patients with thrombophilia and their affected asymptomatic relatives need aggressive prophylaxis before surgery or during periods of immobilisation, such as long aeroplane flights. Surgical prophylactic treatment should include heparin, compressive stockings and foot pumps, and early mobilisation. Long aeroplane flights may be an indication for prophylactic subcutaneous fractionated heparin. Aspirin is of proven benefit for the secondary prevention of venous thrombosis.

4. Pregnant women with a history of DVT require prophylaxis (with heparin) throughout pregnancy and until the puerperium. Warfarin is contraindicated in pregnancy.

5. The detection of antiphospholipid antibodies in women with miscarriages is an indication for treatment with low-molecular-weight heparin with or without low-dose aspirin during pregnancy. Patients should be advised strongly against smoking and should avoid oestrogen-containing oral contraceptives. Progesterone-only preparations appear to be safe.

6. There is still controversy about the long-term treatment of patients with antiphospholipid syndrome but recurrent unexpected thrombosis is an indication for long-term anticoagulation with warfarin maintaining an INR between 2 and 3.

Polycythaemia

The myeloproliferative disorders (Table 8.7) often occur in the clinical examination. They present a diagnostic and management problem. Polycythaemia rubra vera (erythraemia or increased red cell mass) is the most common myeloproliferative disease encountered. This disease occurs in later middle life and is slightly more common in males. No specific gene defect has been isolated, but the condition is a clonal disease. Secondary causes of polycythaemia (erythrocytosis) must be excluded (Table 8.8).

Table 8.7

Myeloproliferative disorders

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Table 8.8

Causes of polycythaemia

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The history

The patient will probably know the diagnosis. If you suspect polycythaemia, ask about:

1. symptoms of polycythaemia or polycythaemia rubra vera:

a. vascular problems, such as transient ischaemic episodes, angina, peripheral vascular disease (thrombosis and digital ischaemia); intra-abdominal venous thrombosis, including the Budd-Chiari syndrome

b. bleeding from the nose

c. symptoms of peptic ulceration (increased four to five times in polycythaemia rubra vera)

d. abdominal pain or discomfort from gross splenomegaly or urate stones

e. pruritus after showering (‘aquagenic pruritis’)

f. gout

2. symptoms owing to disease causing secondary polycythaemia (see Table 8.8), such as chronic respiratory diseases, sleep disorders and OSA, chronic cardiac or congenital heart diseases, renal diseases (especially polycystic kidneys, hydronephrosis or carcinoma); ask about the use of coal tar derivatives, which can cause the production of abnormal haemoglobin such as methaemoglobin, since secondary polycythaemia may occur as a result

3. investigations performed and how the diagnosis was made (e.g. blood counts abdominal imaging, and renal, pulmonary and cardiac investigations); the patient may know if the erythropoietin level and JAK 2 kinase mutation has been measured

4. the treatment initiated (e.g. phlebotomy – how often and for how long, radioactive phosphorus, treatment of renal, pulmonary or cardiac disease)

5. resolution of symptoms with treatment

6. social problems related to chronic disease.

The examination

1. Stand back and look at the patient. Note plethora (see Fig 8.1), the state of hydration, cyanosis and any Cushingoid features.

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FIGURE 8.1 This face is a diagnostic clue for polycythaemia vera. Patients are frequently plethoric and may have rosacea. M R Howard, Haematology: An illustrated colour text, 32, 64–65, Elsevier, 2013, with permission.

2. Examine the patient’s hands for nicotine stains, clubbing and signs of peripheral vascular disease. Note any gouty tophi.

3. Look for scratch marks and bruising on the arms and take the blood pressure (systolic hypertension accompanies an increased red cell mass and phaeochromocytoma is associated with increased erythropoietin).

4. Look at the eyes for injected conjunctivae and examine the fundi for hyper-viscosity changes.

5. Examine the tongue for central cyanosis.

6. Examine the cardiovascular system for signs of cyanotic congenital heart disease, if appropriate, and the respiratory system for signs of chronic lung disease.

7. Examine the abdomen for hepatomegaly (hepatoma must be excluded) and more importantly splenomegaly, which occurs in 80% of cases of polycythaemia rubra vera, but not in secondary polycythaemia. Palpate for renal masses (polycystic kidneys, hydronephrosis, carcinoma). Rarely, uterine fibromas may be found, or very rarely virilisation may be noted.

8. Look at the legs for scratch marks (pruritus may be secondary to elevated plasma histamine levels), gout and evidence of peripheral vascular disease.

9. Auscultate over the cerebellar regions for a bruit (cerebellar haemangioblastoma). Note any upper motor neurone signs (cerebrovascular disease owing to thrombosis or the hyperviscosity syndrome).

10. Check the urine for evidence of renal disease.

Investigations

Confirm the presence of polycythaemia (haematocrit >60% for men or >56% for women) and establish whether this is primary or secondary. Remember that erythrocytosis is an increase in the absolute red cell mass, which occurs as a result of some stimulus (usually hypoxia), and erythraemia (polycythaemia vera) is an increase in red cell mass of unknown aetiology (Table 8.9).

Table 8.9

An approach to the diagnosis of polycythaemia rubra vera

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Note: Red cell mass and plasma volume are no longer routinely measured.

1. In polycythaemia rubra vera the following are increased: haemoglobin value, haematocrit value, red cell count, white cell count (including the absolute basophil count), platelet count and more variably the neutrophil alkaline phosphatase (NAP) score. Check the mean corpuscular volume and red cell distribution width (RDW). Microcytic erythrocytosis can only be caused by polycythaemia rubra vera or hypoxic erythrocytosis (RDW usually elevated), or beta-thalassaemia (RDW normal).

2. The ESR is very low in both primary and secondary polycythaemia.

3. Assess for splenomegaly (and renal disease) with an abdominal ultrasound or CT scan.

4. Check the arterial blood gases (in polycythaemia rubra vera, 80% of patients have an arterial oxygen saturation >92% and in almost all it is >88%).

5. Serum erythropoietin level is usually substantially reduced or absent in polycythaemia rubra vera and elevated in secondary polycythaemia. Remember, however, that certain tumours (haemangioblastoma, renal cell carcinoma, renal sarcoma and carcinoma of the liver) cause polycythaemia by excreting erythropoietin.

6. The total vitamin B12 level is elevated in 75% of cases of polycythaemia rubra vera. The vitamin B12 level is raised owing to increased transcobalamin I and III, made by neutrophils, which have an increased turnover.

7. Rule out renal disease, if indicated.

8. In polycythaemia rubra vera there is significant panhyperplasia and iron stores are often reduced, but in secondary polycythaemia the bone marrow usually shows an erythroid hyperplasia only. There are no consistent cytogenetic markers. Bone marrow biopsy is not essential for the diagnosis: it is only necessary if another myeloproliferative disorder is suspected. Fibrosis maybe seen in the advanced stages of polycythaemia rubra vera.

9. Genetic testing is very useful. The JAK2 mutation is present in most patients with polycythaemia rubra vera.

Treatment

1. The aim is to lower the haematocrit value to 0.42–0.45 (haemoglobin <140 g/L for men and <120 g/L for women) and maintain it at this level. Patients may die of thrombosis, which seems related entirely to the elevated red cell mass. The presence of thrombocytosis does not increase the risk of thrombotic events, and anticoagulation is not indicated. Thrombotic risk can usually be controlled with phlebotomy alone. Untreated cases have a median survival of 2 years because of the thrombotic risk. This is extended to more than 10 years with phlebotomy alone.

2. Polycythaemia rubra vera should be treated by phlebotomy. Frequent venesection is required until a state of iron deficiency has been produced. This will then limit red cell production and the frequency may be reduced to about three-monthly.

3. Radioactive phosphorus (phosphorus-32) irradiates the bone marrow and is easy to use and effective, but it increases the incidence of acute myeloid leukaemia and should be avoided in patients under the age of 70 years (and perhaps in all patients). Alkylating agents (e.g. busulfan) must be monitored closely for the same reason and should not be given routinely. Both P32 and busulfan substantially increase the risk of secondary leukaemia. Hydroxyurea is a much safer drug in these circumstances.

4. Pruritus may not respond to antihistamines, and interferon alpha (IFNα) or PUVA therapy (combination drugs and ultraviolet light) may be required.

5. Hyperuricaemia should be treated with allopurinol.

6. Low-dose aspirin is recommended to prevent thrombosis in patients without excessive gastrointestinal bleeding (avoid high doses).

7. Secondary polycythaemia is treated by removal of the cause, and phlebotomy if the haematocrit exceeds 0.55.

8. Interferon alpha may help with the problem of symptomatic splenomegaly.

Idiopathic myelofibrosis

This is a rare form of chronic myeloproliferative clonal disorder. Patients are often asymptomatic at the time of diagnosis. The condition is frequently diagnosed following a routine full blood count or the discovery of splenomegaly. Myelofibrosis may also be the result of a number of malignant and non-malignant conditions (Table 8.10).

Table 8.10

Causes of myelofibrosis

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Median survival is 4 to 5 years, but patients with severe anaemia (<100 g/L), older age, constitutional symptoms and leucocytosis have a worse prognosis (median survival about 2 years).

Investigations

1. Occasionally, there may be signs of aggressive extramedullary haematopoiesis: bowel or urethral obstruction, ascites, pericardial effusion, skin masses or spinal cord compression. Rapid splenic enlargement can cause splenic infarction (with the sudden onset of left upper quadrant pain and tenderness). The typical patient is over 50 years of age and has marked splenomegaly (>10 cm) and mild-to-moderate hepatomegaly.

2. The white cell counts may be normal, increased or decreased. The blood film will show teardrop poikilocytes and a leucoerythroblastic picture (presence of myelocytes, metamyelocytes and nucleated red blood cells). Any process that infiltrates the bone marrow may cause this picture (e.g. malignancy, TB, fungi).

3. Bone marrow biopsy (aspiration is usually impossible) may reveal karyotypic abnormalities on cytogenetic examination. This finding is associated with a worse prognosis. The JAK 2 V617F mutation is seen in up to 50% of cases.

4. The condition must be distinguished from myelofibrosis secondary to other conditions, such as lymphoma, leukaemia, myeloma, polycythaemia, chronic myeloid leukaemia (CML) and SLE. These may be amenable to specific treatment.

Treatment

Treatment is primarily supportive. Most patients are treated with repeated blood transfusions.

1. Hydroxyurea is helpful for symptomatic patients with organomegaly or marked thrombocytosis.

2. Folate and vitamin B12 may help if they are deficient; erythropoietin has not been particularly effective. Allopurinol is used when there is hyperuricaemia.

3. Splenectomy may be indicated if massive splenomegaly has occurred.

4. Alkylating agents are contraindicated.

5. Cure is possible only with allogenic bone marrow transplantation for the few patients who are young enough and for whom a suitable donor can be found.

6. Leukaemic transformation may occur in 10% of patients.

7. The JAK 2 kinase inhibitor rulxilotinib is effective at ameliorating the natural history and reducing splenic volume.

Essential thrombocythaemia

This is a relatively common form of chronic myeloproliferative clonal disorder. Many patients are asymptomatic and the diagnosis is made on a routine platelet count.

Patients usually present with symptoms related to a high platelet count (>8003 × 109/L) – especially thromboembolism, but also poor memory, erythromelalgia (painful red extremities) and migraine. Up to 50% of patients have haemorrhagic problems, especially from the gut, and easy bruising. A prolonged bleeding time and abnormal platelet aggregation may be present. An acquired deficiency of von Willebrand factor may occur when platelet numbers are very high; the large von Willebrand multimers are destroyed by the platelets. There are, however, no consistent platelet abnormalities.

Modest splenomegaly (<5 cm) is seen in 50% of patients.

Investigations

1. A definitive diagnosis requires exclusion of reactive thrombocytosis secondary to infection, polycythaemia, malignancy, inflammation, bleeding, recent surgery or an asplenic state.

2. Cytogenetic studies may be necessary to exclude CML (Philadelphia chromosome t(9;22) or its products: BCR-ABL fusion mRNA or BCR-ABL protein).

3. The JAK 2 V617F mutation is seen in 50% of cases.

Treatment

1. Asymptomatic patients, even if they have a platelet count of more than one million, often need no treatment. Unexpectedly, bleeding tends to be more of a problem when the platelet count is over one million and thrombosis when it is less than one million.

2. Neurological symptoms and erythromelalgia should first be treated with aspirin. Failure of response is an indication to reduce platelet numbers, usually with hydroxyurea or interferon (IFNα). Anagrelide is a more specific antimegakaryocyte agent that can be useful for symptomatic patients, but hydroxyurea and aspirin may be more effective in preventing vascular events.

3. Bleeding problems may be improved with tranexamic acid; this may be useful if given before surgery.

4. Transformation to acute leukaemia is uncommon (<10%) and often the result of prior alkylating chemotherapy.

5. The condition usually runs an indolent and benign course and the continuing temptation to treat asymptomatic patients should be strongly resisted.

Chronic myeloid leukaemia (CML)

Some patients with CML are diagnosed from routine blood tests – symptoms tend not to be specific (Table 8.11).

Table 8.11

CML symptoms

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Investigations

1. The typical patient has moderate splenomegaly (6–8 cm) and a white cell count >50 × 109/L. The white cell differential count will show two peaks, one at the neutrophil stage and the other at the myelocyte stage.

2. Basophilia and eosinophilia is common.

3. A low NAP score is another typical laboratory feature. In the blast phase over 20% of white cells are blasts.

4. Diagnosis depends on finding the Philadelphia (Ph) chromosome (>90%) – a shortened chromosome 22. Translocation of part of chromosome 22 to chromosome 9 results in a hybrid gene BCR/ABLrearrangement on chromosome 9.

5. The platelet count is usually elevated and there is mild normochromic anaemia.

6. There is no association with alkylating agents and no evidence of a viral cause.

Treatment

Untreated, the disease will eventually undergo blastic transformation.

1. A cure or long-term remission can be achieved with allogenic bone marrow transplantation from a compatible donor in those who fail to respond or are intolerant of tyrosine kinase inhibitor therapy (see below).

2. Imatinib (a tyrosine kinase inhibitor – TKI) has revolutionised treatment of CML. This drug causes aptosis of cells expressing BCR-ABL. It is now the first-line treatment for all patients. Its use can be associated with hepatotoxicity, myalgia and fluid retention. The therapeutic target of all TKI treatment is the achievement of a major molecular response, which is defined as a ≥3 log reduction of the baseline quantitative BCR-ABL assay, preferably before 12 months from the point of commencing treatment (i.e. ≤0.1% BCR-ABL transcript to housekeeping genes is a major response; non-detectable on two samples is a complete response). Some patients will develop mutations in the BCR-ABL transcript that confer resistance to imatinib. Second generation TKIs, dasatinib and nilotinib, are available and may be active in these cases.

3. Interferon alpha therapy is sometimes helpful in the chronic phase. It may induce differentiation of the immature cells and be synergistic with imatnib in achieving a major molecular response.

Lymphomas

These diseases provide complicated diagnostic and management problems. Treatment in expert units is important, because many patients can be cured. Cure should be possible in more than 85% of patients with Hodgkin’s disease and in up to 40% of those with non-Hodgkin’s lymphomas.

Remember that the cell lineage is uncertain for Hodgkin’s disease (although probably mostly B cell), but 80% of non-Hodgkin’s lymphomas are of B cell origin. There are a number of slightly different classification systems. Some are based on the cell type (Table 8.12), some are histopathological (Table 8.13), and others are clinical staging (Table 8.14). The one utilised most in the current academic literature is the WHO (2008) classification.

Table 8.12

World Health Organization (WHO) classification of lymphomas (lymphoid malignancies) – more common types

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MALT = mucosa-associated lymphoid tissue.

Table 8.13

Histopathological classification of lymphoma

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Table 8.14

Staging of lymphoma – Ann Arbor classification

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Hodgkin’s disease (see Table 8.13) presents either with discrete, rubbery, painless nodes or with generalised symptoms (fever, night sweats, weight loss and sometimes pruritus). Mediastinal adenopathy usually occurs in young people with nodular sclerosing disease. Older people with generalised symptoms, in whom the only enlarged nodes may be in the abdomen, often have lymphocyte-depleted Hodgkin’s disease.

The majority of cases of non-Hodgkin’s lymphomas (see Table 8.13) present with painless enlargement of peripheral lymph nodes (a lymph node of >1 cm diameter that has been present for 6 weeks or more for no obvious reason should be biopsied). The great majority of patients with peripheral lymph node enlargement do not have a malignancy. Localised or generalised painless adenopathy with or without hepatosplenomegaly may also occur. It may present with just an abdominal mass. Presentation with mediastinal adenopathy is much less common than in patients with Hodgkin’s disease (except in T lymphoblastic lymphoma and primary mediastinal B large cell lymphoma where mediastinal disease is always present). In some patients the disease may arise at an extranodal site (e.g. the gastrointestinal tract – 5%). These patients may present with abdominal pain, obstruction or haemorrhage.

Most non-Hodgkin’s lymphomas are diffuse and aggressive. Waldeyer’s ring, mesenteric and epitrochlear node involvement are more common in non-Hodgkin’s than in Hodgkin’s disease. Systemic symptoms are less common in non-Hodgkin’s lymphoma. In low-grade non-Hodgkin’s lymphoma, lymphadenopathy has often been present for a long time.

Other uncommon presentations include skin infiltration and direct renal infiltration. Primary neurological infiltration is also uncommon. Low-grade gastrointestinal lymphomas (e.g. MALT – mucosa-associated lymphoid tissue – lymphomas) are less common.

The history

1. Ask about the presenting symptoms and causes of symptoms, such as palpable nodes, cough as a result of mediastinal node involvement, systemic symptoms, bone pain owing to marrow infiltration or pathological fractures, spinal cord compression, splenic pain and alcohol-induced pain (rare).

2. Is there a history of infection (as a result of decreased cell-mediated immunity in Hodgkin’s disease or depressed humoral immunity from chemotherapy or radiotherapy)?

3. Ask about the history of the predisposing condition, such as Klinefelter’s syndrome, HIV infection, congenital or acquired immune deficiency, use of immunosuppressive drugs or autoimmune disease (e.g. Sjögren’s syndrome). Ask also about the use of phenytoin (pseudo-lymphoma).

4. Find out the investigations performed – particularly lymph node biopsy, CT and gallium scans, and bilateral bone marrow aspirations. MRI scanning may have been used for suspected spinal cord, brain or bone marrow involvement. Lymphangiography and staging laparotomy are rarely indicated now. Lumbar puncture is important in high-grade lymphoma investigation if central nervous system involvement is suspected.

5. Ask about the treatment undertaken, as this gives an indication of the stage and type of disease. Ask about the side-effects of any treatment (e.g. mantle radiation can result in pneumonitis, hypothyroidism, pericarditis, myocardial fibrosis and spinal cord injury). Ask whether the patient has been informed about possible long-term complications of treatment.

6. Determine the prognosis given and what the patient’s understanding of this seems to be.

7. Find out about the patient’s social situation – dependent family members, social support, ability to work, reactions to disease (e.g. depression, coping mechanisms), etc. As for other malignancies, work out the ECOG (Eastern Co-operative Oncology Group) performance status (Table 8.15).

Table 8.15

ECOG performance status

GRADE

ECOG PERFORMANCE STATUS

0

Fully active; no restriction on activities compared with before the disease

1

Restricted, but only from strenuous activity. Able to perform light or sedentary work

2

Able to look after self. Mobile but not able to work

3

Only partly able to look after self. In bed or chair more than 50% of waking hours

4

Completely confined to bed or chair. Unable to look after self at all

The examination

1. Examine the haemopoietic system thoroughly. Particularly note any lymph nodes (Fig 8.2) and assess carefully for splenomegaly.

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FIGURE 8.2 Cervical lymphadenopathy. J W Little, D A Falace, C S Miller, N L Rhodus, Dental management of the medically compromised patient, 7th edn. Fig 24-6. Mosby, Elsevier, 2008, with permission.

2. Attempt to stage the disease clinically (Table 8.14). Remember that staging is much less relevant for non-Hodgkin’s lymphomas because spread is haematogenous and not contiguous. Fewer than 10% of even nodular non-Hodgkin’s lymphomas are localised and suitable for local irradiation at the time of presentation.

3. Note any radiotherapy marks (and the field covered).

4. Look for evidence of infection (e.g. herpes zoster).

5. If the patient is clinically anaemic, consider a Coombs’ positive autoimmune process in your differential.

6. Assess for any evidence of the hyperviscosity syndrome (Waldenström’s macroglobulinemia secondary to a monoclonal gammaglobulin): look in the fundi.

Investigations

Investigations are aimed at determining the grade and stage of the disease.

1. The first step is to obtain histological confirmation of disease. Ask to see the pathology report if excision lymph node biopsies have already been performed. Fine-needle biopsy is not good enough to define lymph node architecture. Reed-Sternberg cells are not pathognomonic of Hodgkin’s disease, but may occur in cases of glandular fever, other viral diseases and with other malignancies.

2. The next step is to stage the disease further.

a. Ask for a full blood count and ESR, a bilateral bone marrow aspirate and trephine, liver function tests, and abdominal, pelvic and chest imaging (usually chest X-ray (Fig 8.3) followed by CT scan).

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FIGURE 8.3 Chest X-ray showing bilateral hilar lymphadenopathy (arrows). Figure reproduced courtesy of The Canberra Hospital.

b. If there is a major leukaemic component, order flow cytometry of the peripheral lymphocytes to aid in the diagnosis.

3. In Hodgkin’s disease, agranulocytosis (sometimes with marked eosinophilia or a leukaemoid reaction), an elevated ESR, reversed CD4/CD8 ratio, skin test anergy and a mildly elevated alkaline phosphatase level are often present, but may not indicate widespread disease. The ESR remains the best indicator of disease activity. Lymphangiography is less often done these days, especially if the CT, single-photon emission CT (SPECT) and gallium scans are normal. PET scanning may be more sensitive than gallium scanning in staging the disease at diagnosis and in monitoring residual disease. Staging laparotomies are now only rarely performed, but previously treated patients may bear the scar. Staging in this invasive way is less relevant now that systemic treatment is more often used for all patients. Always re-stage after treatment!

Treatment

HODGKIN’S DISEASE (85% OF PATIENTS ARE CURABLE)

Treatment depends on the stage of the disease (see Table 8.14). Histological type is less important.

• Stages IA, IIA and IIIsA – radiotherapy or abbreviated course of chemotherapy followed by radiotherapy.

• Stage IIIA (with para-aortic node involvement with or without radiotherapy to involved sites), IIIB and IV – combined chemotherapy (e.g. ABVD – adriamycin, bleomycin, vinblastine and dacarbazine).

Salvage treatment

Relapse less than 1 year after initial treatment or failure to achieve complete remission is an indication for second-line therapy. For relapse after more than 1 year, retreatment can be given using the original regimen. Further radiotherapy can be used for relapse outside the radiation field if the patient has early stage disease. Autologous stem cell transplant after high-dose chemotherapy is an alternative.

Prognosis

This depends on the stage, disease bulk, age and performance status In general, in:

• stage I, expect 85–95% 10 years disease-free survival

• stage II, expect 80–90% 10 years disease-free survival

• stage III and IV, expect 60% 10 years disease-free survival.

Complications of treatment

1. The improvement in survival achieved with current treatment means that complications of treatment are more likely to cause death than the disease. Routine annual testing and review is recommended (Table 8.16).

Table 8.16

Routine annual tests for patients treated for Hodgkin’s disease

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2. Secondary malignancies, including leukaemia and carcinomas, are associated with the use of alkylating agents.

3. Breast cancer risk is associated with chest irradiation.

4. Chest radiotherapy also increases the risk of coronary artery disease after 10 years or more, and of hypothyroidism.

5. Radiotherapy and chemotherapy increase the risk of carcinoma of the lung, which is significantly greater again for smokers.

6. Infertility can occur in men and women treated with chemotherapy. The chance of recovery of fertility is much greater for young patients. Sperm or ovarian tissue banking may be offered to patients.

NON-HODGKIN’S LYMPHOMA

Prognosis and treatment depend mainly on the histological type (particularly whether it is nodular or diffuse and based on the International Working Formulation – see Table 8.13); most cases of low-grade lymphomas are stage III or IV at presentation and require only observation if asymptomatic. The International Prognostic Index (Table 8.17) has proved an accurate way of assessing the patient’s likely course. More recently, treatment decisions have been based on the WHO classification (Table 8.12).

Table 8.17

International Prognostic Index – clinical risk factors for a poor outcome

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Treatment protocols: International Working Formulation classification

1. Low-grade lymphoma. These are not curable and treatment does not increase survival. Follicular mixed cleaved cell low-grade lymphoma is indolent. Commonly it presents as stage IVA.

a. For asymptomatic low-grade lymphoma no treatment is indicated.

b. For symptomatic low-grade lymphoma, chlorambucil with or without prednisone, or CVP (cyclophosphamide, vincristine and prednisone), is the usual initial treatment.

  For stages I and II low-grade lymphoma (uncommon), extended field radiation may be used in younger patients with curative intent, but they must be very carefully staged first. More aggressive regimens (as for intermediate-grade) may produce more complete remissions, but have not been shown to increase survival. Maintenance single-agent chemotherapy has not reduced the relapse rate.

2. Intermediate and high-grade lymphoma. These have a poor prognosis if untreated. Diffuse large cell lymphoma and high-grade lymphomas are potentially curable with treatment.

a. Stage I and some stage II: aggressive treatment to try for cure is essential, but careful staging must be carried out first. A combination of immunochemotherapy (e.g. rituximab plus CHOP–RCHOP) and radiotherapy is often used.

b. Stages II, III and IV:

i. diffuse large cell lymphoma – combination chemotherapy, such as CHOP (cyclophosphamide, adriamycin, vincristine and prednisone); high-dose methotrexate and intrathecal methotrexate may be added if indicated

ii. diffuse well-differentiated lymphocytic lymphoma – this is the most indolent type and prognosis is indistinguishable from that for chronic lymphocytic leukaemia; no treatment is required unless symptomatic

iii. other diffuse types: combination chemotherapy

iv. salvage chemotherapy – failure of remission or relapse is an indication of a poor prognosis; salvage treatment is usually attempted with drugs such as cisplatin or cytosine arabinoside, but remission rates are only 20–30%. Autologous stem cell transplantation may be indicated in this setting.

c. AIDS-related lymphomas: these tumours tend to be of the large B cell or Burkitt’s type and very aggressive. Results of combination chemotherapy, so far, have been poor. The best regimens, using central nervous system prophylaxis, granulocyte colony stimulating factor (G-CSF) (to limit neutropenia) and a modified chemotherapeutic combination, have produced 50% complete response rates. There is a high mortality from associated infection in these immunodeficient patients. Rituximab improves results and it is also imperative to treat concurrently with antiviral therapy.

Treatment protocols: WHO classification

1. Precursor B cell neoplasms. Precursor B cell lymphoblastic leukaemia/ lymphoma is usually the childhood malignancy acute lymphocytic leukaemia (ALL). The lymphoma is rare in adults and rapidly progresses to become leukaemia. Combination chemotherapy is used to induce remission and continuing treatment to attempt cure. The cure rate in adults is about 50%.

2. Mature B cell neoplasms. B cell chronic lymphoid leukaemia/small lymphocytic lymphoma is the most common lymphoid leukaemia and represents about 75% of non-Hodgkin’s lymphomas. Patients with only bone marrow involvement and lymphocytosis are not usually treated. They have a median survival of more than 10 years. Once liver and splenic involvement have occurred, treatment is likely to be required at some stage, but may not be recommended until bone marrow failure is present. Oral chlorambucil or the more potent intravenous drug, fludarabine, often combined with rituximab, is most often recommended. Young patients may benefit from bone marrow transplant.

3. MALT-type lymphoma (extranodal marginal zone B cell lymphoma – 8%). These gastric mucosal lymphomas are curable when localised. MALT is associated with Helicobacter pylori infection. Eradication of the infection will usually induce remission (75%). Otherwise, chlorambucil or radiation treatment is used. Endoscopic follow-up is important. Splenic MALT lymphoma may follow hepatitis C infection; once other causes are excluded, splenectomy can induce a long remission.

4. Mantle cell lymphoma (6%). The majority of these present as a systemic disease. Treatment is not very successful. The usual approach is combination chemotherapy followed by radiotherapy. Chemotherapy may be used with rituximab (the anti-CD20 antibody). Bone marrow transplant is offered to younger patients.

5. Follicular lymphoma (22%). Asymptomatic patients may require no treatment. Chlorambucil alone or combination treatment (rituximab, cyclophosphamide, vincristine and prednisone – RCVP or rituximab cyclophosphamide, vincristine and prednisone (RCVP) – RCHOP) can achieve a 75% remission rate. Interferon alpha seems to prolong survival once remission has been achieved, and rituximab upfront is standard now and can be helpful for patients who have relapsed. Between 5% and 7% of patients per year develop histological transformation into diffuse large B cell lymphoma. Follicular lymphoma (low-grade) prognosis can be further estimated from Table 8.18.

Table 8.18

Follicular lymphoma survival rates

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6. Diffuse large B cell lymphoma (30%). Treatment is usually begun with combination chemotherapy (often CHOP). This may be followed by radiotherapy if there is bulky stage I or II disease. Six cycles of treatment will produce a cure in up to 70% of patients. Monoclonal antibody treatment with rituximab is used for most patients. Bone marrow transplant is more effective than further chemotherapy for patients who relapse: it can achieve up to 40% long-term disease-free survival. The International Prognostic Index (IPI), which is based on five pre-treatment characteristics (see Table 8.19), predicts survival.

Table 8.19

Cure rates and 5-year survival rates for diffuse large B cell lymphoma based on the International Prognostic Index (IPI)

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7. Burkitt’s lymphoma. This is a rare disease in Australia, but is more common in Africa. Intensive combination chemotherapy with attention to the central nervous system will produce a cure in about 70% of patients.

8. Hairy cell leukaemia. This is an indolent lymphoma with leukaemic features. The peripheral smear shows lymphocytes with hairy projections. Look for splenomegaly and cytopenia. It responds well to chemotherapy with cladrabine.

9. Immunodeficiency-associated lymphoma. The WHO classifies these lymphomas into four groups:

a. lymphoproliferative diseases associated with primary immune disorders

b. HIV associated lymphomas

c. post-transplant lymphomas

d. methotrexate-associated lymphoproliferative disorders.

These are usually aggressive B cell, CNS and Hodgkin’s lymphomas, and treatment is as for the type of lymphoma.

BONE MARROW TRANSPLANT

Disease resistant to standard-dose chemotherapy can be treated with bone marrow ablation using chemotherapy or radiotherapy, or both. Bone marrow transplant is then performed with autologous stem cells or, less often, from a compatible donor. The mortality rate associated with this procedure (now <5%) and the success of engraftment have improved with the use of haematopoietic growth factors. Long-term outcomes are uncertain, as are the indications for the use of this treatment in patients with less aggressive disease. Follow-up of treated non-Hodgkin’s lymphomas is similar to that for Hodgkin’s lymphoma patients.

Multiple myeloma (myeloma)

This is a disseminated malignant disease of plasma cells. It can present as a diagnostic or a management problem. Myeloma occurs more commonly in the elderly – the median age is 60 years – and more often in men. It is more common in people whose occupations involve exposure to petroleum and in people exposed to nuclear radiation. Chronic antigenic stimulation may play a role in B cell clonal transformation. A number of chromosomal deletions and translocations have been identified in myeloma patients. The most important of these is 13q; its presence has prognostic significance. Some myeloma begin as monoclonal gammopathies of uncertain significance (MGUS). MGUS are much more common than myeloma – they are found in up to 10% of 80-year-olds – and they evolve to myeloma at a rate of 1% a year (‘smouldering myeloma’).

The history

1. Ask about presenting symptoms:

a. bone pain or pain with movement affects nearly three-quarters of patients, occurs particularly in the ribs or axial skeleton and may cause pathological fractures; the association with movement may distinguish it from the bone pain of metastatic malignancy, which can be worse at night (persistent pain suggests a pathological fracture)

b. bacterial infection is the presenting problem in one-quarter of patients particularly pneumonia and urinary tract infections (total immunoglobulins are increased, but the level of normal functional immunoglobulins is reduced as a result of reduced production and increased destruction; in advanced marrow disease there is white cell depletion); the CD4 count is low; the most common organisms are Streptococcus pneumoniaeStaphylococcus aureus and Klebsiella pneumoniae in the lungs, and E. coli in the urinary tract

c. symptoms of anaemia (normochromic and normocytic) – as a result of bone marrow depression from infiltration, chronic disease, renal failure or treatment

d. bleeding tendency – caused by paraprotein inactivation of plasma procoagulants and reduced platelet function (coating of platelets with antibodies) and thrombocytopenia as a result of bone marrow suppression

e. renal disease symptoms (owing to stone formation secondary to hypercalcaemia, hyperuricaemia, tubular damage by light chains, therapy, urinary tract infection, contrast studies, plasma cell infiltration or amyloid) – renal failure affects one-quarter of patients and half develop renal impairment; renal impairment at the time of diagnosis means a poor prognosis

f. hypercalcaemic symptoms owing to bone lysis

g. hyperviscosity symptoms once plasma viscosity exceeds 5 (normal is about 1.8)

h. spinal cord compression or, rarely, diffuse sensorimotor neuropathy

i. skin changes, such as pruritus, purpura, yellow skin, hypertrichosis (rare), erythema annulare (rare)

j. systemic amyloid deposition (10–15%).

2. Find out how the diagnosis was made. This nearly always requires biopsy of the marrow or an extramedullary plasmacytoma.

3. Ask about treatment – ask about drugs (e.g. bisphosphonates, thalidomide) and their side-effects, radiotherapy and bone marrow transplant (actual or planned).

4. Enquire about the patient’s social history, including dependants, work, ADLs etc.

5. Determine the patient’s understanding of this life-threatening condition and its prognosis – how much information he or she has about possible further problems and treatment.

The examination

1. Inspect the patient for signs of weight loss, anaemia, chest infection and general debility.

2. Examine the haemopoietic system. Pay particular attention to a search for bony tenderness. Kyphosis may be caused by compression fractures. Splenomegaly and lymphadenopathy occur only very rarely.

3. Note signs of anaemia and purpura. Look for skin rash.

4. Look for signs of infection (e.g. pulmonary consolidation).

5. Check carefully for any signs of spinal cord compression.

6. Check the urine analysis and temperature chart.

Investigations

1. Once the diagnosis is suspected, check the full blood count (and film) for anaemia (and rouleaux) and a raised ESR. Obtain a protein electrophoretogram (EPG) of serum and urine and an immunoelectrophoretogram (IEPG). An ‘M’ component (monoclonal globulin peak) is found in 95% of cases (any immunoglobulin class may appear as the ‘M’ component). Light chains are present in the urine in 50–75% of patients (Bence-Jones proteinuria cannot be detected by dipstick urine analysis).

2. Analysis of circulating light chains in the serum is a more sensitive way of detecting light chain myeloma as an abnormal κ:λ ratio is seen. It is helpful in monitoring the response to treatment of such patients.

3. The bone marrow must be examined for plasma cells (>10% in myeloma). Check the beta2-microglobulin level (see below).

4. Look at X-ray films of the skull (Fig 8.4), chest, pelvis (Fig 8.5) and proximal long bones for fractures, osteoporosis and lytic lesions. The latter is a result of the secretion of osteoclast-activating factors by the tumour cells. Since there is little osteoblastic activity, bone scans are much less sensitive than plain X-rays.

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FIGURE 8.4 Skull X-ray of a myeloma patient showing multiple lucent areas pepper-pot skull (arrows). Figure reproduced courtesy of The Canberra Hospital.

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FIGURE 8.5 X-ray of the pelvis showing destruction of the left superior ramus of the ischium (arrow). Figure reproduced courtesy of The Canberra Hospital.

5. MRI scans may be the best way to investigate pain and possible nerve root or spinal cord compression.

6. Also check the serum calcium and urate levels and the renal function.

The three major diagnostic features of multiple myeloma, in order of importance, are:

1. plasma cells in the bone marrow (>10% involvement is consistent with the diagnosis)

  In the marrow there will be >10% plasma cells with evidence of at least organ/tissue injury: CRAB (Hyper Calcaemia, Renal disease, Anaemia and Bone lytic lesions)

2. production of serum paraprotein (50% are IgG, 33% IgA, 5% IgM, 10% only light chains, 2% nil)

3. bone destruction (lytic lesions).

The disease can be staged according to certain criteria (Table 8.20). On this basis, median survival can be estimated as follows:

Table 8.20

International staging system

1. Stage 1

Beta 2 microglobulin < 3.5mg/dL and serum albumin ≥ 3.5g/dL

2. Stage II

Neither I or II

3. Stage III

Beta 2 microglobulin ≥ 5.5mg/L

The International Myeloma Foundation.

• stage I – 62 months (median)

• stage II – 44 months (median)

• stage III – 29 months (median).

An elevated serum beta2-microglobulin level (which reflects the myeloma cell burden and renal functional impairment) indicates a reduced median survival. Other poor prognostic features include advanced age and cytogenetic abnormalities (e.g. any translocation, deletion of chromosome 13q).

Treatment

1. Irradiation is helpful for localised bone pain and spinal cord compression. Patients with a single bone plasmacytoma will often get prolonged disease-free survival after treatment with local radiotherapy. Pamidronate or one of the other bisphosphonates should be given to patients with more than stage I disease. Bisphosphonates reduce bone pain, fracture rates and episodes of hypercalcaemia. There is evidence that they improve the prognosis.

2. For those with more diffuse disease, general measures, such as adequate hydration and use of bicarbonate for Bence-Jones proteinuria, are important to prevent renal failure. Intravenous contrast material must be used cautiously and only with excellent hydration. Allopurinol may protect renal function from urate nephropathy related to treatment. Treat hypercalcaemia and bacterial infection. Avoid live vaccines. Erythropoietin may improve the anaemia.

3. Systemic therapy is indicated for patients with stage II or III disease and for those with stage I disease if they are symptomatic or have rising myeloma protein levels or progressive lytic bone lesions. Treatment is begun with high-dose steroids in combination with thalidomide or lenalidomide (reduce tumour necrosis factor alpha). An alternative is bortezomib, a proteosome inhibitor.

4. Alkylating agents should be avoided if the patient may be a candidate for bone marrow transplant. Such drugs may prevent stem cell harvesting by damaging these cells. Melphalan and prednisone were standard treatment; other alkylating agents (e.g. cyclophosphamide) are probably equally effective for patients unsuitable for bone marrow transplant. Resistance to one alkylating agent is often, but not always, associated with resistance to the others.

  Older patients (ineligible for autologous transplant) typically receive melphalan, thalidomide and prednisone (MTP) orally. Bortezomib, melphalan and prednisone (VMP) is an alternative. Typically treatment is given intermittently. A week’s course is repeated 4 weeks later for up to 2 years. The patient’s progress must be monitored with regular protein EPG studies.

5. Relapse is treated for suitable patients with autologous stem cell bone marrow transplant.

DIFFERENTIAL DIAGNOSIS

Monoclonal gammopathy of undetermined significance

A smaller monoclonal peak (<30 g/L), fewer than 10% plasma cells in the bone marrow and absence of lytic bone lesions suggest this diagnosis. Urinary light chains are absent. Infection, renal failure and anaemia are not increased. No therapy is required.

Waldenström’s macroglobulinaemia

The EPG has a peak consisting of monoclonal IgM. These patients are generally older than those with myeloma. The hyperviscosity syndrome is often present; symptoms and signs include lassitude, confusion, bleeding, anaemia, infection, lymphadenopathy and splenomegaly, dilated retinal veins and perivenous haemorrhages, and (rarely) renal failure. Lymphadenopathy and splenomegaly do not usually occur in patients with myeloma. Lytic bone destruction and hypercalcaemia are rare. Ten per cent of the macroglobulins are cryoglobulins. An underlying lymphoproliferative disorder may be present. Treatment with plasmapheresis is effective in removing IgM paraprotein. Prednisone, fludarabine and chlorambucil are useful. Rituximab (anti-CD20 monoclonal antibody) and thalidomide have also been used successfully. Median survival is 4 years.

Localised myeloma

Only one plasma cell tumour is present. Solitary plasmacytomas often occur in the nasopharynx or paranasal sinuses. The major complications of myeloma are absent. Only 50% of cases show a monoclonal peak. Local radiotherapy is the usual treatment.

POEMS syndrome

This is an atypical form of myeloma. The features include:

Polyneuropathy

Organomegaly

Endocrinopathy

Monoclonal gammopathy (osteosclerotic myeloma, or IgA or IgG M proteins with lambda light chains)

Skin changes

There is a progressive sensorimotor polyneuropathy associated with myeloma-like bone lesions. Unlike multiple myeloma patients, over half these patients have hepatomegaly and lymphadenopathy and some have splenomegaly. Male erectile dysfunction and gynaecomastia and female amenorrhoea occur as a result of hyperprolactinaemia. A few patients have hypothyroidism and one-third have type 2 diabetes. Skin changes include clubbing, hypertrichosis, thickening and increased pigmentation.

Elevated vascular endothelial growth factor (VGEF) occurs in two-thirds of patients.

Treatment of the myeloma component in the usual way often helps the other manifestations. Local bone lesions often respond to radiotherapy. Progressive peripheral neuropathy to respiratory failure over years is the natural history.

Bone marrow (haematopoietic cell) transplantation

Bone marrow transplantation is being performed for an increasing number of indications. Patients are chronically ill and often available for examinations. Two groups of patients are treated in this way: those with a malignant condition (Table 8.21), who have their bone marrow destroyed by irradiation or chemotherapy given in marrow-toxic doses to treat a malignancy; and those with a defective bone marrow that is destroyed and then replaced (Table 8.22). Autologous transplants (when the patient’s own marrow or stem cells are stored and then reinfused) are now more common than allogenic transplants (when another person is used as the donor of marrow or stem cells).

Table 8.21

Malignant indications for bone marrow transplant

CONDITION

AUTOLOGOUS

ALLOGENIC

Acute leukaemia

Yes (uncommon)

Yes

Chronic myeloid leukaemia

Yes (rare)

Yes (uncommon now except in TKI failure)

Lymphoma

Yes (common)

Yes

Hodgkin’s disease

Yes (common)

Yes

Carcinoma of the breast

No

No

Carcinoma of the testis

Yes

No

Multiple myeloma

Yes

Yes

Wilm’s tumour

Yes

No

Table 8.22

Non-malignant indications for bone marrow transplant

CONDITION

AUTOLOGOUS

ALLOGENIC

Aplastic anaemia

No

Yes

Sickle cell disease

No

Yes

Thalassaemia

No

Yes

Gaucher’s disease

No

Yes

Severe combined immunodeficiency

No

Yes

Fanconi’s anaemia

No

Yes

Autoimmune disease (RhA, Multiple sclerosis)

Yes

No

The history

1. Ask what the indication for the transplant was.

2. Find out whether there has been a problem leading to the current admission to hospital (if the patient is an inpatient).

3. Ask whether other treatment has been tried unsuccessfully. (For example, bone marrow transplant is often the treatment of choice for relapse after treatment for leukaemia or lymphoma.)

4. Find out whether the bone marrow transplant was autologous or allogenic. How was the marrow ablated before transplant (radiotherapy, chemotherapy, or both) and, if the transplant was autologous, how were the stem cells harvested (from peripheral blood or by bone marrow aspiration)?

5. If the transplant was allogenic, does the patient know the donor? Only about 30% of people have an HLA-compatible relative. For the rest, a volunteer unrelated donor is used. HLA antigens are inherited together and rarely cross over. The patient may know how close the match was.

6. Ask how long the patient was in hospital after transplantation. (Engraftment is usually quicker and complications fewer after autologous transplant.) Ask specifically about problems with infection in the early period and how complications were managed.

7. Find out what effects this complicated illness and treatment have had on the patient’s life and ability to work. Ask about family and financial problems. Young patients are likely to have been made sterile by the treatment. Total body irradiation and the use of alkylating agents are more likely to cause permanent sterility than other treatments. Women more often regain fertility than men. Ask tactfully whether the patient is aware of this.

8. Ask how effective the treatment has been. Does the patient feel better or worse than before and what medium- and long-term prognosis has he or she been given?

9. Ask whether there have been specific transplant-associated problems. Ask specifically about the symptoms and signs of graft versus host disease (GVHD) and the other complications of allogenic transplantation (Table 8.23).

TABLE 8.23

Complications of allogenic bone marrow transplant

image

10. Ask about the patient’s current medications.

The examination

Examine for persisting or recurrent signs of the condition for which the bone marrow transplant was performed.

1. Examine for signs of GVHD. These include skin changes similar to those of scleroderma, dry eyes and mouth (sicca syndrome), alopecia and bronchiolitis obliterans (signs of airflow obstruction).

2. Examine for hepatic enlargement and ascites (veno-occlusive disease of the liver). Feel all the lymph node groups (e.g. enlarged as a result of a second malignancy, such as ALL or melanoma) and examine the eyes (e.g. secondary glioblastoma).

3. Look for signs of infection in the lungs and for herpes zoster.

4. Examine the hips (aseptic osteonecrosis).

5. Patients who have had radiotherapy may show evidence of hypothyroidism.

Management

Detailed discussion about methods of transplantation will not be required.

1. Management after transplant begins with supportive treatment to prevent infection and bleeding before engraftment occurs. Platelet and blood transfusions may be required and the patient is usually kept isolated. Transfused products are irradiated to prevent GVHD from transfused lymphocytes. Most patients receive colony-stimulating factors to speed recovery. Platelet recovery is usually the slowest and tends to determine the time of discharge from hospital.

2. Patients who have had an allogenic transplant are at risk of GVHD. This risk is reduced if the HLA match is a good one (only one locus is mismatched). Prophylaxis against GVHD with some combination of prednisone, methotrexate and cyclosporin is usual. The donor marrow may be treated to remove T cells to reduce the incidence of GVHD, but this increases the risk of graft rejection. The risk of GVHD is also increased by previous exposure to blood products and by previous pregnancy.

3. Acute GVHD can occur even when the major HLA antigens match. It occurs by definition in the first 3 months after transplant and is characterised by diarrhoea, skin rash and liver function test changes. Severe acute GVHD (generalised erythroderma or desquamation) reduces survival and requires aggressive treatment. It is usually treated with high doses of prednisone, antithymocyte globulin and monoclonal antibodies to T cells. Some centres use prophylactic treatment after transplant with methotrexate and tacrolimus or cyclosporin. Remember that the presence of some GVHD reduces the risk of tumour recurrence as a result of graft versus tumour activity.

4. Chronic GVHD develops after 3 months and affects up to half of transplant recipients. Patients develop an autoimmune-like illness with sicca syndrome, arthritis, cholestasis and bronchiolitis obliterans. It is treated with immunosuppression. It is rare for it to persist for more than 3 years.

5. Infection can be a problem at various times after transplant. Bacterial infection is most common during the early period before the neutrophil count reaches normal levels. It is treated with isolation and appropriate antibiotics. Fungal infection can become a problem within a week of transplant but usually resolves once engraftment has occurred. Pneumocystis jirovecci infection and cytomegalovirus (CMV) infection can occur within a week of transplant but are uncommon after 3 months. Interstitial pneumonitis occurs in up to 10% of patients. This is usually the result of CMV infection and is treated with supporting measures and ganciclovir. CMV-negative recipients should receive only CMV-negative blood products, and CMV-positive patients should receive prophylactic ganciclovir. Prophylactic treatment with fluconazole, cotrimoxazole and ganciclovir is often used to prevent these problems.

6. Graft rejection is usually a result of the activity of functional host lymphocytes and is most common in patients who have not had their marrow ablated (e.g. those with aplastic anaemia).

7. Recurrence of leukaemia may be treated with infusion of more donor T cells, although this increases GVHD.

8. Veno-occlusive disease of the liver occurs in up to 50% of patients. Most recover, but in severe cases treatment with tissue plasminogen activator may be indicated. The use of ursodeoxycholic acid may also diminish the incidence.

9. Overall, autologous bone marrow transplant is associated with similar but less severe complications. GVHD, however, does not occur. Transplant-related mortality is much less at 1–2%.

10. The prognosis varies with the indication for the treatment (Table 8.24). In general, malignant conditions have a better prognosis when treated with bone marrow transplant as a primary or secondary therapy than when it is used only after all else has failed. Patients with non-malignant conditions can often be very successfully treated with bone marrow transplant. For example, aplastic anaemia patients can expect up to 90% disease-free survival. Opinions differ about the use of bone marrow transplant as initial treatment for these patients.

Table 8.24

Survival of bone marrow transplant patients

CONDITION

5-YEAR SURVIVAL RATE

Acute myeloid leukaemia (AML)

50%

Acute lymphatic leukaemia (ALL)

50%

Chronic myeloid leukaemia (CML), chronic phase

70%

CML accelerated

40%

CML blast crisis

15%

Chronic lymphocytic leukaemia (CLL)

50%

Hodgkin’s disease

50%

Non-Hodgkin’s lymphoma

40%

Aplastic anaemia

90%

Severe combined immunodeficiency

90%

Thalassaemia

90%

11. Remember that, as with any complicated and life-threatening illness, pay great attention to the patient’s ability to cope and the availability of support at home; these are important matters you must be able to discuss.