ANAEMIA
Case vignette
An 81-year-old female is admitted to the coronary care unit with crescendo angina. She also complains of early satiety, nocturia and pedal oedema. She reports a 10 kg weight loss over 3 months. She has a background history of rheumatoid arthritis. She is currently managed on a non-steroidal antiinflammatory agent and aspirin. On examination she is hypertensive with a pulse rate of 100 bpm. She has significant conjunctival and palmar crease pallor. The ECG shows evidence of left ventricular hypertrophy and diffuse ST segment depression, together with T wave inversion in the inferior leads. Her blood tests reveal an Hb level of 7 g/dL.
Approach to the patient
An Hb level of < 13 g/dL in men and < 12 g/dL in women is considered anaemic in common practice.
History
Ask about:
• the symptoms at presentation—patients may present with constitutional symptoms such as lethargy, malaise, exertional dyspnoea, fatigue or gastrointestinal blood loss in the form of haematemesis or melaena
• easy bruising, uncontrolled blood loss, large joint arthropathy and excessive bleeding post-surgery—features suggesting a coagulation disorder/bleeding diathesis
• other symptoms that would help identify the aetiology, such as change in bowel habits or weight loss suggesting colonic cancer, abdominal discomfort, bloating, anorexia and weight loss of gastric carcinoma, abdominal pain suggesting peptic ulcer disease, night sweats, weight loss and fevers suggesting lymphoma.
Take a detailed medication history, looking for evidence of therapy with non-steroidal antiinflammatory agents, sulfur-containing medications (haemolysis) and myelosuppressive agents. Enquire about alcoholism and general nutrition. Check whether the patient has had any transfusions and whether there have been any adverse transfusion reactions or transmission of blood-borne infections such as hepatitis C and HIV. It is also useful to know the patient’s blood group.
Examination
Look for features of anaemia such as palmar crease pallor, conjunctival pallor, tachypnoea, tachycardia and evidence of high-output cardiac failure. Look for signs that suggest the likely aetiology (see box): characteristic copper-hue pigmentation (the combined effect of melanin deposition, icterus and pallor) of the thalassaemia patient with malar hyperplasia and often stunted growth, pigmented lesions in the mouth (Peutz-Jeghers syndrome), scleral icterus (haemolysis), epigastric tenderness (peptic ulcer disease), abdominal distension or mass lesions, splenomegaly, hepatomegaly, bony tenderness (malignancy), lymphadenopathy (lymphoma), impaired cognition, peripheral neuropathy and dorsal column signs (vitamin B12 deficiency), arthropathy (anaemia of chronic disease or gastrointestinal blood loss secondary to NSAID use), slate-grey pigmentation, peripheral arteriovenous fistula, vascular access device or abdominal Tenckhoff catheter (renal anaemia).
Causes of anaemia
1. Bleeding (acute/chronic)
2. Haematinic deficiency (iron, vitamin B12, folate, vitamin C)
3. Haemolysis (immune/mechanical/toxic/paroxysmal nocturnal haemoglobinuria)
4. Chronic inflammation
5. Chronic renal failure
6. Bone marrow infiltration
7. Bone marrow suppression (e.g. cytotoxics, carbimazole, gold, irradiation)
8. Sepsis (e.g. malaria, Clostridium welchii)
9. Marrow aplasia
10. Myelodysplasia
11. Myelofibrosis
12. Haemoglobinopathies (sickle cell disease, thalassaemia)
13. Sideroblastic anaemia
Anaemia in the long case patient is often multifactorial. The diagnostic work-up should include a comprehensive battery of tests as guided by the clinical setting. Iron deficiency secondary to chronic blood loss, commonly from the gastrointestinal tract, is the most common cause of anaemia in this group of patients. Other differential diagnoses encountered commonly include anaemia of chronic disease, vitamin B12 and folate deficiency, myelodysplasia, aplastic anaemia, sideroblastic anaemia, myelosuppression, chronic renal failure, myelofibrosis and chronic alcoholism (due to a combination of bone marrow toxicity of alcohol, iron and folate deficiency and gastrointestinal bleeding).
Investigations
Investigation of anaemia should be guided by the clinical picture. The more common conditions should be excluded first. Relevant investigations in the anaemic patient include:
Blood picture: Patients with anaemia of chronic disease usually have normocytic, normochromic anaemia. Those with iron deficiency, thallasaemia or sideroblastic anaemia have microcytic, hypochromic anaemia. Microcytic, hypochromic anaemia is also seen in myelodysplastic syndrome.
2. Coagulation profile—international normalised ratio (INR), activated partial thromboplastin time (APTT), bleeding time and clotting time, to exclude a bleeding diathesis
3. Haematinics—iron studies in the form of serum ferritin, serum iron and transferrin saturation, to exclude iron deficiency
4. Serum vitamin B12 and serum and red cell folate levels
5. Haemolytic screen—including blood film, serum haptoglobin level, serum lactate dehydrogenase (LDH) level, serum bilirubin level, the direct Coombs’ test, haemoglobin electrophoresis, Heinz body preparation and, if indicated, the cold agglutinin test
6. Erythrocyte sedimentation rate (ESR)—looking for evidence of chronic inflammation and paraproteinaemia
7. Electrolyte profile and the renal function indices—to exclude renal failure as a cause
8. Erythropoietin levels
9. Thyroid function tests—to exclude hypothyroidism, which can cause a macrocytic anaemia
10. Chest X-ray—to exclude chronic pulmonary disease and pulmonary malignancies
11. Serum protein electrophoresis and immunoelectrophoresis—to exclude any paraproteinaemia
12. If all non-invasive and minimally invasive tests do not help in the correct diagnosis, the next investigation is a bone marrow biopsy with both aspiration and trephine.
Management
Management depends on severity (level of Hb) and the patient’s cardiopulmonary status. Initial steps include identification and correction of reversible, causative factors and replacement of blood with packed cell transfusions and/or the supplementation of haematinics as indicated.
As a general rule, blood transfusion is indicated if Hb is < 7 g/dL. If Hb remains > 10 g/dL, transfusion should be considered only if there is a compelling clinical indication such as precipitation of coronary ischaemia or heart failure.
Gastrointestinal bleeding warrants endoscopy (colonoscopy or gastroscopy) to identify the exact location of the bleeding and for possible therapy or biopsy of suspicious lesions. If gastroscopy and colonoscopy fail to identify the source of bleeding, capsule endoscopy may be warranted, to look for a small intestinal focus.
Patients with chronic renal failure need iron supplementation and at times may need IV iron infusion. Patients with kidney disease may benefit from therapy with erythropoietin or darbapoietin.
It is recommended that patients with chronic kidney disease be maintained at an Hb level of 11 g/dL or more.
Patients with anaemia of chronic disease improve when the underlying disease is well treated. Haematinic replacement and therapy with erythropoietin or darbapoietin is also indicated in this group.
Management of anaemia due to cytotoxic chemotherapy in patients with non-myeloid malignancies is similar to the management of anaemia of chronic disease.
HAEMATOLOGICAL MALIGNANCIES
Haematological malignancies are commonly encountered in the long case. History taking should enquire into the events surrounding the diagnosis, such as presenting symptoms of fatigue, lethargy, weight loss, fever, night sweats, bone pain, how the diagnosis was made, the various investigations that have been carried out, including bone marrow biopsy and/or excision biopsy of lymph nodes, and the treatment given so far, including blood transfusions, chemotherapy and bone marrow or stem cell transplantation. Ask about the side effects of chemotherapy and any episodes of febrile neutropenia, life-threatening sepsis etc. Ask how the patient is coping with the disease, what knowledge they have about the prognosis of the condition, what expectations they have for the future, and the level of social support available.
Following is a discussion of the salient points relevant to the commonly encountered haematological malignancies. The candidate is expected to have an up-to-date knowledge of each disease and to be able to handle wisely the complicated clinical issues associated with the management of these conditions.
MULTIPLE MYELOMA
Case vignette
A 56-year-old man presents with significant lethargy, severe back pain, loss of sensation in the lower extremities and dizziness. He also complains of bleeding gums and frequent blurring of vision. Physical examination reveals mucosal and conjunctival pallor and bony tenderness of the lower back. There are signs of peripheral neuropathy. His blood tests reveal anaemia, renal impairment and hypercalcaemia.
Approach to the patient
Multiple myeloma is a common malignant condition encountered in the long case setting, because patients with multiple myeloma can have many secondary medical complications. Multiple myeloma is due to disordered proliferation of a clone of plasma cells secreting monoclonal immunoglobulins. The clinical presentation of multiple myeloma is variable.
History
Ask about pain, bony fractures, lethargy, fatigue, dyspnoea, mucosal bleeding, fevers and rigors. Enquire about loss of sensation, limb weakness, visual problems and dizziness.
Some common presentations are intractable bone pain, pathological fracture, symptomatic anaemia, pancytopenia, sepsis, renal failure or acute symptomatic hypercalcaemia. Some may present with the hyperviscosity syndrome, with associated neuropathy and coagulopathy (oral and nasal bleeding, blurred vision, headache and vertigo) or amyloidosis. Hyperviscosity syndrome is more common in Waldenström’s macroglobulinaemia, where the paraprotein is IgM. The most common presenting symptom, however, is bone pain, particularly in the vertebral column. Multiple myeloma should be suspected in any patient over the age of 40 years presenting with bone pain, pathological fracture, osteoporosis, lethargy, anaemia and recurrent infections. Incidental discovery of proteinuria, hypercalcaemia, acute renal failure, high ESR or rouleaux formation should alert the clinician to look for multiple myeloma.
Examination
Look for evidence of anaemia and sepsis. Do not forget to look at the temperature chart. Check the mucosa for bleeding. Perform a thorough neurological examination. Look for bony fractures and assess for bone tenderness.
Investigations
1. Full blood count—looking for anaemia or pancytopenia
2. Blood film—looking for a normocytic normochromic picture and rouleaux formation
4. Serum electrolyte profile
5. Renal function indices—looking for renal failure due to light-chain toxicity, sepsis, amyloidosis and hypercalcaemia
6. Serum calcium level and serum albumin level—looking for hypercalcaemia and hypoalbuminaemia
8. Serum uric acid level—can be elevated
9. Serum and urine protein electrophoresis and immunoelectrophoresis—looking for a paraprotein band
10. Skeletal survey—looking for lytic bone lesions
11. Bone marrow biopsy (both aspirate and trephine)—looking for plasma cell infiltration. Bone marrow immunoperoxidase staining will identify kappa or lambda light chains in the plasma cells, confirming its monoclonal nature.
12. Cytogenetic analysis by interphase fluorescence in situ hybridisation (FISH)
Figure 8.1 Lytic bone lesions: anteroposterior (A) and lateral (B) radiographs of the distal forearm demonstrate an expansile destructive lytic lesion with its epicentre in the diametaphysis of the distal radius which abuts the epiphyseal plate
(reprinted from Kai B, Ryan A, Munk P L et al 2006 Gorham disease of bone: three cases and review of radiological features. Clinical Radiology 61:7).
Figure 8.2 Axial CT image of the head in bone window, revealing irregular lytic lesions of the cranial vault in the occipital and left temporal regions
(reprinted from Dinkar A D, Spadigam A, Sahai S 2007 Oral radiographic and clinico-pathologic presentation of Erdheim-Chester disease: a case report. Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontology 103:5)
Figure 8.3 Bone marrow film of a myeloma patient
(reprinted from Kumar V, Abbas A K, Fausto N 2005 Robbins and Cotran Pathologic Basis of Disease, 7th edn. Elsevier, Philadelphia, p 679, fig 14.16)
Diagnostic criteria for multiple myeloma
For the diagnosis of multiple myeloma there should be one major criterion together with one minor criterion or three minor criteria present—these should be clinically manifest.
(Adapted from Grogan T M 2001 Plasma cell neoplasms. In: Jaffe E S, Harris N L, Stein H et al (eds) World Health Organization classification of tumours. Pathology and genetics of tumours of haematopoietic and lymphoid tissues. IARC Press, Lyon, p 142)
(Adapted from Grogan T M 2001 Plasma cell neoplasms. In: Jaffe E S, Harris N L, Stein H et al (eds) World Health Organization classification of tumours. Pathology and genetics of tumours of haematopoietic and lymphoid tissues. IARC Press, Lyon, p 142)
(From Greipp P R, San Miguel J, Durie B J et al 2005 International staging system for multiple myeloma. Journal of Clinical Oncology 23(15):3412–3420)
(From Greipp P R, San Miguel J, Durie B J et al 2005 International staging system for multiple myeloma. Journal of Clinical Oncology 23(15):3412–3420)
Management
Emergent management of acute complications:
General management strategy:
1. If the patient is suitable for autologous bone marrow transplantation (patients aged less than 70 years and with good prognostic features)—initial cytoreduction with combination chemotherapy such as VAD (vincristine, doxorubicin, dexamethasone)/stem cell collection at maximal response/high-dose melphalan followed by stem cell rescue.
2. A second autologous bone marrow transplantation may be indicated if there is less than very good partial response (VGPR; a response less than 90%).
3. Maintenance therapy with thalidomide with or without steroids if in remission.
4. If the patient is not suitable for autologous bone marrow transplantation—thalidomide-based therapy with melphalan and prednisone or dexamethasone.
If the disease relapses or is progressive:
1. Thalidomide-based therapy—for those who have not been treated with thalidomide previously.
2. Bortezomib—for those who have been treated with thalidomide before.
3. Lenalidomide (a thalidomide analogue).
4. Non-ablative allograft bone marrow transplantation from a human leucocyte antigen (HLA)-matched sibling (especially for those aged < 65 years)—this is associated with significant toxicity and therapy-related mortality (e.g. graft-versus-host disease).
5. If the disease is still not responding, consider new and experimental biological therapies or unrelated donor allograft bone marrow transplantation (if the patient is aged < 50 years and in the absence of bad prognostic cytogenetics).
Supportive care:
Differential diagnoses for paraproteinaemias
1. Monoclonal gammopathy of unknown significance (MGUS)—in this condition the patient is asymptomatic, the M component in the serum is < 30 g/L, the plasma cell component in the bone marrow is < 10%, there is no M protein in the urine, there are no bony lytic lesions, there is no anaemia or hypercalcaemia, and the renal function is not impaired.
Risk of progression to multiple myeloma depends on:
2. Smouldering myeloma—in this condition the M protein level in the serum is elevated enough to suggest a diagnosis of multiple myeloma. There are > 10% myeloma cells in the bone marrow, but there is no anaemia, renal failure or skeletal lesions.
3. Solitary plasmacytoma—this disease presents with a single bony lesion. Serum M protein component is not seen. This can be treated with a curative intent using local radiotherapy. Average survival with this condition is 10 years.
4. Waldenström’s macroglobulinaemia—patients with this condition present with fatigue, weight loss, anaemia and the syndrome of hyperviscosity. The patient may also have retinal bleeds, lymphadenopathy, hepatosplenomegaly, an elevated ESR and very high serum IgM levels. Therapeutic options include plasma exchange for hyperviscosity syndrome and/or management of lymphoma with fludarabine or chlorambucil and rituximab.
5. Primary or light chain (AL) amyloidosis
6. Lymphoma
7. Chronic lymphocytic leukaemia (CLL)
Signs of poor prognosis in multiple myeloma
1. Cytogenetic abnormalities—(cytogenetic abnormalities associated with poor prognosis are: del 13q, t(4:14), del 17p)
2. Significant anaemia with a haemoglobin level of < 8.5
3. Hypercalcaemia
4. High M protein production rate
5. Acute or chronic renal failure
6. Low serum albumin level (30 g/L)
7. Elevated beta 2 microglobulin level (5.5 mg/L)
8. Elevated LDH levels
9. Age over 70 years
10. Poor performance status
CHRONIC MYELOGENOUS LEUKAEMIA
Case vignette
A 45-year-old man with massive hepatosplenomegaly was diagnosed with chronic myeloid leukaemia when he saw his GP to discuss his recent significant weight loss. He has a young family and he remains the sole breadwinner.
Approach to the patient
Chronic myelogenous leukaemia (CML) is a clonal myeloid stem cell disorder characterised by three discrete phases:
Without therapeutic intervention, the disease eventually and inevitably progresses to blast phase.
Individuals of all age groups can be affected by this condition, but it is particularly common among those over the age of 55 years.
History
Ask about the diagnosis and the initial symptoms. Ask about fatigue, weight loss, spontaneous bleeding and abdominal fullness. Patients present with the symptoms of fatigue, anorexia and weight loss. However, about 40% of patients are diagnosed incidentally.
Examination
Examine for abdominal organomegaly. On presentation the patient may have massive splenomegaly or hepatosplenomegaly.
Investigations
1. Full blood count and differential—looking for elevation of the white blood cell (WBC) count (with a left shift showing myeloid precursor cells) and the platelet count and sometimes the haemoglobin level. There is basophilia and eosinophilia in the differential WBC count.
2. Bone marrow biopsy—usually shows a hypercellular picture with myeloid hyperplasia.
3. Diagnosis of CML depends on the detection of the BCR-ABL (break point cluster region) transcript (translocation of c-ABL proto-oncogene from chromosome 9 to 22). This is the product of the t (9:22) Philadelphia chromosome.
4. Leucocyte alkaline phosphatase activity is low or normal—this test is only rarely done.
Management
Initial therapy:
1. While awaiting the results of the cytogenetic and molecular tests, the patient’s blood counts can be stabilised with hydroxyurea. Prophylactic therapy with allopurinol against gout due to hyperuricaemia associated with cytoreduction is also important at this stage.
2. Standard therapy during the chronic phase: imatinib (400–600 mg/day)—this agent is a tyrosine kinase inhibitor that has revolutionised the treatment of CML in the chronic phase.
The therapeutic response is monitored by:
3. Good response to the above therapy with maintenance of remission is an indication to continue therapy with regular monitoring (3-monthly bone marrow examinations for 1 year). If the response is maintained, therapy is continued further with annual bone marrow examinations. Dose increases can be considered for suboptimal responses.
4. Allograft bone marrow transplantation is considered for suitable patients in accelerated or blast phase or for those not responding to imatinib therapy. Suitability for allografting depends on patient’s age, performance status and the availability of HLA-matched related or unrelated donors.
5. Second-line tyrosine kinase inhibitors (dasatinib/nilotinib) should be considered for those who do not respond to imatinib therapy even at a higher dose and are not suitable for allografting.
ACUTE MYELOID LEUKEMIA
Case vignette
A 63-year-old female presents with left-sided hemiparesis and visual impairment. She also complains of excessive fatigue preceding the neurological event, together with recent onset of back pain. She has a background history of Hodgkin’s lymphoma, treated curatively 5 years ago. Examination reveals, in addition to the neurological deficit, retinal ischaemia, evidence of anaemia, mucosal bleeding and gum hypertrophy. Blood tests reveal leucocytosis with myeloblasts.
Approach to the patient
The incidence of this condition increases with age, peaking at around age 65 years.
History
Ask about:
• presenting symptoms—patients usually present with fatigue, pallor, dyspnoea, fever, bone pain, gum hypertrophy and spontaneous bleeding
• any visual problems
• monarthritis
• previous malignancies, such as lymphoma, and therapy thereof—secondary acute myeloid leukaemia (AML) due to prior chemotherapy or radiotherapy has a grave prognosis.
Examination
Look for evidence of anaemia, mucosal bleeding, bone tenderness, lymphadenopathy and organomegaly. Lymphadenopathy, hepatomegaly and splenomegaly are less common manifestations. Increased leucocyte count can lead to leucostasis, causing visual impairment due to retinal ischaemia, stroke, bleeding diathesis and acute respiratory distress syndrome. Collectively this is called ‘hyperleucocytosis syndrome’.
Some patients may present with hyperuricaemia, manifesting as gouty arthritis and ureteric colic, or with symptomatic hypercalcaemia. Check the temperature chart for fevers.
Investigations
1. Full blood count—may show circulating myeloblasts with or without a leucocytosis and associated anaemia and thrombocytopenia
2. Electrolyte profile, renal function indices, liver function indices
3. Bone marrow biopsy—this is diagnostic and shows > 20% blast cells
4. Immunophenotyping, cytogenetics and molecular studies—looking for abnormalities such as PML-RARA transcript, CBF leukaemia. These are very important in the diagnostic work-up.
5. Coagulation profile, D-dimers
6. Echocardiogram
Management
Management options differ depending on the patient’s age, performance status and cytogenetic risk category. Patients of good performance state and aged < 70 years are either recruited into a novel chemotherapy trial or treated with induction chemotherapy (e.g. ICE—idarubicin, cytarabine, etoposide or FLAG—fludarabine, cytarabine, combinations) followed by consolidation therapy.
This is followed by further therapy depending on the patient’s cytogenetic risk group (see box):
Patients with acute promyelocytic leukaemia (APML) should be investigated for evidence of disseminated intravascular coagulation.
Cytogenetic associations of AML
Based on the cytogenetic analysis, patients are divided into good risk, standard risk and poor risk categories:
There are an evolving number of molecular variants of AML which, hopefully, will further stratify these cytogenetic subtypes.
These patients can be treated with all-transretinoic acid (ATRA) and idarubicin. Maintenance therapy consists of a combination of ATRA, methotrexate and 6-mercaptopurine.
At relapse, treatment is with arsenic trioxide (As2O3) and ATRA.
ACUTE LYMPHOBLASTIC LEUKAEMIA
Acute lymphoblastic leukaemia (ALL) is less common, and in the adult patient the prognosis is relatively guarded. The prognosis depends on the cytogenetic analysis. Poor prognostic cytogenetic markers include t (4:11) and t (9:22). Patients are enrolled in a therapeutic clinical trial if eligible. The therapeutic regimen usually consists of multiple courses of high-dose prednisolone, combination chemotherapy and central nervous system prophylaxis (intrathecal methotrexate and cranial irradiation).
Consider allograft transplantation after first remission if the patient is less than 60 years old.
CHRONIC LYMPHOCYTIC LEUKAEMIA
Due to the chronicity and the relative stability of the patient in the early stages, it is more likely for a candidate to encounter a patient with chronic lympohocytic leukaemia (CLL) in the examination setting. Patients usually present with lymphadenopathy, anaemia, infections and hepatosplenomegaly. Sometimes the diagnosis is made on incidental observation of an elevated WBC count. Disease stage and severity is classified according to the Rai or the Binet classification. The Binet classification is easy to remember, and goes as follows:
Staging has therapeutic as well as prognostic implications. Stages A and B disease warrant only watchful waiting in the older patient.
Therapy is indicated in advanced disease. Other indications for therapeutic intervention include bulky disease, B symptoms, autoimmune phenomena (autoimmune haemolytic anaemia), rapid doubling time (< 6 months), young age (< 40 years) and poor risk features (see box).
It is ideal to enrol the patient in a therapeutic clinical trial if suitable.
Those less than 70 years of age with good prognostic signs are treated with chemotherapy (fludarabine/cyclophosphamide) and rituximab. Relapses may be treated with alemtuzumab-based therapy. However, if the patient is less than 50 years of age, non-ablative sibling allografting should be considered.
Those aged over 70 or with poor prognostic signs may be treated with fludarabine or chlorambucil together with rituximab.
HODGKIN’S DISEASE
Case vignette
A 35-year-old male presents to the emergency department with fevers, rigors and a productive cough. Examination reveals bronchial breath sounds in the right lower zone on his chest. Sputum mug contains rusty purulent sputum. Chest X-ray shows evidence of consolidation in the right lower zone. In addition, the chest X-ray displays a mass lesion in the mediastinum.
Approach to the patient
History
Ask about the initial diagnosis. Note the patient’s age. Hodgkin’s disease has a bimodal age-related prevalence with an initial peak in the third to fourth decade and a second peak in the sixth decade. The most common presentation is with singular or localised lymphadenopathy without any other symptoms. Some get diagnosed upon the incidental finding of a mediastinal mass on chest X-ray. However, upon enquiry, the patient may describe retrosternal chest discomfort, dyspnoea or cough. Ask about fevers, night sweats and recent weight loss. Some patients may complain of intractable pruritis and rash. Alcohol-induced pain is another late feature of this condition. Ask about any previous history of malignancies and family history of Hodgkin’s disease.
Examination
Identify the distribution of lymphadenopathy and establish its classic rubbery consistency. Examination of the neck region should be very thorough. Listen to the chest for evidence of tracheal or bronchial obstruction due to mediastinal mass. Examine the abdomen for splenomegaly and, less commonly, hepatomegaly. Study the temperature chart to establish the pattern of the fever, which classically is intermittent and often nocturnal (Pel-Ebstein fever). Look for a mediastinal mass in the chest X-ray.
Investigations
Other investigations of prognostic significance:
Staging classification of Hodgkin’s disease
The Ann Arbor staging classification of Hodgkin’s disease is as follows:
Stage 1—disease involving a single lymph node region
Stage 2—disease involving two or more lymph node regions located on the same side of the diaphragm
Stage 3—disease involving lymph node regions on both sides of the diaphragm
Stage 4—disseminated disease.
B symptoms—night sweats, fevers and weight loss of > 10% of the body weight within 6 months.
Management
The disease is classified into early-stage disease (stage I, IB, IIA, non-bulky disease) and advanced-stage disease (bulky disease, stage IIB, III or IV) from a therapeutic perspective. Response to treatment is monitored with CT imaging and PET scanning.
Early-stage Hodgkin’s lymphoma
1. If the patient has more favourable prognostic markers (see box), consider combination chemotherapy (doxorubicin, bleomycin, vinblastine, dacarbazine: ABVD) for 4 months followed by radiotherapy to the sites that were involved at diagnosis.
2. In the absence of good prognostic markers, combination chemotherapy is given for a longer period (6 months).
3. Patients with impaired cardiopulmonary function or of poor performance status or advanced age may not tolerate the ABVD combination. If the patient has demonstrated reduction of the DLCO50 due to bleomycin toxicity, continuation of the combination of AVD (with bleomycin omission) can be considered. Mechlorethamine, vincristine, prednisone and procarbazine (MOPP) is also an alternative combination in this setting.
Advanced-stage Hodgkin’s lymphoma
1. Patients with better prognostic signs with an international prognostic score (IPS) less than four (see box) are treated with combination chemotherapy (ABVD) for 6 months followed by radiotherapy to the sites of bulky disease at the diagnosis and those sites that failed to achieve complete remission after chemotherapy.
2. If the prognostic signs are poor (IPS > 4), consider intensified combination chemotherapy (bleomycin, etoposide, doxorubicin, cyclophophamide, vincristine, prednisolone, procarbazine: BEACOP) provided the patient is younger than 60 years and of good performance status. Otherwise consider longer-term ABVD for 8 months. Combination chemotherapy may be followed by radiotherapy as described above.
3. Some centres enrol patients in novel therapeutic trials and this should be considered if suitable.
4. Long-term adverse effects of combination therapy include acute myeloid leukaemia, non-Hodgkin’s lymphoma (after 10 years), and solid tumours (after 15 years). Resistant disease can be treated with autologous bone marrow transplantation.
International Prognostic Score (IPS)
Each adverse factor scores 1 point:
(From Hasenclever D, Diehl V 1998 A prognostic score for advanced Hodgkin’s disease. International Prognostic Factors Project on Advanced Hodgkin’s Disease. New England Journal of Medicine 339(21):1506–1514)
(From Hasenclever D, Diehl V 1998 A prognostic score for advanced Hodgkin’s disease. International Prognostic Factors Project on Advanced Hodgkin’s Disease. New England Journal of Medicine 339(21):1506–1514)
NON-HODGKIN’S LYMPHOMA
Approach to the patient
History
Ask about:
• the circumstances of diagnosis
• symptoms at presentation
• any evidence of precipitating conditions such as previous malignancies, Sjögren’s syndrome, radiation exposure, immunosuppression, immunodeficiency and infections with HIV or hepatitis C
• any family history of lymphoma or other malignancy.
Patients with gastrointestinal lymphoma may have a history of coeliac disease. Ask about B symptoms of fevers, night sweats and weight loss.
Examination
Perform a thorough lymph node assessment for lymphadenopathy. Check for abdominal organomegaly. Don’t forget to look at the temperature chart.
Investigations
CT scan, PET scan and bone marrow biopsy are used in the staging process.
1. Excisional biopsy of a lymph node
2. Full blood count—looking for anaemia, pancytopenia or lymphocytosis
3. Serum electrolyte profile and renal function indices
4. Liver function tests—looking for abnormalities due to hepatic involvement
5. Serum uric acid level—looking for an elevation
6. Serum calcium level—looking for hypercalcaemia
7. Serum lactate dehydrogenase level—looking for an elevation
8. Serum protein electrophoresis and immunoelectrophoresis
9. Serum beta 2 microglobulin level—looking for an elevation
10. Chest X-ray
11. CT of chest, abdomen and pelvis
12. Bone marrow biopsy
13. PET scan
14. Serology for HIV and tests for hepatitis C infection
Management
The histological subtype of the disease is important in deciding on the management option. Disease is often categorised into aggressive disease or indolent disease, based on the histology.
The stage of the disease and the prognostic score, calculated according to the systems described in the boxes (for aggressive disease and indolent disease respectively), are important factors that influence the therapeutic plan. The scoring system also includes the patient’s age and the functional status, which have a major bearing on the management strategies.
Aggressive lymphomas include diffuse large B-cell lymphoma, mantle cell lymphoma, T-cell lymphoma, Burkitt’s lymphoma and lymphoblastic lymphoma. Indolent lymphomas include follicular lymphoma.
Prognostic grading of intermediate grade/aggressive non-Hodgkin’s lymphoma
Prognosis in non-Hodgkin’s lymphoma is described according to the International Prognostic Index (IPI). The disease is graded according to a scoring system, as follows:
(After Shipp M A, Harrington D P, Anderson J R et al 1993 A predictive model for aggressive non-Hodgkin’s lymphoma. The International Non-Hodgkin’s Lymphoma Prognostic Factors Project. New England Journal of Medicine 329(14):987–994)
(After Shipp M A, Harrington D P, Anderson J R et al 1993 A predictive model for aggressive non-Hodgkin’s lymphoma. The International Non-Hodgkin’s Lymphoma Prognostic Factors Project. New England Journal of Medicine 329(14):987–994)
(After Solal-Céligny P, Roy P, Colombat P et al 2004 Follicular Lymphoma International Prognostic Index. Blood 104:1258–1265)
(After Solal-Céligny P, Roy P, Colombat P et al 2004 Follicular Lymphoma International Prognostic Index. Blood 104:1258–1265)
Intermediate grade/aggressive lymphoma (excluding Burkitt’s lymphoma and lymphoblastic lymphoma)
Diffuse large B-cell lymphoma
This disease has a higher therapeutic response. Aggressive therapy is indicated if the patient’s cardiopulmonary performance status is adequate. Standard therapy is combination chemotherapy with cyclophosphamide, doxorubicin hydrochloride, vincristine and prednisolone (R-CHOP) and radiotherapy. Treatment intensification is considered for younger patients with poor prognostic indicators.
Consider intrathecal methotrexate if there is a high risk of central nervous system relapse. Features that suggest this possibility include high or high/intermediate IPI score, testicular or sinus involvement or stage IV disease.
Relapse of the disease is treated with second-line chemotherapy (fludarabine) followed by autologous stem cell transplants for those responsive to chemotherapy. If this strategy fails, further therapy with hypomethylating agents (epigenetic strategies), new monoclonal antibodies and non-ablative allograft transplantation should be considered.
Mantle cell lymphoma
Though this was considered a ‘low-grade’ lymphoma according to the working formulation, it is treated where feasible as an ‘aggressive lymphoma’ due to its poor prognosis.
T-cell lymphoma
There is no standard therapy for aggressive T-cell lymphomas. Generally CHOP with (or without) upfront autografting is considered.
Burkitt’s lymphoma and lymphoblastic lymphoma
These are managed according to the protocols used for the management of ALL (see p 121).
Indolent lymphoma
Indolent lymphomas such as follicular lymphoma are managed with watchful waiting, and active therapy when required (chemotherapy or radiation to localised disease)—similar to the indications for treatment in CLL (see p 121). Generally these diseases are considered incurable, though novel strategies (e.g. rituximab in combination) are starting to show survival benefits.
MYELODYSPLASIC SYNDROME
Myelodysplasic syndrome should be considered a possible diagnosis in the elderly patient who has a combination of macrocytic anaemia, neutropenia and thrombocytopenia. The condition could be idiopathic, or secondary to previous exposure to cytotoxic chemotherapy or radiotherapy. Diagnosis is made by bone marrow biopsy.
Management
Supportive therapy:
POLYCYTHAEMIA VERA
Case vignette
A 45-year-old female presents with progressive abdominal enlargement and bilateral pain in the upper abdominal quadrant. She denies smoking, alcohol excess or recent overseas travel, and her medication history is negative for potentially hepatotoxic agents. She denies ingestion of any herbal medications. On examination she is jaundiced. She has ascites, caput medusae and hepatosplenomegaly. She is particularly tender in the left upper quadrant with guarding. Liver function tests are grossly abnormal and ultrasonography reveals paucity of venous architecture. Full blood count shows erythrocytosis with low plasma erythropoietin levels. Hepatitis and HIV screen comes negative.
Approach to the patient
Polycythaemia vera is a myeloid stem cell disorder characterised by trilineage (erythrocytes, granulocytes and platelets) hyperplasia, high blood counts and splenomegaly. Polycythaemia rubra vera is characterised by predominant erythrocyte hyperplasia. Prior to the diagnosis of polycythaemia vera in any patient with erythrocytosis it is essential to exclude spurious polycythaemia and secondary polycythaemia.
History
Polycythaemia vera is common among middle-aged and older patients. Often it is an incidental diagnosis in a patient with a high haemoglobin level in the full blood count done for some other reason. Ask about constitutional symptoms of lethargy, malaise and weight loss. Check for neurological symptoms, such as headache, vertigo, tinnitus and visual disturbances. Thrombotic stroke is a possible complication. Some complain of pruritus, of which the precise aetiology is not clear. Ask about diaphoresis, which is due to hyperviscosity associated with erythrocytosis. Patients who present with erythema, warmness and pain in the distal extremities may be suffering from the condition called erythromelalgia, an association of polycythaemia vera. Enquire about bleeding in the form of epistaxis or gastrointestinal haemorrhage, which is a common presentation of this disease. Ask about acute joint pain due to gout.
Examination
Physical examination may reveal plethoric facies, easy bruising, hypertension, neurological deficit and splenomegaly. Perform a thorough neurological assessment. Some may manifest evidence of portal hypertension, because these patients are susceptible to Budd-Chiari syndrome and portal vein thrombosis. Left upper quadrant tenderness mimicking acute abdomen may be due to splenic infarction. Check for abdominal organomegaly. Although rare, do not forget to look for digital infarcts due to erythromelalgia. Some patients may have excoriations due to severe pruritis and gouty tophi (with or without acute joint tenderness). Look in the fundus for venous engorgement.
Investigations
1. Full blood count—looking for raised haematocrit, leucocytosis and thrombocytosis. Ask for red cell mass to exclude relative or spurious polycythaemia due to decreased plasma volume (decreased plasma volume can cause erythrocytosis, and this is called stress erythrocytosis or Gaisböck’s syndrome). Sometimes the red cell mass may still be elevated in secondary polycythaemia due to excess erythropoietin secretion.
2. Serum erythropoietin level (which is elevated in secondary polycythaemia but in polycythaemia vera is usually < 4 munits/mL)
3. Oxygen saturation—to exclude hypoxia as a possible cause
4. Overnight pulse oximetry—to exclude sleep apnoea causing hypoxia
5. Depleted iron reserves, elevated uric acid and elevated serum vitamin B12 levels—would further support the diagnosis of polycythaemia vera
6. Abdominal ultrasound—to exclude erythropoietin-secreting mass lesions
7. Bone marrow biopsy—looking for myeloid cell hyperplasia and typical megakaryocyte morphology
8. Cytogenetic studies
9. Molecular testing for the JAK 2 gene mutation—this has a 95% sensitivity for the diagnosis of polycythaemia vera.
Management
Broad management objectives include: 1) prevent complications of raised haematocrit, such as thrombosis and hyperviscosity; 2) control organomegaly; and 3) manage the symptoms.
1. Raised haematocrit is controlled by venesection.
2. Low-dose aspirin is indicated for the prevention of thrombosis.
3. Chemotherapy with busulfan or P32 is indicated in resistant cases. However, this could increase the risk of secondary leukaemia.
4. Erythromelalgia is managed successfully with salicylate therapy.
5. Hyperuricaemia is managed with allopurinol.
6. Massive splenomegaly may warrant splenectomy.
