Clinical haematology

201. A 48-year-old man with long-standing human immunodeficiency virus (HIV) attends the clinic with a three-week history of rapidly enlarging lymphadenopathy in the left cervical region measuring 8 10 cm. There has been a recent increase in viral load and current CD4 count is 120 106 per litre; haemoglobin is 10.4 g/dl, white blood cell count 3.4 x 109 per litre, and platelets 115 109 per litre; thyroid-stimulating hormone (TSH) is normal and lactate dehydrogenase (LDH) is 1140. What is the most likely diagnosis? Atypical tuberculosis Kaposis sarcoma Thyroid carcinoma Cytomegalovirus infection High-grade non-Hodgkins lymphoma

Your answer

High-grade non-Hodgkins lymphoma (NHL) in a patient with human immunodeficiency virus (HIV) infection is one of the illnesses that defines acquired immunodeficiency syndrome (AIDS) and is usually seen in patients with a CD4 count of less than 200 106 per litre. As well as causing rapidly enlarging peripheral lymph nodes, high-grade NHLs in HIV-positive patients frequently arise in the central nervous system (CNS) as the primary site. Response to treatment is often poor. A raised lactate dehydrogenase (LDH) is not infrequently seen in lymphoma and can be used as a surrogate marker of disease activity. Atypical tuberculosis (TB) may present with lymphadenopathy in this pattern, but the LDH would be expected to be normal. Kaposis sarcoma usually manifests as single or multiple violaceous papular skin lesions. Cytomegalovirus (CMV) infection in advanced HIV disease usually manifests as retinitis (usually with CD4 counts less than 50 106 per litre).

202. 40-year-old man presents with acute weakness and palpitations. He has a history of diarrhoea and weight loss over the past few months. Investigations reveal (normal range in brackets):

Sodium 143 mmol/l (137144) Potassium 6.0 mmol/l (3.54.9) Urea 35 mmol/l (2.57.5) Creatinine 450 mmol/l (60110) Bicarbonate 5 mmol/l (2029) Mean cell volume (MCV) 122 fL (8096) White cell count 2.2 x 109 /l (411) Platelet count 85 109 /l (150400)

What is the most likely explanation for the blood results seen here?

Alcoholic liver disease Aplastic anaemia Folic acid deficiency Hypothyroidism Vitamin C deficiency

Your answer

Folic acid deficiency may be related to nutrition, antifolate drugs such as phenytoin, primidone, methotrexate, pyrimethamine, and trimethoprim, or excess utilisation. In this case it is most likely that this man has an underlying small bowel pathology that has resulted in anorexia and weight loss. He has now become dehydrated and acutely unwell, with renal failure and a blood picture consistent with megaloblastic anaemia caused by folate deficiency. He requires investigation for small bowel pathology such as celiac disease, with the appropriate treatment and correction of folic acid deficiency. Replacement is usually with a dose of 5 mg daily of folate, and it takes around four months to replenish body stores.

203. A patient presents with pancytopenia (anaemia, leucopenia, thrombocytopenia). No material could be obtained from a bone marrow aspiration. Which is the next investigation employed to obtain a diagnosis? Level of LDH in serum Chromosome analysis Bone marrow biopsy and histological examination Your answer Level of alkaline phosphatase in serum Level of vitamin B12 in serum Bone marrow can be examined by needle aspiration, closed needle biopsy, or open surgical biopsy. In adults the sites most easily available are the sternum and the anterior or posterior iliac crests, although the marrow at the iliac crests tends to become rather fatty in elderly subjects. After aspiration of the marrow, films are made and stained with a Romanowsky stain. Needle or surgical biopsy samples are fixed and sectioned by standard methods. A biopsy specimen is particularly useful for looking at overall cellularity and relating the amount of

haemopoiesis to the amount of fatty tissue. It is of particular value if an aspiration yields a dry tap, when it may show replacement by fibrous or tumour tissue, which may not aspirate readily. By using appropriate stains it is possible to estimate the amount of iron and reticulin in the marrow.

204. A 75-year-old man presents with fatigue and weight loss. He has also been noted to be increasingly vague. On examination he is clinically anaemic and his Mini-Mental score is 5/10. He has 2 cm of splenomegaly and 2 cm of hepatomegaly. There are no other positive findings. Investigation shows the following: Hb is 8.3 g/dl (1318), MCV 102 fl (8096), WCC 6.5 109/l (411 109) with a normal differential, platelets 150 109/l (150400 109); urea 10 mmol/l (2.57.5), Na 139 mmol/l (137144), K 4.6 mmol/l (3.54.9), creatinine 135 mmol/l (60110), total protein 88 g/l (6176), alb 24 g/l (3749) and viscosity 8.2 centipoise (1.51.72); IgG 7.0 g/l (7.014.5), IgA 0.55 g/l (0.804.0), IgM 22.7 g/l (0.452.00). What is the most appropriate treatment to improve his clinical state? Urgent plasmapheresis Your answer Transfusion of packed cells Immediate chemotherapy Intravenous fluids Prednisolone This patient has Waldenstroms macroglobulinaemia, a clinical condition due to the presence of a lymphoplasmacytoid lymphoma that produces a monoclonal IgM paraprotein. Patients present with fatigue and weight loss. The paraprotein leads to hyperviscosity. This can cause visual symptoms and retinal changes, including engorgement of veins and haemorrhage. It can also lead to impairment of consciousness and neurological symptoms. Hepatosplenomegaly is a frequent finding. No treatment is required for asymptomatic patients. Symptoms of hyperviscosity are treated with repeated plasmapheresis. His neurological symptoms here may be related to multiinfarct disease secondary to hyperviscosity. Chlorambucil, cyclophosphamide and fludarabine may be useful therapy, and advanced disease may respond to combinations like CHOP (cyclophosphamide, hydroxydaunomycin, Oncovin, prednisone). 205. A 39-year-old, previously well, woman is referred to you with a 3-month history of asthma and wheezing with occasional episodes of haemoptysis. She also tells you that she might be perimenopausal as she has had severe episodes of flushing. You suspect there might be an underlying pathological process. Which of the following investigations is most likely to reveal a cause? Urine catecholamines Urine vanillymandelic acid Urine 5-hydroxyindolacetic acid

Your answer

Urine cortisol Urine calcium Levels of 5-hydroxyindoleacetic acid (5-HIAA), a breakdown product of serotonin metabolism, are raised in carcinoid syndrome. Carcinoid syndrome occurs in about 2% of cases of pulmonary carcinoid tumours, much less frequently than in cases associated with gastrointestinal carcinoid tumours. Bronchopulmonary carcinoid tumours are reported to represent about 10% of all carcinoid tumours and 15% of all lung tumours are carcinoid tumours. Some 25% of patients with a carcinoid pulmonary tumour are asymptomatic. However, the majority of symptomatic patients have symptoms directly involving the bronchopulmonary tree, such as persistent atelectasis, recurrent pneumonia, pulmonary abscess and bronchiectasis. Carcinoid tumours are capable of producing a variety of biologically active peptides and hormones, including serotonin, adrenocorticotrophic hormone (ACTH), antidiuretic hormone (ADH), melanocyte-stimulating hormone (MSH) and others. Excess serotonin production has been implicated in the development of carcinoid syndrome. This syndrome is characterised by tachycardia, flushing, bronchoconstriction, haemodynamic instability and diarrhoea, and occurs in up to 10% of patients with bronchial carcinoid tumours. Although this syndrome usually occurs in the presence of metastatic disease to the liver, in bronchial carcinoid tumours the syndrome can occur in the absence of metastatic disease. The syndrome of inappropriate secretion of ADH (SIADH) can be produced by pulmonary carcinoid tumours, although it is more commonly associated with small-cell lung carcinoma. Urine catecholamines and urine vanillylmandelic acid levels are increased in phaeochromocytomas, and increased urine levels of cortisol may indicate an ACTHsecreting tumour. Urine calcium levels will be increased if there is hypercalcaemia, for example as a complication of squamous-cell carcinoma of the lung.

206. A 60-year-old is taking warfarin long-term for recurrent pulmonary emboli. The patient presents to A&E complaining of vomiting a large amount of bright red blood. On examination he is pale, hypotensive and has epigastric tenderness. Initial blood tests show: Hb 6.5 g/dl, with a normochromic normocytic anaemia; WCC 12.3 109/l; platelets 375 109/l and INR 9.2. How should his coagulation be corrected immediately? Transfusion of fresh blood Transfusion of packed red cells

Transfusion of 20 units cryoprecipitate and 20 mg iv vitamin K Transfusion of 2000 U factor VIII concentrate Transfusion of 4 units fresh-frozen plasma and 5 mg iv vitamin K Your answer This patient has had a life-threatening bleed and must have his prolonged INR reversed immediately. Prothrombin complex concentrate (factors II, VII, XI and X) 50 units/kg should be given if available, but fresh-frozen plasma at 15 ml/kg is immediately available and will supply the necessary coagulation factors. Vitamin K should be given at a dose of 25 mg depending on the size of the patient. Too big a dose can make it very difficult to re-warfarinise the patient.

207. A 57-year-old man presents with weight loss and a neck swelling. He is subsequently confirmed to have a thyroid malignancy. Which of the following descriptions is most appropriate to this condition? 8090% are medullary carcinomas Subtotal lobectomy is the minimum treatment of choice Iodine-[131] therapy is an alternative to total thyroidectomy Serum thyroglobulin measurement is the main method of early detection of Your recurrent papillary and follicular thyroid cancers answer Papillary cell carcinoma of the thyroid produces high calcitonin levels Papillary and follicular carcinomas account for 8090% of thyroid cancers. Total lobectomy is the minimum treatment for thyroid cancer. Iodine-[131] destroys the residual normal thyroid tissue. To maximise therapy, a total or near-total thyroidectomy should be performed in all patients who are to be treated with iodine. Thyroglobulin, a glycoprotein, is produced by normal and neoplastic follicular cells. Serum thyroglobulin measurements are the main modality for the early detection of recurrent differentiated (papillary/follicular) thyroid cancer. Calcitonin is produced by C cells in medullary carcinoma.

208. A 52-year-old woman is referred to the oncology clinic by the local general surgeon. She has undergone mastectomy for carcinoma of the right breast. Which of the following factors is associated with a poor prognosis in patients with breast cancer? Young age Your answer Oestrogen receptor-positive tumour Progesterone receptor-positive tumour Low-grade tumour Negative lymph node status Poor prognostic factors for breast cancer include young age (< 40 years), premenopausal at diagnosis, increased tumour size, high tumour grade, oestrogen and progesterone receptornegative tumour and positive lymph nodes. Breast cancer is the commonest cancer in non-smoking women. The UK breast screening programme and improvements in therapy to involve surgery, chemotherapy and radiotherapy where necessary have improved survival rates, and more conservative approaches to surgery have vastly improved the psychosexual wellbeing in women who suffer from the disease. Radiotherapy is given to the conserved breast after wide local excision to reduce the risk of local recurrence, and after mastectomy if there are risk factors such as proximity to surgical margins or lymph node metastases. Adjuvant radiotherapy reduces the risk of local recurrence by 25% and improves survival by 3%. Premenopausal patients may be considered for endocrine therapy via oophorectomy, radiation-induced ovarian ablation or the use of a gonadotrophin-releasing hormone (GnRH) analogue, with additional tamoxifen, antioestrogens or progesterone. Postmenopausal patients may be given tamoxifen, progesterone or aromatase inhibitors. Chemotherapy is considered for those patients who are unlikely to respond to or fail to respond to hormonal therapy.

209. A 60-year-old woman had her hip replaced for osteoarthritis 2 months ago. She is referred because of a persistently elevated and rising white cell count since the procedure. She has rehabilitated well from the operation but is still feeling tired. There are no other symptoms. On examination the only positive finding is 2 cm of splenomegaly. Her blood picture is as follows: Hb 10.5 g/dl (11.516.5), WCC 32 109/l (411 109), blasts 3%, promyelocytes 5%, myelocytes 34%, metamyelocytes 15%, neutrophils 40%, eosinophils 2%, basophils 1% and platelets 532 109/l (150400 109). What is the most likely cause of her raised white cell count? Chronic lymphocytic leukaemia Chronic myeloid leukaemia Myelofibrosis Acute myeloid leukaemia Chronic staphylococcal infection of the hip joint

Your answer

Chronic myeloid leukaemia is an acquired clonal proliferative disorder. There is a reciprocal translocation between the long arms of chromosomes 9 and 22 resulting in an abnormal chromosome 22 (the Philadelphia chromosome) and the formation of a new fusion gene BCR/ABL. The BCR/ABL gene product is an abnormal protein with tyrosine kinase activity. Up to half the patients are asymptomatic at presentation and the diagnosis is an incidental finding. Symptoms are related to anaemia and the raised white cell count. Usually there is splenomegaly, which may be symptomatic. The white cell count is raised up to 500 109/l, with a complete spectrum of cells in the peripheral blood, anaemia and often a raised platelet count. The tyrosine kinase inhibitor imatinib (Glivec) is now the first-line agent for the treatment of the disease in most patients. The majority of patients obtain a major or complete cytogenetic remission, which may be durable. Allogeneic bone marrow transplant offers the chance of cure in suitable candidates. Without these measures the natural course of the disease involves transformation to acute leukaemia in a median of 34 years.

210. A 75-year-old heavy smoker of 40 cigarettes per day is admitted to the Emergency department. He has a past history of hypertension and atrial fibrillation. Over the past few months he has suffered a chronic cough and has lost approximately 2 stone (about 12.5 kg) in weight. He has been increasingly drowsy over the past few days and his relatives were unable to rouse him this morning. On examination he has a GCS of 6 and you notice that he has been incontinent of urine and faeces. What diagnosis fits with this clinical picture? Subarachnoid haemorrhage Embolic stroke Cerebral meningioma Glioblastoma multiforme Metastatic carcinoma with cerebral metastases Your answer This man is a heavy smoker with a history of chronic cough and weight loss over the past few months, raising the possibility of bronchial carcinoma. The picture of progressively deteriorating conscious level points towards increasing cerebral oedema, almost certainly due to cerebral metastases from the bronchial tumour. Although stroke is a possible alternative diagnosis given the history of atrial fibrillation, presentation would have been more acute. This type of presentation is an indication for urgent CT scanning; treatment may include dexamethasone with or without mannitol iv to reduce cerebral oedema. Often deterioration of this nature is due to haemorrhage into an enlarging cerebral metastasis. Even if there is an initial response to medical treatment and conscious level improves, prognosis with this type of presentation is extremely poor. Around 50% of intracranial tumours are due to metastases, around 35% due to malignant primary brain tumours (astrocytoma or oligodendroglioma), around 10% are caused by benign brain tumours such as meningioma or neurofibroma.

211. A 60-year-old woman presents complaining of feeling unwell for the last 2 months. She has widespread lymphadenopathy. Her full blood count is as follows: Hb 9.5 g/dl (11.516.5), WCC 45 109/l (411 109), platelets 80 109/l (150400 109); abnormal lymphocytes are present on the blood film. Bone marrow aspirate shows lymphocyte infiltration, which on immunophenotyping are CD19+, CD5+, CD10, CD22+ and CD23. Cytogenetics show a t(11;14) (q13;q32) translocation. What is the most likely diagnosis? Chronic lymphocytic leukaemia Hodgkins disease Acute lymphoblastic leukaemia Mantle-cell lymphoma Your answer Follicular lymphoma Mantle-cell lymphoma is a malignancy derived from nave pregerminal cells localised in the primary follicle or the mantle region of the secondary follicle. It was previously known as centrocytic, intermediate or mantle-zone lymphoma, and is part of the spectrum of diffuse small B-cell lymphomas. Cells express CD5 and are negative for CD10. A specific translocation at t(11;14) (q13;q32) is seen in the majority of cases. This leads to deregulation of the cyclin D1 (BCL-1) gene. Overexpression of cyclin D1 RNA or protein is found in over 90% of cases. Patients present with widespread lymphadenopathy, bone marrow infiltration and often a blood spill of tumour cells into the peripheral blood. Patients are treated with chemotherapy, but the prognosis is poor with a median survival of about 3 years.

212. Which of the following would be more suggestive of essential thrombocythaemia compared with a reactive thrombocytosis in a patient with a platelet count of 650 x 109 per litre? Plasma viscosity of 1.95 mPa s Low neutrophil alkaline phosphatase (NAP) score Hypochromic anaemia Cutaneous bruising Reduced bone marrow reticulin

Your answer

In essential thrombocythaemia (ET) the platelet count is raised, usually in the range 600 2000 109 per litre. Despite the thrombocytosis, patients with myeloproliferative disorders can have reduced platelet aggregation, which leads to a bleeding tendency in a proportion of patients. With platelet counts in the region of 500800 109 per litre, differentiation of

ET from reactive causes of thrombocytosis may be difficult, but a raised C-reactive protein (CRP) or plasma viscosity may point to the latter. A low neutrophil alkaline phosphatase (NAP) score is seen in patients with cytomegalovirus (CMV). Although the abnormal bleeding tendency seen in some patients with ET could lead to bleeding, in clinical practice the association of hypochromic anaemia with a moderately raised platelet count is most commonly seen in iron-deficient anaemia caused by gastrointestinal (GI) tract blood loss with an associated reactive thrombocytosis. Often, ET is associated with increased marrow reticulin deposition, which may cause difficulty in marrow aspiration. 213A 52-year-old man is referred to the haematology clinic after a routine FBC showed a WCC of 6 103/mm3, Hb 18.4 g/dl and platelets 142 103/mm3. He smokes and has hypertension that is controlled by atenolol. He was admitted two years ago with a pulmonary embolism after a trans-Atlantic flight, at which time his blood gases showed p(O2) of 6.6 kPa, p(CO2) 3.2 mmHg, pH 7.53, O2 saturation 98%. His FBC results at the time were WCC 9.9 103/mm3, Hb 17.9 g/dl, platelets 198 103/mm3. Clinical examination reveals a normal cardiovascular and respiratory system, with a respiratory rate 12 and BP 121/74. What is the most likely cause of his polycythaemia? Polycythaemia rubra vera (PRV) Chronic pulmonary vascular disease Stress polycythaemia Increased-affinity haemoglobin Chronic obstructive airways disease

Your answer

His blood gases show that when hypoxic, he has oxygen saturations of 98%. This implies that the affinity of his haemoglobin for oxygen is high, ie even at a low p(O2) his haemoglobin is reluctant to give up oxygen to the tissues, thus rendering them hypoxic and driving an increase in red cell production. The O2Hb dissociation curve has been shifted to the left. The high pH and low p(CO2) would also make Hb have more affinity for O2, but not so much as to yield almost full O2 saturation at low p(O2). There are a number of inherited causes of high-affinity haemoglobin. There are no physical signs to suggest chronic pulmonary vascular or airways disease, and PRV and stress polycythaemia will not explain the blood gases.

214.. A 60-year-old man presents with a haemoglobin level of 18 g/dl, raised serum vitamin B12 level, pruritus, neutrophilia, thrombocytosis, and splenomegaly. What is the most likely diagnosis? Polycythaemia rubra vera Secondary polycythaemia Haemochromatosis Your answer

Von Willebrands disease Thrombotic thrombocytopenic purpura Symptomatic patients with polycythaemia rubra vera may present to their physician with a large array of non-specific complaints, including headache, weakness, pruritus, dizziness, excessive sweating, visual disturbances, paraesthesias, joint symptoms, and epigastric distress. Some one-third of patients will have lost 10% of their body weight by the time they present, presumably through the associated hypermetabolism. Joint disease is usually the manifestation of gout, because of the increased production of uric acid. The most important signs on physical examination include ruddy cyanosis, conjunctival plethora, hepatomegaly, splenomegaly, and hypertension.

215. A 10-year-old boy has been complaining of pain in his right leg for 3 weeks. His mother describes him as being off colour. There is nothing to find on examination. Investigation reveals a Hb of 11.5 g/dl (1318), WCC 2.2 109/l (411 109) with neutrophils 0.5 109/l (1.57.0 109), lymphocytes 1.4 109/l (1.54.0 109) and platelets 160 109/l (150400 109), ESR is 50 mm in the first hour (015); urea and electrolytes are normal. Further investigation shows diffuse uptake in both femurs on MRI scan, suggestive of tumour infiltration. What is the most likely diagnosis? Ewings sarcoma Juvenile arthritis HIV infection Acute lymphoblastic leukaemia Your answer Acute myeloid leukaemia Acute lymphoblastic leukaemia is the most likely diagnosis. This child has an abnormal blood count and bone pain, with infiltration shown on the scan. The diagnosis must be proved by bone marrow biopsy. Acute lymphoblastic leukaemia is the commonest form of leukaemia in children, the peak age of incidence being between 3 and 7 years. Children present to a variety of practitioners with symptoms and signs of bone marrow failure, anaemia leading to pallor, dyspnoea and fatigue, neutropenia leading to infections and thrombocytopenia leading to bruising, petechiae and bleeding. They can also have organ infiltration leading to tender bones, lymphadenopathy, hepatosplenomegaly and meningeal involvement with headache, nausea and vomiting and neurological signs.

216. A 40-year-old woman presents with a breast lump, which following biopsy is shown to be malignant. She tells you that she has a family history of a genetic disorder. Which of the following genetic conditions would be most likely to be a relevant risk factor for the development of breast cancer?

von HippelLindau disease ChdiakHigashi syndrome Ataxiatelangiectasia Huntingtons disease Cystic fibrosis

Your answer

A number of syndromes cause solid-cancer proneness. Ataxiatelangiectasia is associated with breast cancer. In ataxiatelangiectasia, the mutated protein (ATM) is a kinase, which acts as a transducer of DNA-damage signalling. In mammals, this complex also contains nibrin, the protein mutated in the Nijmegen syndrome. Nibrin confers new abilities to the nuclease complex, and can also bind to BRCA-1 (one of the two proteins mutated in familial breast cancer). BRCA-1 has a central motif that binds with high affinity to cruciform DNA, a structure present at sites where the DNA loops are anchored to the chromosomal axis or scaffold. One of the BRCA-1 domains can be mono-ubiquitinate, the FANCD-2 protein, mutated in one of the Fanconis anaemia complementation groups, to regulate it. In short, the proteins missing in these syndromes have in common their BRCA1-mediated assembly into multimeric machines responsible for the surveillance of DNA replication, recombinational repair and the removal of DNA cross-links.

217. A 60-year-old pipe lagger is referred to you with a 6-month history of increasing shortness of breath and weight loss. He is a lifelong non-smoker and has always led a fit, healthy life. Clinical examination indicates a left pleural effusion, which is confirmed on the chest X-ray. Which malignant cause is most likely? Mesothelioma Your answer Small-cell lung cancer Squamous-cell lung cancer Bronchial carcinoid Alveolar-cell carcinoma The occupational history and clinical presentation in a non-smoker makes mesothelioma the most likely malignancy. Mesothelioma is linked to asbestos exposure and there is often a considerable lag time (2040 years) between exposure and malignancy. Exposure to crocidolite (blue asbestos) carries the highest risk of mesothelioma. Although the prognosis in mesothelioma remains poor, a few can be surgically resected and for the remainder chemotherapy can result in useful palliation. Non-small-cell cancer (which encompasses squamous-cell, large-cell, adenocarcinoma and alveolar-cell carcinoma) and small-cell carcinoma can all present with a pleural effusion and would need to be excluded. Bronchial carcinoid tumours tend to present with symptoms of bronchial obstruction: coughing, wheezing, haemoptysis and recurrent pulmonary infections.

218. A 36-year-old woman has been investigated for hypercalcaemia and is found to have hyperparathyroidism. There is a family history that makes an underlying diagnosis of multiple endocrine neoplasia type 1 (MEN 1) suspected. Which of the following best fits with the clinical features of this condition? It is inherited in an autosomal recessive manner It includes medullary-cell carcinoma of the thyroid It includes phaeochromocytoma Primary hyperparathyroidism is common Patients have a normal life expectancy

Your answer

Multiple endocrine neoplasia (MEN) is an autosomal dominant disorder characterised by a high frequency of peptic ulcer disease (ZollingerEllison syndrome) and primary endocrine abnormalities involving the pituitary, parathyroid and pancreas. Medullary-cell carcinoma of the thyroid occurs in MEN 2a and MEN 2b. Phaeochromocytomas occur in MEN 2a and MEN 2b. Primary hyperparathyroidism is the most common abnormality. Parathyroid hyperplasia occurs in MEN 1 and MEN 2a. Patients have a decreased life expectancy, with a 50% probability of death by the age of 50 years.

219. An 85-year-old women is in a nursing home and has mild Alzheimers disease. She has ischaemic heart disease with occasional angina on exertion but is otherwise well. Her GP refers her to haematology outpatients because of a persistently raised white cell count. When she is seen she has no complaints and there is nothing abnormal to find on examination. Her full blood picture is as follows: Hb 11.4 g/dl (11.516.5), WCC 27 109/l (411 109), platelets 140 109/l (150400 109), neutrophils 3.6 109/l (1.77.0 109), lymphocytes 21.9 109/l (1.54.0 109), monocytes 1.5 109/l (00.8 109) with smear cells reported as seen on the film. What is the most likely cause of her raised white cell count? Acute lymphoblastic leukaemia Chronic urinary tract infection Hodgkins disease Glandular fever Chronic lymphocytic leukaemia Your answer Chronic lymphocytic leukaemia is characterised by a monoclonal population of lymphocytes in the blood and bone marrow. It represents 25% of all leukaemias and occurs in older patients with a male predominance. Clinically, there may be painless lymphadenopathy and features of bone marrow replacement. Hepatosplenomegaly occurs with more advanced

disease. Infections are common in the later stages of CLL due to neutropenia and immune deficiency. Lymphocytosis is seen with smear cells being reported on the blood film. Patients with early-stage disease do not need treatment and may not progress for many years. Bone marrow failure should initially be treated with prednisolone. Alkylating agents can control the disease for long periods. The antipurine agent fludarabine alone or in combination with cyclophosphamide is useful for second-line therapy; the monoclonal antibody Campath, a new agent, may be effective in some cases.

220. A 16-year-old young man with sickle-cell anaemia is admitted with recent breathlessness. He is febrile and has a clear chest with saturations of 98% on air. From his out-patient notes his usual Hb is 9 g/dl. FBC taken in A&E shows WCC 8.6 103/mm3, Hb 4.7 g/dl, platelets 573 103/mm3 with a bilirubin 25 mol/l. Which investigation is the most useful to perform next? Serum haptoglobin Urinary haemosiderin Parvovirus serology Reticulocyte count Chest X-ray

Your answer

Reductions in Hb in sickle-cell disease are common, and determining the pathophysiological process is crucial for the management of such patients. Haemolysis is less likely as the bilirubin is not high given the large drop in Hb. The one investigation that will confirm an aplastic crisis is a reticulocyte count if this is very low with such a severe anaemia then the marrow is not responding appropriately and urgent supportive measures are needed with very close monitoring of haematological indices. Parvovirus serology may help in confirming the cause of an aplastic crisis but does not in itself demonstrate the lack of appropriate marrow response. Evidence for haemolysis would also be sought in this situation, but from the data given an aplastic crises seems more likely. The drop in Hb can occur suddenly from a parvovirus infection as there is markedly reduced red cell survival in sickle-cell disease, implying that the circulating red cell count is heavily dependent on current marrow function.

221. A 29-year-old Caucasian male with AML is in remission following a course of combination chemotherapy. He has some high-risk features and the decision is made that an allogeneic bone marrow transplant should be carried out. His serology is negative for cytomegalovirus (CMV). His tissue type is A1, A24, B8,

B18. Which of the following relatives, all of whom are fit and healthy, would be the best donor? His sister, A1, A24, B8, B18, CMV-positive His brother A1, A24, B8, B18, CMV-positive His sister, A1, A28, B8, B14 CMV-positive His brother, A1, A24, B8, B18, CMV-negative Your answer His sister A1, A24, B8, B18, CMV-negative

There is a 25% chance that any full sibling (brother or sister) will be a complete 6-antigen genotype match. The patient is fortunate to have a number of siblings who are a 6-antigen match. Sex of the donor and CMV status will influence the decision. Males are preferred to females as statistically transplants from female donors are more likely to give rise to graft-versus-host disease (probably because females have had children). The CMV status is the other factor to be used in making the choice. The patient is CMV-negative, therefore a CMV-negative donor is preferred so that the virus is not transmitted to the recipient.

222. A 40-year-old patient has been complaining of headache, weakness, dizziness, pruritus and weight loss. His laboratory results show erythrocytosis, leucocytosis, thrombocytosis and a very low erythropoietin level. Apart from thromboses, what is the major complication of this disease? Bleeding Your answer Hepatic failure Renal failure Respiratory failure Fractures Patients with polycythaemia vera left without appropriate treatment are at a particularly high risk of developing thrombotic or haemorrhagic events. Haemorrhagic complications are the

cause of death in 210% of patients with polycythaemia vera: 3040% of patients will experience a haemorrhagic event sometime during the course of their disease. Peptic ulcer disease occurs frequently and contributes to the gastrointestinal tract being the most common source of bleeding. The bleeding diathesis may relate to abnormalities in platelet function, and thus occurs frequently after the ingestion of anti-inflammatory agents. Spontaneous bleeding is rare. Recent data suggests that low-dose aspirin might not increase the frequency of life-threatening haemorrhages. The risk of postoperative complications is high in patients with polycythaemia vera. Bleeding, thrombosis, or a combination of both can occur. The risk is higher for those patients who undergo surgery with uncontrolled erythrocytosis. Thrombosis may be the cause of death in up to 3040% of patients. Thrombosis may occur in the deep venous system of the lower extremities, or present as a pulmonary embolism. Cerebrovascular, coronary and peripheral vascular occlusions are not rare. Thromboses at unusual sites are characteristic of polycythaemia vera. They include occlusion of the splenic, portal, hepatic and mesenteric veins. Hepatic venous or inferior vena caval thrombosis is known as BuddChiari syndrome. It is characterised by hepatosplenomegaly, ascites, oedema of the peripheral extremities, jaundice, abdominal pain and distension of superficial abdominal veins due to portal hypertension. Neurological abnormalities are also common and occur in up to 6080% of patients. They include transient ischaemic attacks, cerebral infarction, cerebral haemorrhage, confusional states, fluctuating dementia and involuntary movement syndromes.

223. A 38-year-old patient is investigated for his anaemia. A bone marrow biopsy shows a reduction of haematopoietic cells and a trephine biopsy shows mainly fatty bone marrow. Given the likely diagnosis, what is the most likely complication of this disease? Thromboses Bleeding Infections Malignancy Rupture of the spleen

Your answer

Patients with aplastic anaemia have a high risk of infections, which may arise from the environment or from other sources of bacteria. As with all immunosuppressed patients, significant and lethal infections may arise from contamination with organisms that are not normally pathogenic. Exogenous infections are more likely in a hospital environment than at home, so any patient with aplastic anaemia admitted to hospital must be nursed in a

clean, and preferably sterile, area. Measures to prevent nosocomial infections should be of the highest standards.

224. Which one of the following features is characteristic of immune thrombocytopenic purpura (ITP)? Infants born to a woman with ITP often presents with bleeding diathesis in the first 48 hours Pancytopenia is a recognised complication Leukaemic transformation occurs late in the disease Splenomegaly is found in 50% of cases Autoimmune haemolytic anaemia is a recognised association

Your answer

Immune thrombocytopenic purpura (ITP) refers to thrombocytopenia occurring in the absence of toxic exposure or other diseases associated with low platelets. The immune mechanism involves IgG-type antibodies. The disease is characterised by normal or increased marrow megakaryocytes, shortened platelet survival and the absence of splenomegaly. In neonatal ITP, IgG antibodies are passively transferred across the placenta, the infant platelet count may be normal at birth, but decreases within 1224 hours. It is rarely severe enough to induce bleeding diathesis in the infant. Evans syndrome is a rare condition where autoimmune haemolytic anaemia and thrombocytopenia occur in the same patient. Leukaemic transformation does not occur in ITP.

225. Which one of the following statements BEST describes haemophilia A? Petechiae are more common than soft tissue bleeding Bleeding time is prolonged

Factor 8 inhibitors occur in 10% of patients receiving multiple factor 8 transfusion Iron deficiency anaemia is a frequent and persistent problem Joint deformity is rare despite the fact that haemarthrosis is one of the main recurrent manifestations

Your answer

Petechiae are an extremely important clue in the diagnosis of haemostatic disorder and are only seen in platelet disorders. Haemarthroses are almost pathognomonic of severe haemophilia and often lead to joint damage and deformities. The bleeding in haemophilia is usually confined to soft tissue, muscle and other body compartments. The iron is usually recycled from these sites and iron deficiency anaemia is not a frequent feature of haemophilia. PTT is prolonged, PT and bleeding time are typically normal. Prolonged bleeding time is caused either by thrombocytopenia or by qualitative platelet dysfunction.

226. A 52-year-old black woman comes to you for another opinion regarding a history of anaemia that has been unresponsive to oral iron supplementation. She sought your opinion because her other physician was recommending iron supplementation iv. She has been on nearly continuous iron supplementation therapy ever since her second child was born 23 years ago. Over the years she says her doctors have prescribed her to take anywhere from one to three pills daily, sometimes with vitamin C concomitantly. Although she has never needed a transfusion, she says she has been told that her RBC count has never completely normalized. She is otherwise healthy and has no unusual dietary habits. Her menstrual history reveals relatively normal menstrual periods until about 3 years ago, when she attained menopause. The patient believes that her mother was also iron deficient. Your physical exam is normal. Laboratory values show a haemoglobin of 11.6 g/dl; haematocrit, 33%; MCV, 70 fl; normal white blood cell (WBC) with differential; normal platelet count; serum iron, 70 g/l; iron-binding capacity, 255 g/dl; and ferritin, 158 g/l. At this point you should next Agree with the other physician and recommend iron supplementation iv because she does not appear to be absorbing enough oral iron to totally correct her anaemia Perform a haemoglobin electrophoresis Obtain a serum erythropoietin (EPO) level Discontinue iron supplementation Perform a bone marrow aspirate and biopsy This history is suspicious of two gene -thalassaemia. Deletion of two -genes results in mild to moderate microcytosis and mild anaemia, rarely with any progression or development of other signs or symptoms. Alpha-thalassaemia is probably the most common haemoglobinopathy in the world and the combination of one-gene or two-gene Your answer

thalassemia has an incidence of 20% or more among blacks. It is often mistaken for iron deficiency anaemia and menstruating women with the condition are often treated for prolonged periods with iron supplementation because it is presumed that the mild microcytic anaemia is due to iron deficiency. A haemoglobin electrophoresis is a useful test for -thalassemia wherein one looks for increased levels of haemoglobin A2 and haemoglobin F. However, haemoglobin electrophoresis is generally not helpful for the diagnosis of an -thalassemia disorder.

227. A 12-year-old boy fell while playing in the garden. He developed a very painful swelling of his right knee, aspiration of which revealed the presence of blood. The following laboratory parameters have been obtained: INR normal, APTT increased, fibrinogen normal, antithrombin III level normal, bleeding time 3.3 min. What is the most likely cause? Fibrinogen deficiency Glucose-6-phosphate dehydrogenase deficiency Prothrombin deficiency Haemophilia Your answer Factor VII deficiency Deficiency of either factor VIII (haemophilia A) or factor IX (haemophilia B), which together make up the factor VIIIa/factor IXa intrinsic tenase enzymatic complex, results in the clinical phenotype commonly known as haemophilia. Haemophilia principally presents with haematoma formation, easy bruising and bleeding at the site of venepuncture during the toddler period. In the untreated patient with severe disease, haemophilic arthropathy and joint deformity are inevitable complications. In decreasing order of involvement, the most commonly affected joints include the knee, elbow, ankle, shoulder, wrist and hip. Recurrent bleeding episodes create a hypertrophic synovial lining with chronic inflammation; however, the pathophysiology responsible for recurrent joint bleeding remains unknown. Arthropathies commonly necessitate replacement of affected joints for pain control and improvement of mobility. Soft tissue haemorrhages frequently complicate haemophilia; further complications due to these haemorrhages include compartment syndrome, neurological damage and extensive blood loss from retroperitoneal bleeds. Haematoma formation, a frequent complication of haemophilia, may arise spontaneously or with trauma and require extensive factor replacement and fasciotomy, the necessity for which can be assessed by measuring the mean arterial pressure in a compartment. The management of haemophilia predominantly involves administering the missing protein (factor VIII or factor IX) to a patient. Factor-replacement therapy is most commonly administered in a so-called on-demand regimen, when a patients symptomatology necessitates treatment.

228. A 10-year-old boy is referred for investigation of anaemia. He is generally well but is small for his age. He is progressing well for his age group at school. A male first cousin died of leukaemia. On examination the child is pale and has a few bruises. He is noted to have markedly thickened nails and is below the third centile in height. A blood count shows: Hb is 7.2 g/dl; WCC 1.2 109/l; platelets 20 109/l. What is the most likely explanation for his anaemia? DiamondBlackfan syndrome Aplastic anaemia Dyskeratosis congenita Your answer Acute lymphoblastic leukaemia Fanconis anaemia

Congenital aplastic anaemias include Fanconis anaemia and dyskeratosis congenita. Dyskeratosis congenita is characterised by skin pigmentation, nail dystrophy, leucoplakia and a predisposition to bone marrow failure and malignancy. It has been reported as X-linked recessive, autosomal-dominant and autosomalrecessive diseases. The X-linked recessive form was linked to chromosome Xq28 and the gene DKC1, which encodes for a ubiquitously expressed protein dyskerin. The age of presentation with pancytopenia is variable, with a median age of 8 years. Patients may progress to acute leukaemia. Patients who are progressing to pancytopenia may be cured by bone marrow transplantation.

229. A patient has been diagnosed with severe haemophilia B (factor IX level <1%). What is the mode of inheritance?

Autosomal dominant Autosomal recessive X-linked dominant Y-linked X-linked recessive

Your answer

Haemophilia B is an X-linked recessive blood coagulation disorder caused by functionally defective or reduced plasma levels of coagulation factor IX. Factor IX is a vitamin Kdependent plasma protein that participates in the middle phase of coagulation.

230. A 27-year-old woman is reviewed in the haematology clinic. She was referred with an abnormal chest X-ray and weight loss (50 kg to 40 kg). On examination, she has cervical lymphadenopathy but no other palpable nodes and a normal abdominal examination. Her CT chest/abdomen/pelvis confirms cervical adenopathy and shows upper mediastinal adenopathy, but there are no other abnormalities. A bone marrow aspirate and trephine is normal. FBC shows neutrophils 4.3 103/mm3, lymphocytes 1.4 103/mm3, basophils < 0.1 103/mm3, eosinophils 1.7 103/mm3, Hb 11.6 g/dl, platelets 152 103/mm3. What is the likely diagnosis? Burkitts lymphoma Follicular lymphoma Acute myeloid leukaemia Chronic Wuchereria bancrofti infection Hodgkins lymphoma

Your answer

This young woman has constitutional symptoms (weight loss > 15%) and two regions of lymphadenopathy on the same side of the diaphragm with no other organ involvement. Although a lymph node biopsy is required to make the diagnosis, the raised eosinophil count is the strongest clue in the history that favours a diagnosis of Hodgkins disease. A chronic parasitic infection can cause weight loss and raised eosinophil counts, but would not cause isolated adenopathy in this region without respiratory disease or compromise of the tissues drained by the nodes. Using the Ann Arbor staging, she is in group IIB and her treatment would consist of chemotherapy and probably localised radiotherapy.

231. A 54-year-old man presents with a two-month history of increasing lethargy. He also reports that he has been bruising more easily of late. On direct questioning he admits to passing dark urine, but denies any other urinary symptoms. A year ago he had finished a 6month period of anticoagulant therapy for a spontaneous deep vein thrombosis. His full

blood count demonstrates haemoglobin 6.5 g/dl, white blood cell count 2.8 109 per litre, and platelets 27 109 per litre. What is the most appropriate management for his anaemia? Erythropoietin injections Folic acid therapy Transfusion with plasma-reduced washed red cells Androgen hormonal therapy Transfusion with blood substitutes

Your answer

Paroxysmal nocturnal haemoglobinuria is an acquired clonal defect of stem cells in which the cells are deficient in several glycosylphosphatidylinisotol (GPI)-anchored membrane proteins, such as CD59, CD55, and CD16. This manifests as an increased sensitivity to complement-mediated lysis of red cells. Nocturnal haemoglobinuria, thrombotic manifestations, and organ damage can be seen. The patients usually have low white cell and platelet counts even in the absence of associated aplastic anaemia. The anaemia can be managed with blood transfusions. Traditionally washed red cells (devoid of complement) have been used because it was thought that transfusion inevitably led to some activation of complement with a paroxysm of haemolysis. Folate therapy, androgenic steroids, and iron replacement (if there is a deficiency) may all help in the long term. Acute leukaemia or aplastic anaemia may complicate PNH in the long term. Transfusions with blood substitutes have been tried anecdotally.

232. A 72-year-old man with minimal change disease and nephrotic syndrome presents to the Emergency Department with acutely worsening shortness of breath. On examination his blood pressure (BP) is 100/60 mmHg, pulse 100/min regular. His respiratory rate is 38/min and auscultation of the chest reveals no signs of pulmonary oedema. He has gross swelling of his lower limbs consistent with his underlying renal disease. Arterial blood gas measurement (air):

pa(O2) 6.6 kPa pa(CO2) 3.8 kPa

Which underlying clotting disorder is most likely to be the cause of his presentation on this occasion? Protein C deficiency Protein S deficiency Factor V Leiden mutation Antiphospholipid antibody syndrome Occult pelvic malignancy

Your answer

This man has suffered a pulmonary embolus as evidenced by his hypoxia and hypocapnoea in the presence of a relatively clear chest on auscultation. Patients with nephrotic syndrome are predisposed to pulmonary embolus not just because of lack of mobility but also due to renal antithrombin III losses and protein S deficiency. Management in this case involves oxygen therapy and acute heparinisation followed by commencement of warfarin therapy. In the event that he fails to respond to oxygen and heparinisation and his pa(O2) and blood pressure worsen, thrombolysis may be considered.

233. Most cancer cells activate telomerase. What is the most likely biological result of this activation? Cell death Angiogenesis Immortalisation Tumour suppression Major histocompatibility complex activation

Your answer

Telomeres are structures at the end of chromosomes, which in normal cells progressively shorten with each cell division. Without telomerase action terminally short telomeres cause cell-growth arrest. Suppression of telomerase is a tumour-suppressor and ageing mechanism. In contrast, most cancer cells activate telomerase, resulting in stable telomeres and immortalisation. Normal stem cells may express telomerase in the adult, allowing perpetuation, while tumours arising from stem cells may have a similar prolongation of survival. Telomerase inhibition is a therapeutic target to force cell senescence.

234. A 72-year-old non-smoker presents with bone pain, constipation and malaise. Baseline investigations reveal an elevated serum calcium. Physical examination was normal. Which tumour marker investigation might be most useful for this man? Carcinoembryonic Antigen (CEA) Prostate specific antigen (PSA) Your answer Alpha-fetoprotein (AFP) Beta-subunit of human chorionic gonadotropin (b-hCG) CA 19-9 Monoclonal antibodies are used to detect serum antigens associated with specific

malignancies. These tumour markers are most useful for monitoring response to therapy and detecting early relapse. With the possible exception of prostate-specific antigen (PSA), tumour markers do not have sufficient sensitivity or specificity for use in screening. PSA can be used to screen for prostate cancer, although population screening is controversial. It can also be used to detect recurrence of the malignancy, and is useful in the investigation of adenocarcinoma of unknown primary. Carcinoembryonic antigen is used to detect relapse of colorectal cancer, and CA 19-9 may be helpful in establishing the nature of pancreatic masses. AFP is a marker for hepatocellular carcinoma. Combined AFP and b-hCG testing is an important component in the evaluation and treatment of non-seminomatous germ-cell tumours, and in monitoring the response to therapy. AFP and b-hCG also may be useful in evaluating potential origins of poorly differentiated metastatic cancer.

235. A 60-year-old white man comes to see you because he was told he had 'a high blood count'. Physical exam is normal except for a ruddy complexion, which he says he has had most of his adult life .He has smoked two packs of cigarettes per day since he was 16 years old. A blood screen shows a normal white blood cell (WBC) count and differential, normal platelet count, haemoglobin of 18.4 g/dl and a haematocrit of 57%. Red cell volume is elevated, erythropoietin levels are low and leucocyte alkaline phosphatase score is high, suggesting primary polycythaemia. Which of the following statements fits best with primary polycythaemia? Around 10% of cases progress to acute myeloblastic leukaemia Around 40% of cases progress to myelofibrosis Venesection is only used where chemotherapy has failed Administration of radioactive phosphorous carries no increased risk of leukaemia H2-receptor antagonists may be useful in relieving itching Your answer

Primary polycythaemia is a clonal stem disorder in which there is excessive proliferation of erythroid, myeloid and megakaryocytic progenitor cells. This is due to a failure of apoptosis as a result of deregulation of the Bcl-x gene. Usual presentation is in patients over 60 years of age with tiredness, depression, vertigo, itching or visual disturbance. Hb, PCV and red cell volume are increased. Erythropoietin is reduced, leucocyte alkaline phosphatase may be increased and bone marrow aspiration reveals erythroid hyperplasia and increased numbers of megakaryocytes. Around 30% of cases may develop myelofibrosis and acute myeloblastic leukaemia is seen in around 5% of patients. Some are managed with venesection as sole treatment; in other cases hydroxyurea is most commonly used as chemotherapy. One dose of radioactive phosphorous may give control for up to 18

months, but carries increased risk of transformation to acute leukaemia. H2-receptor antagonists are occasionally effective for control of itching.

236. A 32-year-old woman who was investigated for infertility presented with postoperative bleeding from her abdominal wound. Her full blood count (FBC) showed Haemoglobin Hb 9.2g/dl, total white cells very high, presence of pro-myelocytes, platelets 932x109/l, INR was raised to 1.4. What is the next step in management? Give fresh frozen plasma Give platelet infusion Give hydroxyurea Give interferon alpha Give vincristine Your answer

This patient has acute promyelocytic leukaemia (APML), occurring in association with a t(15:17) translocation. APML is associated with disseminated intravascular coagulation (DIC). Patients may present, as in this case with severe bleeding, and the most appropriate treatment in this case would be FFP. Despite the fact that the platelet count is high, platelet function is ineffective. Occurrence of DIC is thought to be due to abnormal expression of annexin II, which accelerates activation of plasmin, and therefore fibrinolysis. All-trans retinoic acid (ATRA) induces differentiation of the leukaemic cells into mature granulocytes, and ameliorates both DIC and bone marrow failure associated with APML. Chemotherapy is usually given for the condition without cytarabine, and ATRA is continued for at least 1 year after post-remission therapy has been completed. Providing remission can be achieved, survival is better than with other subtypes of AML.

237. You are contacted by the cardiothoracic registrar for advice about a surgical patient. A 65-year-old man had an aortic valve replacement and coronary artery bypass grafting earlier in the day. The operation was uneventful but the patient has continued to ooze from his wounds and is bleeding considerable amounts into drains. You are told that his haematology is as follows: Hb 10.7 g/dl, WCC 14.2 109/l, with a normal differential, platelets 136 109/l, PT 18 s (normal range 1217), APTT 72 s (normal range 2438), TT 32 s (normal range 1422) and fibrinogen 2.1 g/l (normal range 25). The reptilase time was 16 s (normal range 1518), FDP 10 g/ml (normal range < 10).

What is the cause of his coagulation abnormality? Heparin in the sample Acquired haemophilia Disseminated intravascular coagulation Coagulation factor deficiency due to dilution Surgical bleeding Your answer

This patient may have surgical bleeding but the cause of his abnormal coagulation screen is heparin in the sample. This is shown by the fact that the activated partial thromboplastin time (APTT) is prolonged but the reptilase time is normal. When a sample is taken from an iv line, small amounts of heparin can stick to the plastic and affect the test result even if a considerable amount of blood has been discarded. To obtain a true result it is necessary to take a fresh sample from a vein.

238. You are attending a meeting where the introduction of a new screening programme to detect early lung cancer is being discussed. What is the most important criterion when deciding whether such a programme should be introduced? The specificity of the test The sensitivity of the test A clinically effective and cost effective method of early treatment Your answer The cost-benefit of a screening programme Current technology makes early detection possible This type of screening is concerned with the detection of a disease, in this case lung cancer, at its earliest stage to maximise the possibility of cure. Screening programmes for a particular disease should not necessarily be introduced merely because it is technically possible to detect the condition at an earlier stage there has to be evidence that early diagnosis will affect the outcome for the patient. The other answers are all valid aspects that need to be assessed once clinical benefit has been established. The specificity of a test is a measure of its ability to correctly identity healthy people as not having the disease, and therefore a highly specific test would give a low number of false-positives. The sensitivity of a test is a measure of its ability to detect the disease when it is present, and therefore a highly sensitive test would have very few or no missed cases. Randomised controlled trials are currently being conducted to determine whether improved detection by techniques such as spiral CT will translate into reduced lung cancer mortality rates.

239. A 55-year-old man presents for review. He attended for an insurance medical and the reviewer noticed there was lymphadenopathy on palpation of the neck, axillas and groins. Chest X-ray confirmed the presence of hilar lymphadenopathy. Bone marrow biopsy revealed multinucleated giant cells (ReedSternberg cells). Given the likely diagnosis, which of the following features would be most consistent with a good prognosis in this condition? Young age Your answer Presence of pain on consumption of alcohol Lymphocyte-depleted picture on histology Mixed cellularity picture on histology Presence of night sweats, indicating active immune response Absence of B symptoms such as night sweats, or early stage at presentation, young age, lymphocyte-predominant histology and nodular sclerosis on histology are all associated with a better prognosis in patients with Hodgkins disease. Hodgkins disease has a bimodal age distribution, occurring between the ages of 15 and 34 years and over 50 years of age most commonly. Concordance for Hodgkins disease in identical twins suggests a genetic susceptibility, and it is thought to be an association with EpsteinBarr virus infection. The disease is commoner in males, Caucasians and in higher socioeconomic groups. The incidence of Hodgkins disease is around 4/100,000. Histological classification includes: lymphocyte-predominant, mixed cellularity, nodular sclerosing and lymphocyte-depleted. Staging is according to the Ann Arbor classification. The overall 10-year survival rate is now above 60%.

240. A 38-year-old woman is referred to the haematology out-patients department by her GP with anaemia. Her Crohns disease has recently flared up after a prolonged course of non-steroidal anti-inflammatory drugs (NSAIDs) prescribed for her painful lower back. She has never had abdominal surgery. Her results show Hb 8.3 g/dl, MCV 101 fl, WCC 8 103/mm3, platelets 480 103/mm3, bilirubin 39 mol/l, lactate dehydrogenase (LDH) 378 U/l, normal renal and liver function, her red cell folate level is low as is her serum vitamin B12. What is the most likely cause of her anaemia? NSAID-induced gastritis Anaemia of chronic disease Pernicious anaemia

Dietary deficiency of vitamin B12 and folate Terminal ileal disease

Your answer

This woman has a macrocytic anaemia with no white cell or platelet count abnormality. A raised bilirubin and LDH with normal LFTs (liver function tests) may well represent haemolysis. The low red cell folate level reflects a lack of intracellular folate synthesis rather than a simple deficiency, which is better reflected by the serum folate level. Vitamin B12 deficiency can explain all the indices, as vitamin B12 is necessary for normal folate metabolism. It is a cofactor in the conversion of methyltetrahydrofolate to tetrahydrofolate, which is the active intracellular form of folate used in the single-carbon transfer in DNA synthesis. Of all the options presented, terminal ileal disease due to Crohns disease (leading to reduced vitamin B12 absorption) is more likely, rather than postulating another disease process like pernicious anaemia.

241. Which of the following is being used as a prognostic marker in acute myeloblastic leukaemia? Elevated lactate dehydogenase (LDH) Karyotype of bone marrow Monocytic morphology The number of blasts in the bone marrow White cell count at diagnosis

Your answer

Bone marrow karyotype is the prognostic marker in acute myeloblastic leukaemia. Patients with chromosome t(8;21) or chromosome 16 inversion have a low risk of relapse. Patients with changes in chromosomes 3, 5 or 7 have a high risk of relapse.

242. You are on call and are contacted by the gynaecology registrar. A 23-year-old woman has a ruptured ovarian cyst and needs to go to theatre soon. She has mild von Willebrands disease and has had previous operative procedures carried out without requiring blood products. Currently her Hb is 12.5 g/dl (11.516.5), WCC 5.2 109/l (411 109), platelets 190 109/l (150400 109), PT 15s (1217), APPT 40 s (2438), TT 17 s (1422), fibrinogen 3.1 g/l (25) What would be the most appropriate management of the surgery? Transfusion of Haemate P

Transfusion of fresh-frozen plasma DDAVP and tranexamic acid Your answer Blood transfusion Transfusion of platelets Von Willebrands disease is a disorder of abnormal platelet adhesion associated with VW factor activity. A gene on chromosome 12 encodes the VW factor, a large multimeric molecule. It is stored in WeibelPalade bodies in endothelial cells and platelet a-granules. This protein is involved in platelet adhesion and is the carrier molecule for factor VIII, so preventing its premature destruction. Inheritance is autosomal-dominant and point mutations and major deletions of the gene have been described. Treatment includes: desmopressin (DDAVP), which may boost factor VIII levels as well as VW factor levels; factor VIII concentrates (Haemate P), which contains significant amounts of VW factor; and antifibrinolytic inhibitors, eg tranexamic acid. This patient has not been exposed to blood products in the past. Therefore, if at all possible, she should not be exposed to blood products like fresh-frozen plasma or those from large donor pools, eg factor VIII concentrates.

243. A 41-year-old man presents with a neck lump, weight loss, night sweats and alcoholinduced pain. On examination, you note he has hepatomegaly. What is the likeliest diagnosis? Hodgkins disease Large-cell lung carcinoma High-grade B-cell non-Hodgkins lymphoma Low-grade non-Hodgkins lymphoma High-grade T-cell non-Hodgkins lymphoma

Your answer

High-grade B-cell non-Hodgkins lymphoma is the commonest type of high-grade lymphoma. High-grade lymphomas are usually associated with B symptoms and low-grade lymphomas are not. T-cell lymphomas are very rare the main one is mycosis fungoides, which causes Szary syndrome. High-grade lymphomas respond well to therapy and lowgrade lymphomas do not, but low-grade lymphomas are slow growing.

244. A 22-year-old patient who is a vegan and very active has been complaining of tiredness and shortness of breath for the last 2 months. On examination she looks anaemic. What is the most likely vitamin deficiency causing her anaemia? Vitamin A Vitamin B1 Vitamin B6 Vitamin B12 Vitamin C

Your answer

Nutritional vitamin B12 deficiency is observed in true vegans, particularly in the Indian subcontinent. Infants born of mothers with sprue or postinfective malabsorption who are fed on breast or goats milk containing insufficient vitamin B12 may develop megaloblastic anaemia with locomotor complications during the early months of life.

245. A patient presents with jaundice and a painless enlargement of the gallbladder (Courvoisiers law). What is the most likely diagnosis? Liver cirrhosis Carcinoma of the ampulla of Vater Your answer Carcinoma of the gallbladder Gallstones in the cystic duct Progressive hepatitis B

If the malignant obstruction is below the level of the cystic duct, the gallbladder is distended and may be palpable (Courvoisiers law). The urine is dark and the stools pale. In cancer of the ampulla of Vater, a film of blood on the pale stool may give it a silvery colour (silver stools). An ultrasound or CT scan examination will reveal dilatation of the biliary tree and may demonstrate the level of the obstruction. Ultrasound-guided percutaneous needle biopsy may be employed to provide a histological diagnosis. Bile duct carcinoma frequently

causes obstruction at the porta hepatis and, consequently, at laparotomy the extrahepatic biliary tract appears non-dilated. Even if an operative cholangiography is performed, the contrast medium frequently fails to pass the obstruction and fill the dilated intrahepatic biliary tree. Therefore it is important to establish the diagnosis precisely before surgery is contemplated by performing an ERCP (endoscopic retrograde cholangiopancreatography) or PTC (percutaneous transhepatic cholangiography). This is particularly important because most of these patients are best treated by endoscopic or percutaneous biliary stents rather than by surgery.

246. A 15-year-old girl from India who recently immigrated to England has been referred by her GP because she looks anaemic. On examination you notice frontal bossing of the skull and chronic leg ulcers. Her Hb is 70 g/l (120160 g/l) and HowellJolly bodies are seen. What is the most likely diagnosis? Thalassaemia Sickle-cell disease Your answer Aplastic anaemia Myeloma Acute lymphocytic leukaemia This patient presents with sickle-cell anaemia. Sickle-cell anaemia is an autosomal-recessive genetic disorder caused by a defect in the HBB gene, which codes for haemoglobin. Typically the haemoglobin levels are in the 60 to 80 g/l range with a reticulocyte count of 1020%. There is chronic, mild icterus with an elevated bilirubin level. Examination of the peripheral blood film shows anisochromia and poikilocytosis with a variable number of sickled erythrocytes. As the children grow older the haematological changes of hyposplenism develop with the appearance of pits on the surface of the red cells, Howell

Jolly bodies and distorted red cells. The white cell and platelet counts are usually normal or slightly elevated. Growth and development are usually otherwise normal, although there may be some skeletal deformities, including frontal bossing of the skull due to expansion of the bone marrow. Chronic leg ulceration is also common. There is hyposplenism as evidenced by the blood film, this means that sickle-cell anaemia is much more likely than thalassaemia.

247. A 30-year-old woman presents to her GP with a 3-day history of menorrhagia. She has no previous history of menstrual irregularity and was previously well. On examination she is pale and has a number of bruises on her arms and legs. Blood tests are sent immediately to the hospital and are reported as follows: Hb of 7.5 g/dl (11.516.5), WCC 1.5 109/l (4 11 109) with occasional abnormal immature cells reported on the blood film, platelets 15 109/l (150400 109), PT 19 s (1217), APTT 45 s (2438), TT 22 s (1422), fibrinogen 1.2 g/l (25). What is the most likely diagnosis? Acute promyelocytic leukaemia Your answer Immune thrombocytic purpura Meningococcal septicaemia Acute lymphoblastic leukaemia Non-Hodgkins lymphoma This patient has pancytopenia with abnormal cells in the peripheral blood suggesting an acute leukaemia. She has bleeding, bruising and abnormal coagulation parameters, which would point in the direction of acute promyelocytic leukaemia. Acute myeloid leukaemia is defined as 20% or more myeloid blasts in the bone marrow (WHO classification). It is the common form of acute leukaemia in adults and is subdivided on the basis of morphology, immunophenotype and cytogenetics. Acute promyelocytic leukaemia (M3) is characterised by the presence of promyelocytes and the cytogenetic translocation t(15;17). The promyelocytes have a typical heavily granulated appearance and tend to precipitate disseminated intravascular coagulation leading to bleeding manifestations often after starting chemotherapy.

248. A 60-year-old woman is referred to you with numbness affecting her hands and feet. Electrophysiological testing confirms the presence of peripheral neuropathy. She recently completed a course of chemotherapy for breast cancer.

Which chemotherapeutic agent is most likely to be responsible? 5-Fluorouracil Epirubicin Docetaxel Cyclophosphamide Doxorubicin

Your answer

Peripheral neuropathy is a well-known complication of many chemotherapeutic agents, in particular vinca alkaloids (vincristine and vinblastine), platinum analogues (carboplatin and cisplatin) and taxanes (docetaxel, paclitaxel). It is often only partial reversible and can be very disabling. Loss of deep tendon reflexes is an early sign, and it can present as a burning sensation in the fingers and toes. Peripheral neuropathy can also be a paraneoplastic condition. 5-Fluorouracil can cause palmarplantar syndrome (erythema, paraesthesia and burning sensation in the hands and feet) which is fairly rapidly reversible on cessation of the drug . Doxorubicin and, to a lesser extent, epirubicin are cardiotoxic and can cause a dilated cardiomyopathy.

249. A 78-year-old woman attends the haematology clinic for further investigation. She receives vitamin B12 injections every six months, having been diagnosed with pernicious anaemia four years ago. She is currently asymptomatic. Her FBC shows Hb 10.3 g/dl, MCV 101 fl, platelets 136 103/mm3, WCC 5.9 103/mm3. Other investigations show TSH < 0.1 mU/l, AST 39 U/l, GGT 67 U/l, INR 1.1. What is the likely diagnosis? Reticulocytosis Constitutional macrocytosis Myelodysplastic syndrome (MDS) Thyroid dysfunction Vitamin B12 deficiency

Your answer

MDS is a tri-lineage disorder that is characterised by peripheral cytopenia with the marrow full of developing cells, but the maturation is abnormal and there is reduced cell survival. Classification is on bone marrow appearance (divided into refractory anaemia (RA), RA with ring sideroblasts, RA with excess blasts, RA with excess blasts in transformation, and chronic myelomonocytic leukaemia). Moreover, a number of cytogenetic abnormalities are associated, eg chromosome 5p deletion and trisomy 8. It can initially be detected from the presence of abnormal red cell maturation (ie a raised MCV) in the absence of other causes, with anaemia. Hypothyroidism rather than hyperthyroidism causes a raised MCV and she is vitamin B12 replete (folate deficiency is rare in the absence of bowel disease).

250. You are asked to see a 25-year-old White man who experienced marked weakness and dyspnea 4 days after being admitted for a compound arm fracture after falling from a tree. Estimated blood loss from the initial fracture episode was 600 ml and the patient was transfused with one unit of packed erythrocytes. The initial crossmatch was reported as compatible by the transfusion service. The patient has never been transfused before this incident and has no other serious medical illnesses. The patient's arm fracture was treated with surgical pinning and prophylactic antibiotics consisting of a cephalosporin iv every 12 h. On examination, the patient is febrile and mildly tachycardic, with no evidence of wound infection or compartment syndrome. Laboratory data show a haematocrit of 15%, a raised reticulocyte count and total bilirubin of 70 mol/l with a conjugated bilirubin of 9 moll/l. The peripheral smear shows many spherocytes. No haemoglobinaemia or haemoglobinuria is seen on visual inspection of the plasma and urine. The transfusion service reports that the direct Coombs' test is now strongly positive using anti-IgG and only weakly positive with anti-C3d antisera. They further report that routine compatibility tests show no new erythrocyte antibodies in the patient's serum and that, when they attempted to elute antibody from the patient's RBCs and test against normal RBCs, the results were negative. What is the most likely diagnosis? Haemolytic transfusion reaction caused by an ABO incompatibility Delayed haemolytic transfusion reaction Autoimmune haemolytic anaemia of warm antibody type Autoimmune haemolytic anaemia of cold antibody type Druginduced immune haemolytic anaemia

Your answer

Decreased haematocrit, raised reticulocyte count and raised unconjugated bilirubin all point towards a diagnosis of haemolytic anaemia. Druginduced immune haemolytic anaemia of the hapten type is recognised in patients exposed to high doses of penicillin, other drugs that are associated with haemolytic anaemia include methyldopa, quinidine, quinine, chlorpromazine and the sulphonamides. In this patient the strongly positive direct Coombs test shows that this is an immune haemolytic anaemia. Three findings suggest the diagnosis of a druginduced mechanism rather than an autoimmune mechanism: (1) the patient received a cephalosporin known to induce a hapten-type reaction, (2) routine tests for RBC antibodies in the patient's serum were negative even though the patient's RBCs were strongly coated for antibody and (3) eluate from the patient's RBCs was not reactive with normal RBCs. The anaemia should begin to improve after drug withdrawal.

251. A 72-year-old lady with confirmed anaplastic thyroid carcinoma is being screened for metastases. Which of these organs is the most likely to be involved with metastases?

Brain Lung Your answer Oesophagus Spleen Kidney Anaplastic carcinoma of the thyroid is an aggressive form of cancer of the thyroid gland. It represents less than 2% of all thyroid cancers, ranging from 1.23.8 per 100 000 individuals. Clinically, most patients have a dominant fixed mass of 5 cm or more in diameter, multiple other nodules in both thyroid lobes, and enlarged lymph nodes; 2050% of patients have distant metastases, chiefly in the lungs but also the bones, liver and brain.

252. A 32-year-old man is seen in the casualty department complaining of breathlessness, which has gradually worsened over the last weeks following an emergency appendicectomy. He received no blood products at the time of operation. He has not noticed any frank blood loss. Currently, he is taking prn diclofenac for postoperative pain relief. This man has a past history of recurrent deep vein thromboses, the last of which was complicated by a pulmonary embolism two years ago. He declined long-term anticoagulation. A full blood count shows: Hb 8.8 g/dl; MCV 89 fl; platelets 105 103/mm3; WCC 6.3 103/mm3 and urinalysis shows the presence of haemosiderin. Which investigation is most reliably diagnostic? Bone marrow trephine Blood immunophenotyping Your answer Coombs test Acid lysis test Serum haptoglobin

This young man, with a history of thrombotic events, is likely to be acutely anaemic from his symptomatology and evidence of intravascular haemolysis (haemoglobin released in the plasma is excreted in the urine as haemosiderin) with a slightly reduced platelet count. This has occurred after an infective and traumatic event, ie the removal of an inflamed appendix, and is a characteristic presentation of paroxysmal nocturnal haemoglobinuria (PNH) caused by a red cell membrane defect that renders the cell more liable to complement-mediated lysis. (Affected cells do not express GPI (glycosylphosphatidylinositol) which anchors the decay-accelerating factor (DAF) and membrane inhibitor of reactive lysis (MIRL), both of which help to degrade complement proteins.) Serum haptoglobins are low, but this is nonspecific for intravascular lysis, a bone marrow trephine may show reduced cellularity and the acid lysis, or Hams test, which can demonstrate greater complement susceptibility, is not always positive over the course of the disease. Immunophenotyping will demonstrate the absence of expression of the CD 59 antigen (GPI protein) due to the abnormal red cell clone. A significant proportion of patients with PNH goes on to develop aplastic anaemia or acute leukaemia.

253. A 20-year-old man has a painful swollen knee, a prolonged activated partial thromboplastin time (APTT), a prolonged bleeding time, and a normal prothrombin time. What is the most likely diagnosis? Anaphylactoid (HenochSchnlein) purpura Salicylate poisoning Factor VII deficiency Haemophilia A Type III von Willebrands disease

Your answer

HenochSchnlein purpura is not associated with any defect of coagulation or platelets. It is the leakage of red cells from capillaries damage by an immunoglobulin A (IgA)mediated vasculitis. A prolonged activated partial thromboplastin time (APTT) implies a problem with the intrinsic or final common coagulation pathways. Both of the inherited sex-linked defects haemophilia A (factor VIII deficiency) and Christmas disease (haemophilia B or factor IX deficiency) result in recurrent haemarthroses in their severe form, but do not cause prolongation of the bleeding time, which is a test of in-vivo platelet function. Factor VII lies in the extrinsic pathway and causes a prolonged prothrombin time. Von Willebrands disease (vWD) leads to a prolonged APTT and a prolonged bleeding time, but typically causes mucosal bleeding. However, the severe Type III form of vWD, caused by almost total absence of Von Willebrand factor (vWF), can have a phenotype very much like the severe haemophilias.

254. In cancer therapy, what is the rationale behind using combinations of chemotherapeutic agents rather than single agents? Fewer side-effects occur in combination therapy Combination therapy can be given over a shorter period of time Combination therapy decreases the chances of drug resistance developing Metastases are less common in combination therapy Combination therapy is less likely to result in long term toxicity There are two main reasons for using combinations of chemotherapeutic agents. Different drugs exert their effects through different mechanisms, so carefully combining them will increase the number of tumour cells killed in each cycle. Second, there may be an even greater effect with drugs that are synergistic. As cells might be killed through a number of different mechanisms they are less likely to develop resistance. Drug combinations have to be chosen carefully otherwise the side-effects and long-term toxicity could be potentially more severe, eg if two drugs both had significant hepatotoxicity. Combination therapy may not affect the duration of therapy and sometimes it turns out to be less effective, so metastases would not necessarily be less common.

Your answer

255. A 45-year-old lady was found to have purpuric rash on her legs associated with easy bruising which started after minor trauma. The following blood results were obtained:

White cell count (WCC) 2.7 109/l Red blood cells (RBC) 8.2 109/l Platelets 10 x 109/l mm3 Fragemented red blood cells and increased reticulocyte Serum lactate dehydrogenase and bilirubin levels elevated

What is the most likely diagnosis? Aplastic anaemia Autoimmune thrombocytopenia

Thrombotic thrombocytopenic purpura Myelodysplasia Acute myeloblastic leukaemia

Your answer

Thrombotic thrombocytopenic purpura (TTP) is caused by either a congenital deficiency of, or an acquired inhibitor to, a serum metalloprotease which is responsible for cleaving unusually large multimers of von Willibrands factor. Left uncleaved, the large von Willibrands factor multimers induce TTP by causing the agglutination of circulating platelets. Most episodes of TTP occur without an obvious inciting event. However, TTP has been associated with infection, pregnancy, transplantation, AIDS, and drugs such as mitomycin C, ticlopidine, ciclosporin, and tacrolimus. TTP occurs mainly in adults and more commonly involves the central nervous system. The onset is often sudden with fever, purpura, petechiae, anaemia, thrombocytopenia, and neurological abnormalities. The neurological sequelae include convulsions, coma, paralysis, delirium, and stroke. The peripheral smear demonstrates schistocytes, thrombocytopenia, and a reticulocytosis. During acute episodes front-line therapy includes steroids and daily plasma exchange with fresh-frozen plasma or virally inactivated solvent-detergent plasma (SD plasma).

256. A 45-year-old woman who is currently 4 weeks into a course of postoperative radiotherapy for locally advanced cervical carcinoma is admitted with abdominal pain and diarrhoea. What is the most likely cause of the clinical picture? Complication of surgery Radiation enteritis Your answer Bowel obstruction Local malignant infiltration Bowel perforation Radiation enteritis is a radiation-induced inflammation of the bowel and is a function of the volume of bowel irradiated and the radiation dose. The acute type occurs during therapy and manifests as ileitis, colitis or proctitis with abdominal pain and diarrhoea. Usually conservative management with stool softeners suffices. Late radiation enteritis occurs 624 months after therapy and

may present with colicky abdominal pain and intermittent diarrhoea. The clinical picture is unlikely to be due to a surgical complication given the time frame, and is less suggestive of bowel obstruction or perforation. Local malignant infiltration to the bowel is most likely to present with obstruction.