Fever For Medical Finals (based On Newcastle University Learning Outcomes)

Hospital based practice – Fever. • •

Most fevers are due to viral illness and are self limiting. Pyrexia of unknown origin (PUO) is o Persistent and unexplained fever lasting more than 3 weeks. o Still unexplained after a week of investigations in hospital.

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Causes. o Infections.  20 – 40% o Connective tissue disorders.  20% o Malignancy  10 – 20%  Normally lymphoma  Sometimes solid tumours, particularly: • Renal cell CA • Gastrointestinal CA. o Unknown.  20% o Drugs.  Eg. phenytoin  Rare cause.

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History in patient with PUO. o Be thorough to fully inform diagnosis. o Particularly make note of:  Foreign travel. • Incubation period of many tropical diseases means that fever often starts after returning home.  Contact with animals • Looking for zoonoses • Leptospirosis • Q fever • Salmonellosis • Cat – scrath fever • Psittacoses and ornathoses • Toxoplasmosis • Hydatid disease • Toxocariasis • Meningitis • Anthrax.  Contact with infected people  Sexual history.  History of any IV drug use.  Alcohol intake  Previous illnesses. • Recent infections • History of immunocompromise  Previous surgery or accidents  Rashes

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Diarrhoea Full drugs history. • Including over – the – counter drugs. Immunization history Associated symptoms. • Sweats • Weight loss • Itching. Lumps Familial disorders. • Eg. Familial Mediterranean fever.

o All symptoms should be explored thoroughly. o •

Diagnosis often made by repeatedly going over history to find additional or missed clues.

Examination Head: Temporal artery tenderness Ears: Otitis media

Eyes: Conjunctival petechina

Mouth: Dental/ pharyngeal sepsis

Lymph nodes

Lungs: Respiratory exam

Spleen: Splenomegaly

Heart: Murmurs, stigmata of endocarditis Liver: Hepatomegaly, hepatic bruit

Hands: Nail infarcts Kidneys: Renal cell carcinoma

PR & PV: Masses & infections

Joints: Active infection or inflammation.

Legs: DVT

Skin: Rashes, Petechiae, infarctions (vasculitis)

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Temperature and pulse should be recorded every 4 hours.

Investigations. o Directed by history and examination findings. o Often a full screen is appropriate to try and elicit clues. o

FBC.

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Neutrophil leucocytosis • Bacterial infection • Myeloproliferative disorders • Malignancy. o Eg. Liver metasteses. • Collogen vascular diseases. Leucopaenia.

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• Viral infections • Lymphoma • SLE • Brucellosis • Disseminated TB • Drugs Monocytosis. • Subacute bacterial endocarditis • Inflammatory Bowel Disease • Hodgkin’s disease • Brucellosis • TB Abnormal mononuclear cells. • EBV • CMV • Toxoplasmosis Eosinophilia • Parasitic disease. o Trichiasis o Hydatid disease • Malignancy. o Especially Hodgkin’s disease • Drug reactions • Pulmonary eosinophilia.

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Inflammatory markers.  High ESR suggests. • Multiple myeloma • SLE • Temporal arteritis • Polymyalgia rheumatica • Still’s disease • Rheumatic fever • Lymphoma • Subacute bacterial endocarditis.  CRP is an acute phase reacant. • Short half life. • Varies much faster than ESR. • Good for measuring disease progression.

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U&Es.  Renal impairment  Hyponatraemia. • Often due topneumonia in the feverish patient.

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LFTs.  

Abnormal results may lead to more detailed investigations of the liver. As well as liver disease, other things that may raise ALP include. • Metabolic bone disease • Hodgkin’s disease

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Still’s disease Polymyalgia rheumatica. Bony Metts.

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Bacteriology & Serology.  Microscope and culture every available site.  Urine. • Bacteria • Haematuria. o Subacute bacterial endocarditis o Hypernephroma  Blood cultures. • Several samples are needed from different veins at different times of the day.  Faeces. • Microscopy for. o Ova o Cysts o Parasites.  Vaginal and cervical swabs.  Urethral swabs. • Particularly in men.  Sputum. • Microscopy and culture  Throat swab • Cultures.

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Chest X – ray.  May reveal. • TB • Subphrenic abscesses • Bilateral hilar lymphadenopathy. o Suggests sarcoidosis.

Further investigations. o Directed by history, examination and previous investigations. o If no clues are apparent, it may be appropriate to proceed blindly.  Immunoglobulins and protein electrophoresis  Antibodies. • Rheumatoid factor • Autoantibodies • Anti – streptolysin titre • Tumour markers  Mantoux test. • For TB

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 Bone marrow aspiration  Lumbar puncture. Non – essential drugs should be stopped on admission.  May be necessary to withhold drugs one at a time for 48 hours each.

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If there is still no clue as to the cause, the system most likely should be investigated with things such as.  Echocardiogram  CT chest and bronchoscopy  CT scan of abdomen  Braium studies  Liver biopsy  Radio – labelled white cell scan  Exploratory laproscopy. • Possibly  Exploratory laparotomy. • Rarely.

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Very rare causes should be considered if not already investigated  Hyperthyroidism  Phaeochromocytoma  Familial Mediterranean fever.

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If all else fails, start blind therapy.  Antituberculosis drugs.  Chemotherapy  IV antibiotics for endocarditis  Steroids for vasculitides.

Facticious fever. o Deliberate manipulation of the thermometer. o Classically occurs in young women. o Diagnosis suspected if  Other causes have been excluded.  No evidence of chronic illness  No tachycardia when pyrexial  Patient looks innapropraitely well for the degree of fever.

Connective tissue disorders. Systemic Lupus Erythematosus • • • •

Multisystem, autoimmune connective tissue disorder. UK Prevalence of 1 in 1000 o Nine times commoner in women o Commoner in blacks than in Caucasians. Peak onset is 20 – 40 years. Aeitology o Unknown o Probably multifactorail o Predisposing factors.  Family history  Drugs. • Eg. hydralazine  UV light  Viral infection  Immunological mechanisms.

Clinical features • Commonest early features are: o Fever o Arthralgia o Malaise o Tiredness o Weight loss •

Other systems which may become involved include. o Musculoskeletal.  Invovled in > 90% of cases.  Arthralgia that is clinically similar to RA. • Examination often normal  May be: • Myalgia • Myositis

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Skin.   

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CNS.  

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Rarely there can be deforming arthropathy. • Jaccoud’s arthropathy. • Due to capsule laxity. Aseptic necrosis of knee or hip may occur. • Rare

Involved in about 80% of cases. Classically there is a butterfly rash over the cheeks and bridge of nose. Other skin features include: • Photosensitivity • Alopecia • Livedo reticularis • Raynaud’s phenomenon • Nail – fold infarcts • Purpura • Urticaria • Oral ulceration. Benign form of SLE exists. • Known as Discoid Lupus • Skin symptoms only. • Discoid erythematoud plaques on face, progressing to: o Scarring o Pigmentation • May develop into SLE.

Involved in 60% of cases. Can cause psychiatric disturbances. • Depression. o Commonly • Psychosis o Occasionally Other features include: • Seizures • Strokes • Cerebral nerve lesions • Aseptic meningitis • Peripheral neuropathies. Effects are due to: • Arteritis and ischemia • Immune complex deposition.

Respiratory system.  Involved in about 50% of cases.  Pulmonary manifestations include; • Pleurisy with pleural effusions • Pneumonia with atelectasis • Restrictive defects. o “shrinking lung syndrome”

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Diffuse reticular – nodular shadowing on CXR.

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Renal system.  Involved in about 50% of cases.  Renal involvement is associated with a poor prognosis  Haematuria and prontienuria are common.  May be minimal change and membranous or proliferative glomerulonephritis.  Clinically, patient may present with: • Nephrotic syndrome • Nephritic syndrome • Hypertension • Chronic renal failure.

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Cardiovascular system.  Involved in about 40% of cases.  There may be: • Pericarditis, with pericardial effuions • Myocarditis, leading to heart failure • Haemolytic anaemia • Leucopaenia • Thrombocytopaenia • Generalised lymphadenopathy • Hepatosplenomegaly • Arterial and venous thrombosis. o May be part of the antiphospholipid syndrome.

Drug induced lupus. o May occur with hydralazie in patients who, genetically, are “slow acetylators”. o May also occur with:  Procainamide  Isoiazid  Chlorpromazine  Anticonvulsants. o Remits when drug is stopped. o Renal and CVS involvement is rare.

Investigations • ESR. o Raised. • CRP. o Usually normal. o If raised, suspect additional pathology, such as infection. • FBC may show. o Anaemia o Leucopaenia o Thrombocytopaenia • Antinuclear antibody o Positive in almost all cases. o Classically.75% sensitive  Homologous staining  Anti – dsDNA

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 Specific for SLE o Titre rises in active disease. Serum complement levels. o Reduced in active disease o Immunoglobulins raised Renal biopsy. o If there is kidney involvement. o Shows characteristic histological changes.

Management. • Mild disease can be managed with o Aspirin or NSAIDs for joint pain. o Anaemia can be treated with transfusions o Sun block can protect from photosensitivity. o For acute exacerbations.  High dose steroids.  Gradually taper off in response to symptoms, signs and ESR changes. • Immunosuppression reserved for. o Renal involvement o CNS involvement o Drug used have a steroid sparing effect.  Azathioprine  Chlorambucil  Cyclophosphamide. • If patients are resistant to NSAIDs, or skin problems predominate, consider hydroxychloroquine. o Normally used as an anti – malarial o Can cause retinal degeneration.  Formally check vision at regular intervals. Antiphospholipid syndrome • Manifests as increased risk of: o Arteiral thrombi o Venous thrombi o Miscarriage. • Associated with antibodies against phospholidpid, known as. o Anticardiolipin antibody

Lupus anticoagulant  In vitro causes prolonged APPT time.  In vivo is pro – coagulant. First described in SLE patients, but can be primary. o Ie. in the absence of SLE Management. o Specialist directed. o Often requires high – dose anticoagulants. o

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Polymyalgia rheumatica. • Syndrome characterised by proximal muscle pain & stuffness. • Incidence increases with age. o Prevelence of about 2% in patients over 60 years. o Two to three times more common in women than men o More common in Northern eurpoeans than Southern Europeans. o Rare in non – whites. • Closely associated with giant cell arteritis, but either condition can occur without the other. •

Clinical features. o Discriminating features include.  Bilateral shoulder pain, with or without stiffness.  Bilateral upper arm tenderness  Illness of less than 2 weeks duration  Morning stiffness lasting for > 1 hours  Depression, with or without weight loss  Age greater than 65 years  Initial ESR of at least 40 mm/hour. o o

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Distribution may be symemetrical and systemic. Common systemic features include  Sweating  Malaise True weakness does not occur.  Power and range of movements may be limited by pain.

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Differential diagnoses o Late onset RA o Musculoskeletal  OA  Rotator cuff disease  Non – specific back pain  Trochantic bursitis. o Other neuromuscular conditions.  Polymyositis  Proximal myopathy. o Hypothyroidism.  Common cause of myalgia and malaise.

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Investigations. o ESR.  Usually over 40 mm/hour.  Very high values can occur. o Acute phase proteins.  Eg. CRP  Increased o LFTs.  ALP raised in about 30% of patients. o FBC.  Mild normochromic, normocytic anaemia is common.  Platelets tend to be increased. o Temporal artery biopsy is rarely helpful. o Tests to exclude differential diagnoses.  Rheumatoid factor  TFTs  Creatinine Kinase • If muscle weakness suspected.  Autoantibodies. • If connective tissue diseases suspected.

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Management. o Corticosteroids.

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Prednisolone 15 – 20 mg PO OD • Continue for 1 month. • Gradually reduce to 10 mg/day. • Gradually discontinue over proceeding few months. • Some patients require permanent steroids. o Acceptable to leave a patient on 2 – 3 mg/day prednisolone for life. 80% of symptoms will improve within a few days. ESR will fall within 2 – 3 weeks. CRP returns to normal within 1 week, No indication for prophylaxic high dose steroids in absence of giant cell arteritis. • Warn patients to watch out for any signs of visual disturbance or headache.

About half of patients manage to be steroid free by 2 years. Management should be based on clinical response.  However, a rise in ESR should prompt a review. Relapses are common within the first year.  Associated with reduction in steroid dose.  Incidence of relapse falls after 1 year. Normally necessary to give prophylaxis against osteoporosis. Addition of NSAID to cover ache and stiffness may be of use. If patients are developing side effects of steroid use, consider a steroid sparing immunosuppressant.  Eg. Azothioprine.  Requires expert supervision.

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Prognosis. o Good, providing steroid dose is not excessive. o Most patients can be reassured that treatment can normally be discontinued after 2 – 4 years, with a low rate of recurrence. Systemic Sclerosi/ Scleroderma. • Multisystem disorder. • Mainly affects middle aged women

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Presents with Raynaud’s phenomenon in more than 75% of cases. There are abnormalities of both humoral and cellular immunological response. Early in the disease. o Skin becomes oedematous o Blood vessels become inflamed and thickened. o Increase in collagen o Progressive fibrosis of viscera.

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Aeitiology. o Unknown. o Familial cases occur at higher frequency with:  HLA – B8  HLA – DR3

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Clinical features. o Generally.

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Malaise Lassitude Fever Weight loss Thickening and hardening of the skin. • Associated with increasing collagen content Classically. • Beaked nose • Facial telangiectasia • Small mouth. o Due to skin tightening around the mouth. • Smooth and waxy skin • Skin becomes atrophic, with increased or decreased pigmentation. • Sclerodactyly o Causes “Sausage shaped” fingers. • Subcutaneous calcification. Morphoea or localised scleroderma is a relatively benign condition. • Only affects the skin. • Especially found on trunk and limbs. • Plaques evolve to produce waxy, thickened skin and induration. o May enlarge. o New plaques may appear over time. • Resolution is associated with hyperpigmentation. • Only rarely progressed to full blown scleroderma.

GI system.  Oesophageal involvement is very common. • Delayed peristalsis • Dilation • Stricture formation  In about 50% of patients, leads to: • Dysphagia • Heartburn.  Dilatation and atony of small bowel may lead to: • Bacterial overgrowth • Malabsorption • Steatorrhoea Respiratory system.  Main problem is interstitial fibrosis. • Predominantly affects lower lobes.

• Can be diffuse. May cause restrictive lung deficit. May progress to respiratory failure. May be: • Aspiration pneumonia • Pulmonary hypertension. Musculoskeletal system.  Problems due to tendon fibrosis. • Polyarthralgia • Flexion deformities  Myopathy and polymyositis may occur. Cardiovascular system.  Myocardial fibrosis may can. • Arrythmias • Conduction defects.  Pericardial effusions may occur.  Right heart failure may occur. • Secondary to lung disease. Renal system.  Due to obliterative endarteritis of renal vessels. • Progressive renal failure • Hypertension  Can be fatal. Eyes.   

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Sjögren’s syndrome may occur.

CREST syndrome. • Form of systemic sclerosis that involves. o Calcinosis of subcutaneous tissues. o Raynaud’s phenomenon o oEsophageal dysmotility o Sclerodactyly o Telangiectasia • Prognosis tends to be better than systemic sclerosis • Associated with anti – centomere antibodies. •

Investigations. o Anti – nuclear antibodies.

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 Present in 80% of patients.  Nucleolar pattern in scleroderma  Rheumatoid factor is positive in 30% ESR.  Often raised FBC.  Normochromic normocytic anaemia  Haemolytic anaemia Hand X – ray.  May show calcinosis Barium swallow/ oesophageal manometry.  Demonstrates motility problems.

Management. o Symptomatic treatment.  Raynaud’s. • Nifedipine • Electrically heated gloves.  Heartburn • Antacids

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H2 – receptor antagonists • PPI Joint pain. • Physiotherapy • NSAIDs Hypertensive renal crises are emergencies. • Treat aggressively o ACE inhibitors o Supportive critical care

Polymyositis and Dermatomyositis. • Polymyositis is a disorder of muscle • Unknown aeitiology, but suggestions include: o Immunological factors o Viral factors. • Pathologically there is. o Necrosis of muscle fibres o Regeneration and inflammation. • When rash is also present, known as dermatomyositis.

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Occurs at any age. o Peak onset at around 50 years. o Women affected twice as often as men o About 10% associated with an underlying malignancy, normally.  Bronchus  Breats  Stomach  Ovary o Malignancy associated dermatomyositis is:  More common in men  Increased incidence with age.

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Clinical features. o Onset.  Acute or chronic.  Progressive. o Muscle weakness.  Can affect oesophagus, leading to dysphagia.  Can affect respiratory muscles, which may need ventilatory support. o Proximal muscle wasting. o Muscle pain and tenderness.  About 50% of patients. o Joint pain and stiffness.  About 50% of patients. o Fibrosis.  Flexion deformities of the limbs. o Skin involvement.  Purple “heliotrope” around eyes. • Sometimes affects the whole face.  Violaceous, oedematous lesions over knuckles. • Gottron’s papules.  Telangiectasia  Nail – fold infacts. o Raynaud’s phenomenon o Lung fibrosis o Sjögren’s syndrome

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Investigations. o Creatinine kinase.  Raised  Can be used to monitor course of disease.  Raised CKMB or troponin may be found. • Rarely linked to myocarditis.

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Characteristic electromyographic changes.  Fibrillation potentials Muscle biopsy.  Necrosis of muscle fibrosis.  Swelling and disruption of muscle cells  Fibrosis  Thickening of blood vessels  Inflammatory changes. ESR.  Usually raised.  May be normochromic normocytic anaemia  Antinuclear antibodies may be positive  Jo – 1 antibodies may be positive. Investigations for underlying malignancy.

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Management. o High dose steroids.in the acute phase.  Can be gradually tailed off. o Immunosuppressive drugs may be required if there is poor response to steroids. Eg.  Methotrexate.  Azothioprine. o Physiotherapy may help to rebuld muscle power.

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Prognosis. o Adults do better than children.  Unless there is an underlying malignancy o May be progressive. o May wax and wane. o Death usually occurs from:  Respiratory failure  Cardiac failure.

Sjögren’s syndrome. • Chronic autoimmune disease causing destruction of epithelial exocrine glands. • Can be a primary condition, or secondary to another connective tissue disorder.

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o Eg. RA. Association with HLA – B8 and HLA – DR3. Other exocrine glands may b e involved.

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Results in: o o o o o o o o o o

Dry eyes  Keratoconjunctivitis sicca. Dry mouth  Xerostomia Arthrlagia Polyarthritis Raynaud’s phenomenon Renal involvement.  In 20% of patients. Fibrotic lung disease Parotid gland enlargement.  In 30% of cases Vasculitis. Increased incidence of lymphoma.

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There is an association with organ specific autoimmune diseases. o Thyroid disease o Vitiligo o Pernicious anaemia o Primary biliary cirrhosis o Chronic active hepatitis.

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Pathologically, there are lymphocytic and plasma cell infiltrates of secretory glands.

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Investigations. o Autoantibodies.  High anti – La  High anti – Ro o Immunoglobulins.  Raised. o Schirmer’s test.  Allows quantification of conjunctival dryness.  Filter paper is put under lower eyelid.  The distance along the paper than tears are absorbed is measured.  Should be more than 10 mm in 5 iminutes.

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Management. o Mainstay is conservative measures.  Protect the eye  Relieve oral symptoms. o Attempts to modify progression have had limited success.  Hydroxycloroquin is most promising treatment based on trials.

Mixed connective tissue disease. • Term used when signs and symptoms don’t neatly fit into one of the well – defined conditions. • Affects women more than men. • Tends to present in young adults. • ANA is often positive in a speckled pattern. • High titres to extractable nuclear antigens. o Eg. ribonucleoprotien. • Condition may respond to steroids. Polyarteritis nodosa. • Necrotising vasculitis. • Causes aneurysms of medium – sized arteries. • Rare in the UK. o More common in women than men o Peak incidence is 20 – 50 years. o Association with Hep B surface antigen. •

Clinical features. o General.  Fever  Malaise  Weight loss  Myalgia o Renal.  Main cause of death.  Hypertension  Protienuria  Acute nephritic syndrome  Nephritic syndrome  Renal failure o Cardiac.  Second commonest cause of death.  Angina  MI  Pericarditis o Others.  Mononeuritis multiplex  Pulmonary infiltrates  Late onset asthma  Arthralgia  Visceral infarctions.

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Investigations. o FBC. 

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In 30% of cases, there is a: • Normochromic normocytic anaemia • Leucocytosis • Eosinophila ESR & CRP.  Usually raised 10% pANCA positive Biopsy.  Affected organs may show • Fibrinodi necrosis • Cellular infiltration of arteries. Angiography.  Microaneurysms in affected viscera.

Management. o Symptomatic  Steroids  Immunosuppressives. o Course of disease may progress radily or slowly.  5 – year survival is 70% if properly treated.

Immunological tests in connective tissue disease. Associated disorder SLE RA Sjögren’s syndrome MCTD Systemic sclerosis Anti double – stranded DNA SLE Rheumatoid factor RA SLE MCTD Sjögren’s syndrome Anti – Ro Sjögren’s syndrome Anti – La Sjögren’s syndrome Anti – cardionolipin Antiphospholipid syndrome Lupus anticoagulant Antiphospholipid syndrome Anti – ribonucleoprotein MCTD Jo – 1 antibodies Polymyositis Dermatomyositis Peripheral Antineutrophil cytoplasmic antibodies Polyarteritis nodosa (pANCA) Classical Antineutrophil cytoplasmic antibodies Wegener’s granulomatosis (cANCA) Antiacetylcholine receptor antibodies Myasthenia graivs Anti – GM1 Multifocal motor neuropathy Guillain – Barre syndrome Anti – GAD Stiff – man syndrome. Test Antinuclear factor (ANA)

Malignancies and fever. Leukaemias. • Group of conditions characteristed by malignant proliferation of leucocytes in bone marrow. • Cells spill out into blood stream, and may infiltrate other organs. • In the acute forms. o Proliferation of myeloid and lymphoid precursors, which do not mature.  Myeloblasts  Lymphoblasts o Clinical course is very aggressive and fast without treatment. • In the acute forms. o Proliferation of mature cells.  Neutrophils  Leucocytes. o Slower and more indolent progression. • All leukaemias should be managed by specialists. o Chemotherapy is rapidly evolving, so most patients are in a clinical trial. Acute lymphoblastic leukaemia. • Most common malignancy in children < 15 years old. • Aeitiology unknown, but probably multifactorial. • Risk factors include: o Family history  Concordance in twins o Down’s syndrome o Ataxic telangiectasia. •

Pathology. o Lymphoblasts accumulate in bone marrow.  Causes bone marrow failure o Lymphoblasts enter and circulate in the blood stream, infiltrating.  Lymph nodes  Liver  Spleen  Kidneys  Testicles  CNS o Pathology classified using the FAB classification.  L1. • Small cells • Homogenous • Small or absent nucleoli • Scanty cytoplasm  L2. • Large cells • Heterogenous • Occasional large nucleoli

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More cytoplasm

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Large cells Homogenous Prominent nucleoli Abundant cytoplasm

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Can also be catagorised according to phenotype.  B Cell  T Cell  Common  Null

Presentation. o Two ranges of peak incidence  < 5 years  > 65 years o Short history.  Due to aggressiveness of disease.  Days – weeks. o Symptoms are due to rapidly expanding tumour cells in bone marrow.  Bone pain  Bone marrow failure. • RBC failure o Anaemia  Lethargy  Dyspnoea  Pallor • WBC failure. o Neutopaenia.  Recurrent infections  Fever • Platelet failure. o Thrombocytopaenia  Bleeding  Bruising  Purpura  Fever  Lymphadenopathy  Hepatosplenomegaly  Neurological signs.

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Investigations. o FBC.   

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Normochromic normocytic anaemia. Low reticulocyte count. Raised WCC. • Due to lyumphoblasts  Neurtopaenia  Thrombocytopaenia. Bone marrow biopsy.  Hypercellular  Dominated by lymphoblasts. • Usually > 50% Cytogenetic abnormalities.  Hyperdiploidy  Philadelphia chromosome. Raised urate Raised LDH CXR.  Mediastinal mass in T – Cell disease. Lumbar puncture.  Lymphoblasts  Increased pressure  Increased protein.

Treatment. o All chemotherapy requires cocurrent supportative measures. o Ensure good hydration o Prophylactic anti – infection agents

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Antibiotics  Antiviral drugs  Antifungal drugs Protection of sites of common infiltration.  CNS prophylaxis. • Cranial irradiation • Intrathecal methotrexate.  Testes. • No specific protection. • Often a site of relapse. • Give radiotherapy if relapse occurs Septic surveillance.

Blood products for pancytopaenia Bone marrow colony – stimulating factor  Eg. Granulocyte colony – stimulating factor. o Monitor coagulation o Allopurinol prophylaxis.  For increased puring metabolism  Gout  Tumour lysis syndrome. o Cytotoxic chemotherapy.  Induction of remission  Consolidation  Maintainance o Bone marrow transplant.  Allogenic or autologous.  Can be curative.. Prognosis. o Children.  60% survival at 5 - years o Adults.  30% survival at 5 – years. o Poor prognostic indicators include.  Increasing age  Increasing white cell count  Null cell or T cell phenotype  Male sex  Presence of Philadelphia chromosome. o o

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Acute myeloid leukaemia & Acute non – lymphatic leukaemia. • Account for 20% of all leukaemias. o 85% of acute leukaemia. •

Aetiology. o Most cases aqrrive with no clear cause. o Some risk factors include.  Ionizing radiation. • Survivors of Hiroshima  Benzene exposure. • Leather workers • Rubber workers  Previous chemotherapy. • Alkylating agents.  Predisposing diseases. • Myeloproliferative disorders • Multiple myeloma • Aplastic anaemia • Myelodysplasia. o Can transform into acute leukaemia o This is often the cause of death.

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Pathology. o Accumulation of immature haemopoetic blast cells in bone marrow.

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 Can cause bone marrow failure Blasts can infiltrate.  Gums  Liver  Spleen  Skin  CNS. • Less common. Traditionally classified as.  M1: Undifferentiated myeloblastic.  M2: Myeloblastic. • Most common form.  M3: Promyelocytic. • Often causes death via DIC  M4: Myelomonocytic. • Infiltration of: o Gums o Skin o Meninges  M5: Monocytic. • Infiltration of: o Gums o Skin o Meninges • Lymphadenopathy may occur.  M6: Erythroleukaemia. • Particularly in older patients.  M7: Megakaryocytic. As with most haematological malignancies, immunohistochemistry and cytogenetics are replacing morphology in classification and prognosis.

Presentation. o More frequent in increasing age.  Median age at presentation is 50 years. o Symptoms are due to skin infections or infiltration by leukaemic cells.  Lethargy  Dyspnoea  Pallor  Recurrent infections  Fever  Bleeding  Bruising  Purpura. o Predominant symptoms may be:  Bone pain  Joint pain  Malaise o Hepatomegaly is common o Moderate splenomegaly o Lymphadenopathy is rare.  Except in Monocytic form

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Circulating white cell count is very high.  Leucocostasis may occur.  May result in hyperviscosity symptoms.

Investigations. o FBC.      

Normochromic normocytic anaemia Low reticulocytes. Raised WCC Neutropaenia Thrombocytopaenia Blasts containing Auer rods. • Diagnostic of AML o Bone marrow biopsy.  Hypercellular bone marrow  Normal marrow replaced with blast cells o Cytogenetic abnormalities.  Present in about 50% of cases. o Other biochemisty  Raised Urate  Raised LDH  Raised calcium  Raised phosphate. Treatment. o Should be managed in a specialised unit. o Supportive care, as for all leukaemias. o Intensive cytotoxic chemotherapy. o Bone marrow transplant.  In some patients. o Immunotherapy.

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Growing area Eg. Gemtuzumab • An immunotoxin • Tends to work best in cancers that express CD33.

Prognosis. o In most patients, complete cure should be the aim.  Most patients enter remission  Further therapy produces total cure in 25%. o Poor prognostic factors include.  Increasing age  Very high WCC  Secondary leukaemia. • Eg. Previous myelodysplasia  Certain cytogenetic abnormalities • Monosomy 5 is associated with a poor outcome.  Presence of DIC o 8:21 translocation is associated with a good outcome

Myeloproliferative disorders.

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Concept was introduced in 1951 to tie together what had previously been thought to be separate conditions. o Originally thought to be arbitrary. o Now known to have good molecular basis. o Neoplastic proliferation of haemopoetic cells. o Normally from one cell lineage, but over production of all cell lines. o Fibrosis is a secondary event. Myeloproliferative disorders are: o Primary Proliferative Polycythaemia (PPP)  Polycythaemia vera (PV) o Primary thrombocythaemia (PT)  Essential thrombocythaemia (ET) o Myelofibrosis (MF)  Agnogenic myeloid metaplasia  JAK2 mutations are present in over 90%, so now is the first line test for MF o Chronic myeloid leukaemia (CML)  Chronic granulocytic leukaemia  Chronic myelogenous leukaemia

Chronic lymphoblastic leukaemia. • Most common leukaemia in the developed world. o 30% of all leukaemias • Increasing incidence with age. o 90% of cases in 50 years • More common in males. • Aeitiology is unknown. •

Pathology. o Proliferation of small lymphocytes in bone marrow, blood and lymphoid tissues. o Cells are morphologically mature, but functionally abnormal o 95 – 98% of cases are B – Cell phenotypes.  Remainder are T – Cells.

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Presentation. o Often asymptomatic.  Found as incidental finding when doing FBC for other reasons. o Malaise o Weight loss o Night sweats o Recurrent infections o Bleeding o Lethargy o Lymphadenopathy.

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 In 60% of cases Hepatosplenomegaly.

Investigations. o Monoclonal lymphocytosis with “smear” or “smudge” cells seen on film. o Anaemia may be due to.  Marrow infiltration  Autoimmune haemolysis. (Coomb’s positive). o Thrombocytopaenia may be due to:  Marrow infiltration  Autoimmune destruction o Bone marrow shows accumulation of mature lymphocytes. o Cytogenetic and immunological analysis will offer diagnostic and prognostic information o Hypogammaglobulinaemia in 50%

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Treatment. o Watchful waiting is first line.  Only if mild, asymptomatic disease o As molecular nature is further explored, more tailored therapies will become available. o Chlorambucil.  Oral alkylating agent.  Well tolerated in older patients. o Fludarabine.  Intravenous use is preferred agent.  Antimetabolite drug. o Prednisolone.  Good response in autoimmune phenomena. o Radiotherapy.  May be beneficial in symptomatic, localised disease. o Splenectomy.  Sometimes used in refractory hypersplenism. Chronic Myeloid Leukaemia. • Approx 1:100,000 incidence o About 600 new cases per year in the UK • Many asymptomatic o Tiredness, malaise o Splenomegaly, (bruising)

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Normally found incidentally when a blood count is performed. o WBC > 100 is almost always leukaemia. o When FBC comes back (or at the same time if CML suspected clinically), next test is a blood film to look for dark neoplastic neutrophils.

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Natural history is: o Chronic phase, lasting 2 – 6 years. o Acute phase.  Median survival is 3 months.  66% convert to acute myeloid leukaemia.  33% convert to acute lymphoblastic leukaemia.

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95% of patients have the “Philadelphia chromosome”. o Translocation of BCR gene from chromosome 22 to influence ABL gene on chromosome 9. o ABL produces a tyrosine kinase called p210 RT – PCR for BCR – ABL is 97.5% sensitive. The lower the level of Ph. Chromosome in the bone marrow, the better the prognosis.

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Diagnosis • Diagnosis is based on: o FBC, looking for high WBC. o Blood film, looking for neoplastic neutrophils. o RT – PCR, looking for BCR – ABL. o Cytogenetics.  Including FISH, looking for BCR – ABL.

Treatment. • Hydroxyurea. o Ribonuclease reductase inhibitor. o Basically disrupts RNA synthesis, so reduces formation of neoplastic cells. o Also used as an antiretroviral. o Only gives temporary relief. • Signal transduction inhibitors o Imatinib (Glivec)  First line therapy.

Possibly a cure, trials off therapy currently on going. Potent inhibition of Abl-K, c-kit and PDGF-R • Blocks phosphorylation of the kinase by ATP.  Salts are soluble in water, so orally bioavailable  Not mutagenic o Dasatinib (Sprycel) o Nilotinib (Tasigna) o Others: bosutinib, homoharringtonine, VX680 etc. Stem cell transplantation o Allograft  

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Only ‘known cure’  Sibling or unrelated ( so called ‘MUD’)  Autograft Alpha-interferon o Not really used any more. Novel therapies o Abl TK inhibitors  Imatinib (Novartis)  Nilotinib (AMN107, Novartis) o Dual Abl/Src inhibitors  Dasatinib (BMS 254825, Bristol-Myers Squibb)  SKI-606 (Wyeth Ayerst)  AP23464 (Ariad Pharmaceuticals)  AZD0530 (Astra-Zeneca) o Dual Abl/Lyn inhibitor  NS-168 (Nippon-Shinyaku) o Non-ATP-binding inhibitors active against T315I  ON 012380 (Onconova)  VX-680 (Aurora kinase inhibitor) à Merck 0467  SGX-70430 (SGX Pharma)  GNF-2 (Genomics Novartis Foundation)

Ethics of treatment. • Anti – CML drugs are hugely expensive. • Post code lottery as to whether your health trust will allow prescription of the drugs. • Public pressure can force trusts to allow prescription of the drug, even if it is not cost effective. •

Bone marrow transplants are the only definite cure we have.

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However, they have a very high mortality rate. o Related donor has 20% mortality rate.  50-60% 5 year disease free survival o Matched Unrelated Donor (MUD) has 30% mortality rate.  35-40% 5yr DFS o Risk to donor mainly from anaesthetic, and new ways are being developed to extract the marrow under local anaesthetic. Comparing Imatinib and Transplant: o Imatinib:  Unlikely to die from therapy  Severe side effects unlikely  Pretty impressive therapy  Still early days  Unknown yet if it is curative. o Transplant:  You might die (20%)  You may live but have severe complications  You could get through the transplant but then relapse  Reasonable chance of being cured (60%) Relapse can now be treated with donor lymphocyte infusions (DLI)

Monitoring post – transplant. • Blood count • Bone marrow chromosome test (cytogenetics) o Bone marrow o FISH test • Blood PCR test o Can pick up maybe 1 in 100,000 to 1 in million leukaemic cells

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Mutation analysis? Cytogenetic response is degree of reduction in abnormal chromosomes. o In this case, the Ph. Chromosome. o Test performed on a sample of bone marrow every 6 months or so o If you have a ‘major’ response you probably live longer  Major response is > 35% Ph. chromosomes in the bone marrow. o If you have a ‘complete’ response you probably live even longer  Complete response is 0% Ph. chromosomes in the bone marrow. o If you sustain a complete response for several years it COULD mean that you’re cured.

Muliple myeloma. • Principle features are: o Skeletal abnormalities

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Production of monoclonal protein. Accumulation of plasma cells in the bone marrow.

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Incidence is 5 in 100 000 o 1% of all malignancies. o 10 – 15% of haematological malignancies.

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Pathology. o Neoplastic proliferation of a single clone of a plasma cell.  Plasma cell is a terminally differentiated B – Cell.  Can form tumourous plasmacytoma. o Malignant cell secrete a monoclonal immunoglobulin on light chain. o Normal immunoglobulin production suppressed. o Osteoclast activity i9s increased.  Results in bone reabsorption. o Systemic amyloidosis affects 10% of cases.

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Presentation. o Disease mainly of the elderly.  Peak incidence in 60s. o Bone pain.

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Due to osteolytic lesions.  Pathological fractures affect 60% of cases. Recurrent infections.  Impaired antibody response.  Hypogammaglobulinaemia Symptoms of anaemia may be present.  Examination usually reveals pallor. Amyloidosis, causing.  Splenomegaly.  Peripheral neuropathy. Compression by tumour or vertebral collapse.  Spinal cord compression  Radiculopathy. Hyperviscosity syndrome.  Polymerisation of monoclonal antibody.

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Investigations. o Normochromic normocytic anaemia o Blood film.  Rouleaux (clumping of RBC)  Background immunoglobulin staining. o Riased ESR o Serum protein electrophoresis.  Monoclonal paraprotien. • 60% is IgG • 25% is IgA • 15% have Bence – Jones protein in urine. o Skeletal survey.  Generalised osteopaenia.  “Punched out” osteolytic lesions. • “Pepper – pot” skull.  Pathologicla fractures. o Radionuclide bone scan is not helpful.  Only detects osteoblast activity. o Bone marrow aspirate.  Over 10% are plasma cells  Cytogenetic analysis is increasing helpful for prognosis. o Calicum.  High, due to osteoclastic activity.  ALP usually normal. o Raised urate. o Renal failure.  Hypercalcaemia  Hyperuricaemia  Preciptated light chains  Amyloidosis  NSAIDS prescribed for bone pain. o Raised β2 – microglobulin.

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Treatment. o Watchful waiting should only be used in uncomplicated asymptomatic disease. o Supportative treatment.  Antibiotics  Blood products  Analgesia  Correction fo hypercalcaemia. o Chemotherapy.  Vincristine  Adriamycin  Dexamethasone. o Drugs to reduce tumour burden and symptoms.  Melphalan  Prednisolone. o High doses chemotherapy with autologous stem cell rescue.  Durable remission  Not permanent cure. o Allogeneic transplantation.  May be curable  High mortality  Option for younger patients. • Need to discuss risks. o Radiotherapy.  May be useful in localised disease causing bony pain. o In certain cases, specialists may use:  Interferon  Thalidomide  Other immunotherapy.

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Prognosis o Median survival is 3 years. o Poor prognostic factors include:

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High β2 – microglobulin • Most accurate measure. High paraprotein levels High urea Low haemoglobin Increasing age Low albumin.

Differential diagnoses. o Monoclonal gammopathy may be present in absence of myeloma. o These patients should be monitored under long – term review. o Progression to malignant disease may occur.

Malignant lymphomas. • Neoplastic proliferation of lymphocytes. • Form solid tumours within lymphoid tissues.

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Split into two broad categories on histology. o Hodgkin’s lymphoma.  Presence of Reed – Sternberg cells o Non – Hodgkin’s lymphoma.  Absence of RS Cells.

Some subtypes of lymphomas. • B-cell neoplasms o Precursor lymphoblastic leukemia/lymphoma o Mature (peripheral)  Chronic lymphocytic/small lymphocytic  Plasma cell myeloma  Marginal zone/MALT  Mantle cell  Diffuse large B-cell  Follicular  Burkitt’s • T-cell/NK-cell neoplasms o Precursor lymphoblastic leukemia/lymphoma o Mature (peripheral)  Mycosis fungoides  Angioimmunoblastic  Peripheral (NOS)  Anaplastic large cell • Hodgkin’s lymphoma Hodgkin’s lymphoma. • Incidence is 5 per 100 000. o One of the most common malignancies in young adults. • Unknown aetiology. o Definite, but unclear link with EBV. •

Pathology. o Characteristic RS cells in a background of inflammatory infiltrate.  Large bi– or multinucleated cells.  Prominent “owl eye” nuclei. o Divided using Rye classification.  Lymphocyte predominant. • 10% of cases • Excellent prognosis  Mixed cellularity. • 30% of cases • Intermediate prognosis  Lymphocyte depleted. • < 5% of cases • Poor prognosis  Nodular sclerosis. • 60% of cases • Variable prognosis

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Presentation. o Bimodal ages of presentation.  20 – 29 years. • Male preponderance.  > 50 years. o Principally affects whit population. o More common in higher socioeconomic groups. o Symptoms are due to  Painless lymphadeopathy. • Particularly. o Cervical o Axillary o Mediastinal  Dry cough  Exertiopnal dyspnoea • Supradiaphragmatic in 90% of patients. • May be painful with alcohol. • Feel rubbery on examination.  “B” symptoms. • Weight loss. o > 10% of initial weight. o Over previous 6 months. • Drenching night sweats

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Fever > 38 oC. Some patients report pruritis. Pallor Hepatosplenomegaly.

Investigations. o Diagnosis usually made on lymph node biopsy.  Staging is performed to informed appropriate treatment. • Stage I o One lymph node site only • Stage II. o Two lymph node sites. o Same side of the diaphragm. • Stage III. o Lymph node involvement on both sides of the diaphragm. • Stage IV. o Disseminated disease involving one or more extralymphatic organs.

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FBC. • Normochromic normocytic anaemia. • Neutrophilia • Eosinophilia • Thrombocytosis Raised ALP. • Calcium may also be high. LDH raised in bulky disease. • Prognostic indicator. • Marker of disease activity. High urate. ESR may be raised CXR. • Mediastinal lymphadenopathy. CT scan to assess extent of disease. • Chest • Abdomen • Pelvis. Bone marrow aspirated. • Usually shows reactive marrow only. • If Hodkin’s present in bone marrow, demonstrates Stage IV disease. Staging laparotomy. • With splenectomy. • Formerly performed for early disease. • Now very rarely necessary.

Treatment. o Local disease.  Stage Ia – IIa  Radiotherapy  Often with chemotherapy. o Stage IIB – IIIA  Not clear the best way to combine radiotherapy and chemotherapy. o Extensive disease.  Stage IIIB – IVB  Chemotherapy with ABVD. • Doxorubicin • Bleomycin

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• Vincristine • Daunorubicin  Therapy used to be with MOPP. • Mustine • Oncovin • Procarbazine • Prednisolone. If relapse after radiotherapy, give chemotherapy. If relapse after chemotherapy.  Alternative chemotherapy regimen  High – dose chemotherapy  Autologous bone marrow transplants  Stem cell transplant.

Prognosis. o Outlook for younger patients is good. o 5 year survival is 75%.  Greatly affected by histological type and stage at presentation. o Treated Stage IA and IIA disease has 10 – year survival of > 80% o Even advanced disease has 5 – year survival rate of 50%. o Poor prognostic indicators include:  B symptoms  High stage  Lymphocyte depleting histology  Increasing age  High ESR  High LDH.

Non – Hodgkin’s lymphoma. • Accounts for 4% of all cancers. • Incidence is increasing for unknown reasons. • Incidence increases with age: o Uncommon before 40 years o Median age is 50 years. • Condtion si more common in males. • Aetiology is probably multifactorial and includes: o Genetic predisposition o Immunosuppression  HIV infection  Transplant recipients. o Viruses.  EBV • Particulalry in Burkitt’s lymphoma. o Ionising radiation.  A bomb survivors.

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Pathology. o Neoplastic proliferation of lymphocytes within lymphoid system forming solid tumours without RS cells. o Huge group of conditions.  Over 50 defined so far. o May be B or T-cell in origin  90% of lymphomas are B Cells, so we’re good at dealing with these because we have a lot of experience. • B Cell lymphomas are CD20 +ve • Hodgkin’s lymphoma is also CD 30 +ve  10% are T Cells, so we’re less good at dealing with these. o Classification is complex, controversial and changes frequently e.g. Kiel (1987), IWF (1988), R.E.A.L. (1996), WHO (2000)  For more than half a decade, clinicians have been in pursuit of a uniform “gold standard” classification system for NHL. (Harris et al, 2000; Armitage and Weisenburger, 1998)  Early classification systems were driven by the thought that a single basis of classification was an important prerequisite for clinical acceptance.  Sophistication of histopathologic diagnosis of NHL as well as enhancement of immunologic and genetic techniques has led to an increased understanding of NHL (Adult NHL, cancer.gov, 2003)  Therefore, a new classification system, the Revised European American Lymphoma (REAL) classification, was created by European and American hematopathology societies. (Adult NHL, cancer.gov, 2003)  The World Health Organization (WHO) has adopted and updated the REAL system. This new system is based upon the inclusion of 4 disease features: morphology, immunophenotype, genetic features, and clinical features (Harris et al, 2000) o Diagnostic differences of opinion are not infrequent, even between ‘experts’! o Increasingly we are using microarrays to look at genetic markers in the neoplastic cells to reach a diagnosis.

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Presentation. o Usually presents with painless lymphadeopathy or “B symptoms” o May also involve extranodal sites.

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Investigations. o Diagnosis is usually made on lymph node biopsy. o Staging investigations should be performed to determine extent of disease.  As with Hodgkin’s lymphoma. o Circulating lymphoma cells are sometime seen on the peripheral film. o LDH high in bulky disease o Urate high o Paraprotienaemia and immunoparesis may be found. o Bone marrow may be infiltrated by lymphoma cells.  May cause bone marrow failure. o Lumbar puncture should be performed.  To look for CNS involvement. o CT scans can determine extent of the disease.  Chest  Abdomen  Pelvis. o

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 Skin  Lung  Bowel  CNS  Bone Low grade NHL.  Indolent course  Not curable High grade NHL.  Presents aggressively.  Can be cured in 40% of cases. Lymphadenopathy Hepatosplenomegaly Pallor

Cytogenetic analysis is becoming more important to provide information on classification and prognosis.  Chromosomal rearrangements.  Immunohistochemistry.

Treatment. o Low – grade NHL.  Asymptomatic. • Watchful waiting  Localised disease. • Radiotherapy  Symptomatic of progressive disease. • Chlorambucil • Cyclophosphamide.

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 Combination chemotherapy can be given in refractory disease. High – grade NHL.  Localised lesion. • Radiotherapy.  Most patients require cytotoxic chemotherapy. • CHOP. Is gold standard. o Cyclophosphamide o Doxorubicin o Vincristine o Prednisolone  High – dose chemotherapy with autologous bone marrow transplant should be considered in young, fit patients. Rituximab.  Monoclonal antibody against B – Cell surface antigen CD20.  Proved highly effective against B Cell NHL.  Use is likely to increase  List of indications likely to increase.

Prognosis. o Low – grade NHL.  Median survival is about 8 – 10 years. o High – grade NHL.  40% survival at 5 years. o Poor prognostic factors include.  Increasing age  High LDH  Extensive disease  T Cell phenotype  Extranodal sites  Poor performance status  Low – grade NHL that has turned into high – grade NHL.