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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.
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.
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 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
o 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. Neutrophil leucocytosis
Bacterial infection Myeloproliferative disorders Malignancy.
o Eg. Liver metasteses. Collogen vascular diseases.
Leucopaenia. Viral infections Lymphoma SLE Brucellosis Disseminated TB Drugs
Head: Temporal artery tenderness
Eyes: Conjunctival petechina
Lymph nodes
Spleen: Splenomegaly
Hands: Nail infarcts
Kidneys: Renal cell carcinoma
Joints: Active infection or inflammation.
Legs: DVT
Skin: Rashes, Petechiae, infarctions (vasculitis)
PR & PV: Masses & infections
Liver: Hepatomegaly, hepatic bruit
Heart: Murmurs, stigmata of endocarditis
Lungs: Respiratory exam
Mouth: Dental/ pharyngeal sepsis
Ears: Otitis media
Monocytosis. Subacute bacterial endocarditis Inflammatory Bowel Disease Hodgkin’s disease Brucellosis TB
Abnormal mononuclear cells. EBV CMV Toxoplasmosis
Eosinophilia Parasitic disease.
o Trichiasiso Hydatid disease
Malignancy.o Especially Hodgkin’s disease
Drug reactions Pulmonary eosinophilia.
o 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.
o U&Es. Renal impairment Hyponatraemia.
Often due topneumonia in the feverish patient.
o 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 Still’s disease Polymyalgia rheumatica. Bony Metts.
o Bacteriology & Serology.
Microscope and culture every available site. Urine.
Bacteria Haematuria.
o Subacute bacterial endocarditiso Hypernephroma
Blood cultures. Several samples are needed from different veins at different times of
the day. Faeces.
Microscopy for.o Ovao Cystso Parasites.
Vaginal and cervical swabs. Urethral swabs.
Particularly in men. Sputum.
Microscopy and culture Throat swab
Cultures.
o 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
Bone marrow aspiration Lumbar puncture.
o Non – essential drugs should be stopped on admission. May be necessary to withhold drugs one at a time for 48 hours each.
o 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.
o Very rare causes should be considered if not already investigated Hyperthyroidism Phaeochromocytoma Familial Mediterranean fever.
o 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 womeno Commoner in blacks than in Caucasians.
Peak onset is 20 – 40 years.
Aeitologyo Unknowno Probably multifactorailo Predisposing factors.
Family history Drugs.
Eg. hydralazine UV light Viral infection Immunological mechanisms.
Clinical features Commonest early features are:
o Fevero Arthralgiao Malaiseo Tirednesso 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
Rarely there can be deforming arthropathy. Jaccoud’s arthropathy. Due to capsule laxity.
Aseptic necrosis of knee or hip may occur. Rare
o Skin. 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 Scarringo Pigmentation
May develop into SLE.
o CNS. Involved in 60% of cases. Can cause psychiatric disturbances.
Depression.o Commonly
Psychosiso Occasionally
Other features include: Seizures Strokes Cerebral nerve lesions Aseptic meningitis Peripheral neuropathies.
Effects are due to: Arteritis and ischemia Immune complex deposition.
o Respiratory system. Involved in about 50% of cases. Pulmonary manifestations include;
Pleurisy with pleural effusions Pneumonia with atelectasis Restrictive defects.
o “shrinking lung syndrome”o Diffuse reticular – nodular shadowing on CXR.
o 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.
o 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 Anaemiao Leucopaeniao Thrombocytopaenia
Antinuclear antibodyo Positive in almost all cases.o Classically.75% sensitive
Homologous staining Anti – dsDNA Specific for SLE
o Titre rises in active disease. Serum complement levels.
o Reduced in active diseaseo Immunoglobulins raised
Renal biopsy.o If there is kidney involvement.o Shows characteristic histological changes.
Management.
Mild disease can be managed witho Aspirin or NSAIDs for joint pain.o Anaemia can be treated with transfusionso 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 involvemento CNS involvemento 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 – malarialo Can cause retinal degeneration.
Formally check vision at regular intervals.
Antiphospholipid syndrome Manifests as increased risk of:
o Arteiral thrombio Venous thrombio Miscarriage.
Associated with antibodies against phospholidpid, known as.o Anticardiolipin antibodyo 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.
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 meno 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 Distribution may be symemetrical and systemic.o Common systemic features include
Sweating Malaise
o True weakness does not occur. Power and range of movements may be limited by pain.
Differential diagnoseso Late onset RAo 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.
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.
Management.o Corticosteroids.
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.
o About half of patients manage to be steroid free by 2 years.o Management should be based on clinical response.
However, a rise in ESR should prompt a review.o Relapses are common within the first year.
Associated with reduction in steroid dose. Incidence of relapse falls after 1 year.
o Normally necessary to give prophylaxis against osteoporosis.o Addition of NSAID to cover ache and stiffness may be of use.o If patients are developing side effects of steroid use, consider a steroid sparing
immunosuppressant. Eg. Azothioprine. Requires expert supervision.
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 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 oedematouso Blood vessels become inflamed and thickened.o Increase in collageno Progressive fibrosis of viscera.
Aeitiology.o Unknown.o Familial cases occur at higher frequency with:
HLA – B8 HLA – DR3
Clinical features.o Generally.
Malaise Lassitude Fever Weight loss
o Skin. 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.
o 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
o 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.
o Musculoskeletal system. Problems due to tendon fibrosis.
Polyarthralgia Flexion deformities
Myopathy and polymyositis may occur.o Cardiovascular system.
Myocardial fibrosis may can. Arrythmias Conduction defects.
Pericardial effusions may occur. Right heart failure may occur.
Secondary to lung disease.o Renal system.
Due to obliterative endarteritis of renal vessels. Progressive renal failure Hypertension
Can be fatal.o Eyes.
Sjögren’s syndrome may occur.
CREST syndrome. Form of systemic sclerosis that involves.
o Calcinosis of subcutaneous tissues.o Raynaud’s phenomenono oEsophageal dysmotilityo Sclerodactylyo Telangiectasia
Prognosis tends to be better than systemic sclerosis Associated with anti – centomere antibodies.
Investigations.o Anti – nuclear antibodies.
Present in 80% of patients. Nucleolar pattern in scleroderma Rheumatoid factor is positive in 30%
o ESR. Often raised
o FBC. Normochromic normocytic anaemia Haemolytic anaemia
o Hand X – ray. May show calcinosis
o Barium swallow/ oesophageal manometry. Demonstrates motility problems.
Management.o Symptomatic treatment.
Raynaud’s. Nifedipine Electrically heated gloves.
Heartburn Antacids H2 – receptor antagonists PPI
Joint pain. Physiotherapy NSAIDs
Hypertensive renal crises are emergencies. Treat aggressively
o ACE inhibitorso Supportive critical care
Polymyositis and Dermatomyositis. Polymyositis is a disorder of muscle Unknown aeitiology, but suggestions include:
o Immunological factorso Viral factors.
Pathologically there is.o Necrosis of muscle fibreso Regeneration and inflammation.
When rash is also present, known as dermatomyositis.
Occurs at any age.o Peak onset at around 50 years.o Women affected twice as often as meno 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.
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 phenomenono Lung fibrosiso Sjögren’s syndrome
Investigations.o Creatinine kinase.
Raised Can be used to monitor course of disease. Raised CKMB or troponin may be found.
Rarely linked to myocarditis.o Characteristic electromyographic changes.
Fibrillation potentialso Muscle biopsy.
Necrosis of muscle fibrosis. Swelling and disruption of muscle cells Fibrosis Thickening of blood vessels Inflammatory changes.
o ESR. Usually raised. May be normochromic normocytic anaemia Antinuclear antibodies may be positive Jo – 1 antibodies may be positive.
o Investigations for underlying malignancy.
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.
Prognosis.o Adults do better than children.
Unless there is an underlying malignancyo 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.
o Eg. RA. Association with HLA – B8 and HLA – DR3. Other exocrine glands may b e involved.
Results in:
o Dry eyes Keratoconjunctivitis sicca.
o Dry mouth Xerostomia
o Arthrlagiao Polyarthritiso Raynaud’s phenomenono Renal involvement.
In 20% of patients.o Fibrotic lung diseaseo Parotid gland enlargement.
In 30% of caseso Vasculitis.o Increased incidence of lymphoma.
There is an association with organ specific autoimmune diseases.o Thyroid diseaseo Vitiligoo Pernicious anaemiao Primary biliary cirrhosiso Chronic active hepatitis.
Pathologically, there are lymphocytic and plasma cell infiltrates of secretory glands.
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.
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 meno 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.
Investigations.o FBC.
In 30% of cases, there is a: Normochromic normocytic anaemia Leucocytosis Eosinophila
o ESR & CRP. Usually raised
o 10% pANCA positiveo Biopsy.
Affected organs may show Fibrinodi necrosis Cellular infiltration of arteries.
o 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.Test Associated disorderAntinuclear factor (ANA) SLE
RASjögren’s syndromeMCTDSystemic sclerosis
Anti double – stranded DNA SLERheumatoid factor RA
SLEMCTDSjögren’s syndrome
Anti – Ro Sjögren’s syndromeAnti – La Sjögren’s syndromeAnti – cardionolipin Antiphospholipid syndromeLupus anticoagulant Antiphospholipid syndromeAnti – ribonucleoprotein MCTDJo – 1 antibodies Polymyositis
DermatomyositisPeripheral Antineutrophil cytoplasmic antibodies (pANCA)
Polyarteritis nodosa
Classical Antineutrophil cytoplasmic antibodies (cANCA)
Wegener’s granulomatosis
Antiacetylcholine receptor antibodies Myasthenia graivsAnti – GM1 Multifocal motor neuropathy
Guillain – Barre syndrome
Anti – GAD Stiff – man syndrome.
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 syndromeo Ataxic telangiectasia.
Pathology.o Lymphoblasts accumulate in bone marrow.
Causes bone marrow failureo 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 More cytoplasm
L3.
Large cells Homogenous Prominent nucleoli Abundant cytoplasm
o 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 failureo Anaemia
Lethargy Dyspnoea Pallor
WBC failure.o Neutopaenia.
Recurrent infections Fever
Platelet failure.o Thrombocytopaenia
Bleeding Bruising Purpura
Fever Lymphadenopathy Hepatosplenomegaly Neurological signs.
Investigations.o FBC.
Normochromic normocytic anaemia. Low reticulocyte count. Raised WCC.
Due to lyumphoblasts Neurtopaenia Thrombocytopaenia.
o Bone marrow biopsy. Hypercellular Dominated by lymphoblasts.
Usually > 50%o Cytogenetic abnormalities.
Hyperdiploidy Philadelphia chromosome.
o Raised urateo Raised LDHo CXR.
Mediastinal mass in T – Cell disease.o Lumbar puncture.
Lymphoblasts Increased pressure Increased protein.
Treatment.o All chemotherapy requires cocurrent supportative measures.o Ensure good hydrationo Prophylactic anti – infection agents
Antibiotics Antiviral drugs Antifungal drugs
o 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
o Septic surveillance.o Blood products for pancytopaeniao Bone marrow colony – stimulating factor
Eg. Granulocyte colony – stimulating factor.o Monitor coagulationo 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 - yearso 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.
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 leukaemiao This is often the cause of death.
Pathology.o Accumulation of immature haemopoetic blast cells in bone marrow.
Can cause bone marrow failureo Blasts can infiltrate.
Gums Liver Spleen Skin CNS.
Less common.o Traditionally classified as.
M1: Undifferentiated myeloblastic. M2: Myeloblastic.
Most common form. M3: Promyelocytic.
Often causes death via DIC M4: Myelomonocytic.
Infiltration of:o Gumso Skino Meninges
M5: Monocytic. Infiltration of:
o Gumso Skino Meninges
Lymphadenopathy may occur. M6: Erythroleukaemia.
Particularly in older patients. M7: Megakaryocytic.
o 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 commono Moderate splenomegalyo Lymphadenopathy is rare.
Except in Monocytic formo 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 AMLo 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.
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. 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 abnormalo 95 – 98% of cases are B – Cell phenotypes.
Remainder are T – Cells.
Presentation.o Often asymptomatic.
Found as incidental finding when doing FBC for other reasons.o Malaiseo Weight losso Night sweatso Recurrent infectionso Bleedingo Lethargyo Lymphadenopathy.
In 60% of caseso 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 informationo Hypogammaglobulinaemia in 50%
Treatment.o Watchful waiting is first line.
Only if mild, asymptomatic diseaseo 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, malaiseo Splenomegaly, (bruising)
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.
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.
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.
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 inhibitorso 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 transplantationo Allograft
Only ‘known cure’ Sibling or unrelated ( so called ‘MUD’) Autograft
Alpha-interferon o Not really used any more.
Novel therapieso 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. 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 marrowo FISH test
Blood PCR testo Can pick up maybe 1 in 100,000 to 1 in million leukaemic cells
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 soo 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 abnormalitieso Production of monoclonal protein.o Accumulation of plasma cells in the bone marrow.
Incidence is 5 in 100 000o 1% of all malignancies.o 10 – 15% of haematological malignancies.
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.
Presentation.o Disease mainly of the elderly.
Peak incidence in 60s.o Bone pain.
Due to osteolytic lesions. Pathological fractures affect 60% of cases.
o Recurrent infections. Impaired antibody response. Hypogammaglobulinaemia
o Symptoms of anaemia may be present. Examination usually reveals pallor.
o Amyloidosis, causing. Splenomegaly. Peripheral neuropathy.
o Compression by tumour or vertebral collapse. Spinal cord compression Radiculopathy.
o Hyperviscosity syndrome. Polymerisation of monoclonal antibody.
Investigations.o Normochromic normocytic anaemiao Blood film.
Rouleaux (clumping of RBC) Background immunoglobulin staining.
o Riased ESRo 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.
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.
Prognosiso Median survival is 3 years.o Poor prognostic factors include:
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. 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/lymphomao 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 neoplasmso Precursor lymphoblastic leukemia/lymphomao 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
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 Cervicalo Axillaryo 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 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.
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 Vincristine
Daunorubicin Therapy used to be with MOPP.
Mustine Oncovin Procarbazine Prednisolone.
o If relapse after radiotherapy, give chemotherapy.o 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 yearso Median age is 50 years.
Condtion si more common in males. Aetiology is probably multifactorial and includes:
o Genetic predispositiono Immunosuppression
HIV infection Transplant recipients.
o Viruses. EBV
Particulalry in Burkitt’s lymphoma.o Ionising radiation.
A bomb survivors.
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.
Presentation.o Usually presents with painless lymphadeopathy or “B symptoms”o May also involve extranodal sites.
Skin Lung Bowel CNS Bone
o Low grade NHL. Indolent course Not curable
o High grade NHL. Presents aggressively. Can be cured in 40% of cases.
o Lymphadenopathyo Hepatosplenomegalyo Pallor
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 diseaseo Urate higho 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 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.
Combination chemotherapy can be given in refractory disease.o High – grade NHL.
Localised lesion. Radiotherapy.
Most patients require cytotoxic chemotherapy. CHOP. Is gold standard.
o Cyclophosphamide
o Doxorubicino Vincristineo Prednisolone
High – dose chemotherapy with autologous bone marrow transplant should be considered in young, fit patients.
o 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.
