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

Head: Temporal artery

tenderness
Ears: Otitis media
Eyes: Conjunctival
petechina
Mouth: Dental/
pharyngeal sepsis
Lymph nodes

Lungs: Respiratory exam Spleen: Splenomegaly

Hands: Nail infarcts

Heart: Murmurs,
stigmata of endocarditis Kidneys: Renal cell
carcinoma
Liver: Hepatomegaly,
hepatic bruit Joints: Active infection
or inflammation.

PR & PV: Masses &

infections
Legs: DVT

Skin: Rashes, Petechiae, infarctions

(vasculitis)

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
 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.

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 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.

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 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
  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 Scarring
o Pigmentation
• May develop into SLE.

o CNS.
 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.

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 Anaemia
o Leucopaenia
o Thrombocytopaenia
• Antinuclear antibody
o 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 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
 o 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 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 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 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.

• 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 oedematous
o Blood vessels become inflamed and thickened.
o Increase in collagen
o 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 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.
  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 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.
• 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.

• 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

• 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 potentials
o 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 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.
 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 Arthrlagia
o Polyarthritis
o Raynaud’s phenomenon
o Renal involvement.
 In 20% of patients.
o Fibrotic lung disease
o Parotid gland enlargement.
 In 30% of cases
o Vasculitis.
o Increased incidence of lymphoma.

• 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.

• 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 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.
 • Investigations.
o FBC.
 In 30% of cases, there is a:
• Normochromic normocytic anaemia
• Leucocytosis
• Eosinophila
o ESR & CRP.
 Usually raised
o 10% pANCA positive
o 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 disorder
Antinuclear factor (ANA) 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.
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
 • 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 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.
• 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 urate
o Raised LDH
o 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 hydration
o 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 pancytopaenia
o 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.

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.

• Pathology.
o Accumulation of immature haemopoetic blast cells in bone marrow.
  Can cause bone marrow failure
o 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 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.
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 common
o Moderate splenomegaly
o Lymphadenopathy is rare.
 Except in Monocytic form
 o 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.
 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 abnormal
o 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 Malaise
o Weight loss
o Night sweats
o Recurrent infections
o Bleeding
o Lethargy
o Lymphadenopathy.
  In 60% of cases
o 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%

• 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)
• 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 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
 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.

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

• Incidence is 5 in 100 000

o 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 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.
 • 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.

• Prognosis
o 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/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
• 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
• 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 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.
• 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 Lymphadenopathy
o Hepatosplenomegaly
o 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 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 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 Doxorubicin
o Vincristine
o 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.