Cancer Flashcards
Benefits of mammography screening
Reduction in breast cancer mortality Detects cancer earlier Can find smaller cancers - Decreases extensiveness of treatment required - Allows for breast conserving surgery
Limitations of mammography screening
Not 100% accurate False negatives - miss 20% of cancers False positives - cause anxiety and result in extra testing Overdiagnosis leading to over treatment Pain Anxiety Radiation risk
Epidemiology of breast cancer
Most common female cancer in the UK Most common cancer (15%) Increases with age More common in females Highest in Caucasians (Western Europe) FHx - yes especially BRCA1 or 2 gene
Alcohol COCP HRT ionising radiation Raised BMI Smoking Hodgkin's lymphoma Digoxin Diabetes Decreased parity Increased age at giving birth Increased age of menopause Decreased age at menarche
Signs and symptoms of breast cancer
Breast mass - hard, immobile, attached to chest wall Discharge - unilateral, bloody Skin changes - dimpling, peau d'orange Inverted nipple Lump under arm Lymphadenopathy mets may cause symptoms
Breast lump - indications of malignancy
Hard Painless Irregular margins Fixation to skin or chest wall Skin dimpling Discharge that is unilateral and bloody Nipple retraction
Breast lump - indications it’s benign
Firm or rubbery Often painful Regular or smooth margins Mobile No skin changes If discharge bilateral, no blood No nipple changes
Gene associated with breast cancer
BRCA1 or 2
Most common breast cancer type
Almost all are from glandular epithelium lining lactiferous ducts - adenocarcinomas
Investigations for breast cancer
Routine bloods (LFTs for ?mets)
Mammography
- Superior in elderly and in lower density breasts
- Over 40
- On everyone with proven malignancy
US
- More effective in younger patients
- Done in pregnancy or lactation or under 40s
MRI
- In difficult cases: breast implants, BRCA mutation, suspected tumour with multiple foci
If mass found non-palpable
- Core needle biopsy
- Open biopsy
If palpable
- FNA (not ideal if lesion <1cm)
- Core needle biopsy (also provided pathological result)
- Excision biopsy or incisional biopsy
CXR
CT if mets suggested
Can do sentinel node biopsy
Triple assessment for breast cancer
Imaging - US or mammography
Clinical examination
FNA or core biopsy
Need all 3 negative to exclude carcinoma
Tumour marker in breast cancer
CA 15-3
Can be used for prognosis
Hisological markers in breast cancer
Oestrogen and progesterone receptor status
HER2 - human epidermal growth factor 2
Likely met sites for breast cancer
Bone
Brain
Lung
Liver
Staging of breast cancer
0 - in situ 1 - up to 2cm 2 - 2-5cm or nodes on same side 3 - over 5cm of adherent nodes 4 - mets
Management of breast cancer
Surgery, chemotherapy, radiotherapy
<4cm or DCIS then conservative surgery + whole breast ratiotherapy
> 4cm or multifocal then mastectomy and chest wall radiation if high risk
If Node involvement = node resection then radiotherapy + chemotherapy
Hormonal therapy
- Oestrogen receptor POSITIVE - aromatase inhibitor (anastrazole) if post menopausal. Tamoxifen if pre-menopauseal
Biological
- HER2 positive = trastuzumab (Herceptin)
Types of breast cancers
Invasive ductal (90%) Invasive lobular (8%) Mucinous or tubular = rare DCIS = pre invasive
Prognosis of breast cancer
Depends on biological characteristics and therapy given
Increased risk of recurrence if node positive or oestrogen receptor negative
Nottingham Prognostic index
Recurrence 2-5% at 5-20 years
Complications of breast cancer
Psychological implications
- Can be reduced with less destructive surgery, counselling, nipple preservation, reconstructive surgery
Post op complications
Lymphoedema of the arm
Risk factors for lymphoedema
Increased number of lymph nodes removed
Axillary lymph node dissection
Multiple surgery to chest or more extensive surgery - increased chance of disruption
Radiation therapy
Chemotherapy - causes weight gain which is a RF
Breaks in skin
being overweight or obese
Infection or injury on the same side - leads to inflammation and causes increased work on the lymph system
Treatments for lymphoedema
Elastic sleeve or elastic vest (breast swelling) Compression bandaging Manual lymphatic drainage (massage) Combined physical therapy Exercises Compression pumps Weight loss Kinesio taping methods Low level laser therapy
Pathogenesis of cancer mets
Transformation Angiogenesis Motility and invasion (capillaries, venules and lymphatics) Embolism and circulation Transport Arrest in capillary beds Adherence Extravasation into organ parenchyma Response to micro environment Tumour cell proliferation and angiogenesis mets
Lab pathway of tissue sample
- Sample collected and placed in formalin
- Transferred to lab - delay from porter
- Allowed to fix overnight - time delay
- Placed in cassette
- Processed to wax overnight - time delay
- Sectioned and stained
- Added to pile of slides for pathologist - time delay with staffing levels
- Reported by pathologist
- Written report typed - time delay by secretary staffing
- Report checked and signed by pathologist
- Report sent to requesting physician
- Report received by requesting clinician
- Read
- Report acted on
Minimum of 2-3 days,
Describe bronchoscopy process
Fibre optic bronchoscope in thickness of pencil
Usually done as outpatient or day case
- Numb inside of nose and back of throat with a spray
- Sedative to relax
- May be given additional oxygen
- Tube passed through nose or mouth down to trachea and bronchi
- May cause cough
- 20-30 minutes
- Can do biopsies or bronchial lavage
Role of coroner
Independent official with legal responsibilities for the medical legal investigation of certain deaths: sudden, unexplained, unnatural or violent in nature
Deaths reportable to coroner
Sudden deaths from unknown causes
Cause of death unknown
Any vehicle, aeroplane, train or boat accident
Suspicious circumstances
Suicide
Not been seen by doctor in last 28 days
? due to negligence, misconduct or malpractice
Any death within 24 hours of admission
Any death caused by a treatment or anaesthesia
Any infant death or still birth
Reasons for retaining tissue from a post mortem
Microscopic examination
Complex abnormality requiring detailed examination
Sample may need to undergo prep before examination
Prep may take several weeks
Benefits of a post-mortem
Provides valuable info on cause of death
Provides information for future treatment or research
Gives relatives information which could impact on their health
Data can improve and assess medical care and research causes and prevention
Assists education of doctors
Provides accurate mortality and morbidity stats to improve mental health
Epidemiology of lung cancer
3rd most common cancer in the UK 2nd most common in men and women Increases with age More common in men (slightly) Increased in Caucasians FHx - yes
RFs
- Smoking
- Asbestos exposure
- Past cancer
- Radon
- COPD
- TB
- Pneumonia
- Silicosis
- Ionising radiation
- Coal dust
Small cell lung cancer
15% of lung cancers
WORST PROGNOSIS
Also called oat-cell carcinoma Arises from Kulchintsky cells Cells often act as hormones or neurotransmitters Grow rapidly Highly malignant Metastasise early Normally inoperable at presentation Respond to chemo but poor prognosis
Types of non-small cell lung cancers
Squamous (42%) Adenocarcinoma (40%) Large cell (8%) Carcinoid tumours (6%) Bronchoalveolar cell (4%)
Squamous cell lung cancer
42% of non-small cell Present as obstructive lesions of the BRONCHUS Can lead to infection Local spread common Mets occur late
Adenocarinoma of the lung
40% Arises from the mucus cells most common in NON SMOKERS associated with ASBESTOS Invasion of the pleura and mediastinal lymph nodes common Often mets to brain and bone
Large cell carcinoma of lung
8%
Less differentiated forms of adenocarcinoma and squamous cell carcinoma
Mets early
Signs and symptoms of lung cancer
Cough haemoptysis weight loss SOB Chest pain Clubbing Fever Weakness Dysphagia
SVC obstruction
Hoarseness
Horner’s syndrome
Investigations for lung cancer
FBC - Raised WCC, CRP, low Hb
U&Es
LFTs
CXR - urgent if 3 weeks of one of: cough, chest pain, dyspnoea, weight loss, hoarseness, clubbing, lymphadenopathy or chest signs
Contrast CT for staging - done before bronch and biopsy
PET/CT is offered to all potentially curable patients
Bronchoscopy - histological diagnosis and to assess operability
Neck US - for visualising lymph nodes
Percutaneous transthoracic needle biopsy - for superficial lymph nodes and peripheral lesions
Biopsy (surgical) if not possible in other methods
Cytology of sputum or pleural fluid
Histological testing for EGFR-TK mutation as may change treatment
- Epidermal growth factor receptor tyrosine kinase
Management of non-small cell lung cancer
Smoking cessation
Lung function tests on all prior to surgery
Surgical resection - if stage 1 or 2 with hilar lymph node sampling
- If complete resection then adjuvant chemo
- If partial resection then radiotherapy
Radiotherapy - stage 1-3 not suitable for surgery. Can do radical radiotherapy if good performance status
Chemotherapy - offered to all
- In stages 3&4 can increase survival and quality of life
- If EGFR-TK positive ERLOTINIB
Cisplatin most commonly used
Management of small cell lung cancer
Smoking cessation
Multi-drug regimen
In limited stage: 4-6 cycles of cisplatin combination chemo with thoracic irradiation
If there is a good response then prophylactic cranial irradiation
In extensive disease
- Maximum 6 cycles
- Supportive and palliative care
Supportive and palliative care in lung cancer
Breathlessness: strong opiate, psychological support + breathing control
Bronchial obstruction - radiotherapy or debulking bronchoscopy
Pleural effusions: aspiration or drainage. Talc pleurdiesis
Haemoptysis: radiotherapy or debulking bronch
Cough: opioids, radiotherapy
Hoarseness: refer to ENT
Chest pain: radiotherapy
SVC: chemo and radiotherapy. stent insertion.
Cerebral mets: corticosteroids + radiotherapy
Complications of lung cancer
Recurrent laryngeal nerve palsy phrenic nerve palsy horner's syndrome pancoast's syndrome SVC obstruction pericarditis Rib erosion AF
SVC obstruction
Can be due to external pressure, involvement of the vessel by tumour tissue or clot obstructing the lumen
SVC extends from innominate veins to RA, early compressed due to thin walls.
4 collateral routes in SVC obstruction
Azygous system
Internal mammary system
Long thoracic venous system
Femoral and vertebral veins
Epidemiology of SVC obstruction
Most common in men
85% of cases are linked to lung cancer
30-40 more likely to be benign
40-60 years more likely to be malignant
Symptoms of SVC obstruction
dyspnoea cough Chest pain Neck and face swelling Arm swelling Dizziness Nausea Headache Disturbed vision Nasal stuffiness Stupor Syncope Can be gradual or acute
Aggravated by bending or lying down
Signs to SVC obstruction
More pronounced when arms lifted
Dilated veins over arms, neck and anterior chest wall
oedema of upper body, extremities and face
Severe respiratory distress
Cyanosis
Engorged conjunctiva
Convulsions and coma
Link between tobacco and lung disease
DOSE RESPONSE RELATIONSHIP
- Causes many lung disease
- Worsens chronic lung disease
- Increases risk of resp infections
- Acute respiratory illness
- Impaired lung growth in childhood and adolescents
- Early onset and accelerated decline in age related lung function and respiratory symptoms
- Asthma
- Poor asthma control
- COPD morbidity and mortality
- Decreased lung function in infants with maternal smokers
- Increase risk of lung cancer (80% of cases are attributable)
Contents of cigarette smoke
Acrolein - cilia tonic, impairs lung defence Formaldehyde - irritant and cilia toxic Nitrogen oxides - oxidant activity Cadmium - oxidative injury Hydrogen cyanide - oxidative
Free radicals cause oxidative stress which results in DNA damage
Links between cocaine and lung disease
Depends on route of entry, dose and freq
Increases risk of
- acute respiratory symptoms
- Increased infection and aspiration pneumonia
- Increased barotrauma and pneumothorax due to inhalation
- Airway injury - nasal wall, septum
- Asthma: precipitates bronchospasm and wheeze
- Haemoptysis due to capillary damage
- Crack lung: 2y to prolonged inflammation associated with fever, hypoxia, haemoptysis, resp failure and diffuse eosinophilia alveolar infiltrates
- Emphysema
Links between cannabis and lung disease
Greater exposure to smoke as long inhalation time Increased resp symptoms Increased COPD Injuries to bronchial mucosa Decreased cilia Increased lung cancer Increased pneumothorax
Side effects of chemotherapy
Myelosuppression: anaemia, low WCC Alopecia Nausea and vomiting Infertility Fatigue Impaired wound healing Mouth ulcers Teratogenicity Menopausal symptoms Decreased libido Extravasation
Types of radiation therapy in lung cancer
External beam radiation therapy - focused beam from outside the body
- intensity modulated
- Stereotactic
brachytherapy
- Internal radiation therapy
- Shrinks tumours in airway to relieve symptoms
- Done through surgery or bronchoscope
Complications of radiotherapy - ACUTE
General fatigue Erythema Desquamation Skin tanning Hair loss GI: decreased taste, oral mucositis, D&V, N&V Immunosuppression Pneumonitis
Complications of radiotherapy for lung cancer - CHRONIC
Neck fibrosis Jaw muscle fibrosis Lymphoedema Infertility Delayed healing Telangiectasia Salivary dysfunction Transverse myelitis Increased CV risk Hypothyroidism Hearing loss Cataracts or retinitis
Increased risk of secondary cancer
Aims of TNM staging
Aid clinician in planning of treatment
To give indication of prognosis
To assist evaluation of results of treatment
To facilitate the exchange of information between treatment centres
To contribute towards the continuation of investigation into human cancer
TNM staging
T - size of the primary tumour and degree of local spread /4
N - size, location and number of lymph nodes affected /3
M - mets present or not /1
Cancer staging never changes
If there is any doubt, use the lower level. All cases should be confirmed microscopically
Epidemiology of colon cancer
3rd most common cancer cause 2nd most common cause of cancer death 47 per 100,000 Increased in males Increased with age
RFs
- FHx under 60
- Past history of colorectal cancer
- Polyposis syndromes: HNPCC, FAP, Turcot’s syndrome, Peutz-Jegher’s syndrome, juvenile polyposis syndrome)
- UC/Crohn’s
- Pelvic radiotherapy
- Obesity
- Sedentary lifestyle
- Diet high in meat and fat
- Increased alcohol
- Diabetes
- Cholecystectomy
Symptoms of colon cancer
Dependent on site
left sided - early obstruction, fresh rectal bleeding, tenesmus, mucus, early change in bowel habit, mass in LIF
right sided - anaemia from occult bleeding, altered bowel habit, weight loss, anaemia. More advanced at presentation
Can have symptoms of obstruction of perforation
hepatomegaly from mets
Abdominal distension
Lymphadenopathy
Locations of colon cancer
45% is rectosigmoid
30% ascending
15% descending
10% transverse colon
Common met sites for colon cancer
Liver
Lung
Bone
Pathophysiology of colon cancer
Malignant transformation of benign adenomatous polyp
Accumulation of multiple genetic mutations
APC gene - progession of early adenoma development
K-Ras gene - failure leads to cell proliferation
p53 gene - cell proliferation and impaired apoptosis
Investigations for colon cancer
FBC (anaemia)
Raised CRP
LFTs - normal unless mets
U&E - normal unless ureter compression
Colonoscopy - gold standard + biopsy for histological analysis
Double contrast barium enema - apple coring or mass (used if colonoscopy can’t be tolerated)
CT colonography but will need colonoscopy for biopsy
Once diagnosed CT TAP for mets
Liver US
CEA - carcinoembryonic antigen - not used for screening but can be used to predict relapse
Causes of raised CEA
Bowel cancer breast cancer Lung cancer Cancer of: Stomach Oesophagus Pancreas mesothelioma Medullary thyroid cancer
Management of rectal cancer
Determine risk of local recurrence
LOW - No lymph nodes T<3
MODERATE - T>3 or lymph
HIGH - <1mm resection margin, encroaching on local structures
Low = surgery
Moderate - pre-op radiotherapy then surgery
High = pre-op chemo, time to shrink, surgery
MDT
May need MRI to determine capsular involvement
Management of colon cancer
Stage 1 - resection II, low risk = resection II, high risk = adjuvant chemo III - adjuvant chemotherapy IV - symptom control, consider resection, MDT for management decision
FBC findings in iron deficiency anaeamia
Low Hb Low serum ferritin Hypochromic cells (Low MCH) Low MCV (microcytic) Low Iron
Causes of iron deficiency anaemia
Occult GI blood loss
- Aspirin/NSAID
- Colon/oesophageal/gastric cancer
- Benign gastric ulceration
- Angiodysplasia
- Oesophagitis
Malabsorption
- Coeliac disease
- Gastrectomy
- H. pyori infection
- less common: gut resection or bacterial overgrowth
Non GI blood loss
- menstruation
- blood donation
Management of iron deficiency anaemia
If anaemic:
- Check coeliac serology
- If positive: small bowel biopsy
- If negative and post-menopsaual then colonoscopy & OGD
If premenopausal, coeliac negative and anaemia
- If upper GI symptoms = OGD
- If FHx of colorectal cancer or lower GI symptoms = colonscopy
- If no GI symptoms = iron replacement and investigate further if becomes transfusion dependent
If no anaemia and under 50 then iron placement
- If no anaemia develops then no further investigation required
- If over 50 precede as if anaemic
Locations for gastric cancer
50% pylorus
25% lesser curve
10% cardia
8% lymphomas
Epidemiology of gastric cacncer
Increases with age (95% are over 55)
More common in men
8th most common cancer worldwide, 13th UK
Increased in Japan, China, South America
FHx - yes (2-3x increase if 1st degree family member)
RFs
- H. pylori infection
- Diet high in salt, preserved food, decreased fruit and veg
- Poor socioeconomic status
- Smoking
- Alcohol
- Atrophic gastritis
- Post-gastrectomy
- Blood group A
- meniere’s
Histological types of gastric cancer
Type 1 - intestinal - well formed glandular structures. Differentiated, more common in distal stomach. Strong environmental association
Type 2 - diffuse - poorly cohesive cells, particularly in cardia. Poorer prognosis. Loss of expression of cell adhesion moleucule E-Cadherin. Occurs in the younger population
Pathophysiology of gastric cancer
Correa’s cascade
- Chronic non atrophic gastritis
- Atrophic gastritis
- Intestinal metaplasia
- Dysplasia
- Cancer
90-95% adenocarcinoma
1-5% lymphomas
2% GI stromal tumours
Symptoms of gastric cancer
Early satiety Weight loss Dysphagia Epigastric pain Dyspepsia Nausea or vomiting Decreased appetite Haematemesis or melena
Signs of gastric cancer
Palpable enlarged stomach Succession splash Hepatomegaly Periumbilical masses Enlarged Virchow's node Anaemia
Investigations for gastric cancer
Urgent 2 week referral if
- Dyspepsia + one of: anaemia, dysphagia, weight loss, persistent vomiting, epigastric mass
- 55 with new onset dyspepsia
- dysphagia, obstructive jaundice, unexplained upper abdo pain, weight loss
Bloods - FBC (anaemia), LFTs
Endoscopy + biopsy (antisecretory therapy should be withheld until after endoscopy
Endoscopic US for local staging and depth of penetration
CT TAP for staging or PET/CT
Management of gastric cancer
Operable - preferred: pre-op chemo - surgery Distal cancer = sub total, proximal = total gastrectomy If curable remove D2 lymph nodes - post op chemo - consider adjuvant chemoradiation
Inoperable
- palliative chemotherapy
- HER2 negative then platinum based chemotherapy
- HER2 positive then trastuzumab
Blood transfusion for symptomatic anaemia
Corticosteroids for anorexia
Coeliac plexus nerve block for pain
Hallmarks of cancer
Genome instability and mutation Resisting cell death Sustaining proliferative signalling Evading growth suppressors Enabling replicative immortality Inducing angiogenesis Activating invasion and mets Reprogramming energy metabolism Tumour promoting inflammation Evading immune destruction
Role of TP53
Induces apoptosis when there is cell damage
If mutation or loss of TP53 then cancer
Interpreting the FBC
Hb
Haemoglobin
Shows the CONCENTRATION of Hb in blood
If low = anaemia
Interpreting the FBC
MCV
Mean cell volume
Low = microcytic
Normal = normocytic
High = macrocytic
Interpreting the FBC
Reticulocyte count
Concentraiton of immature red cells
Increased in blood loss and haemolytic anaemia
What goes Hct or PVC show on FBC
Haematocrit or packed cell volume
Shows the % of red blood cells in the blood
Causes of microcytic anaemia
Iron deficiency
Haemoglobinopathies
Sideroblastic
Myelodysplastic syndrome
Causes of normocytic anaemia
Anaemia of chronic disease
Acute blood loss
Haemolytic anaemia
Sickle cell
Causes of macrocytic anaemia
Alcoholism B12 and folate deficiency Reticulocytosis Liver disease Oestrogens Methotrexate Hypothyroidism Bone marrow failure Pregnancy
Blood tests for suspected anaemia
FBC
Haemotinics - B12, folate, ferritin
Iron studies
TFTs
Blood film +/- marrow biopsy if relevant (if ?bone marrow/haemolytic/sideroblastic)
Hb electrophoresis (if ?thalassaemia or sickle cell)
Bilirubin in haemolysis
Causes of B12 deficiency
Pernicious anaemia
Malabsorption (gastrectomy/ ileum resection)
Causes of folate deficient
Dietary (alcoholism, neglect)
Increased requirements (pregnancy, haematopoiesis)
Malabsorption (coeliac, pancreatic insufficiency, gastrectomy, Crohn’s)
Drugs (phenytoin, methotrexate, trimethoprim)
Causes of haemolytic anaemia
Inherited
- Sickle cell
- Thalassaemia
- Hereditary spherocytosis
- Elliptocytosis
- G6PD deficiency
- Pyruvate kinase deficiency
Acquired
- Autoimmune
- Drug induced
- DIC
- TTP
- Toxins (lead, uraemia, drugs)
- Malaria
- Paroxysmal nocturnal haemoglobinuria
Causes of polycythaemia
Relative:
- Acute dehydration
- Obesity
- HTN
- Alcohol
- Smoking
Absolute
- Ruba vera
- Raised EPO
- Hypoxia e.g. COPD
Causes of raised neutrophils
Bacterial infection Inflammation Necrosis Corticosteroids Malignancy Myeloproliferative disorder Stress
Causes of low neutrophils
post-chemotherapy agranulocytosis from drugs Viral infection Hypersplenism Bone marrow failure e.g. leukaemia Felty's syndrome
Drugs that cause agranulocytosis
Carbamazepine
Clozapine
Colchicine
Carbimazole
Causes of raised eosinophils
Allergy Eczema Parasite infection (Leishmaniasis) Drug reactions Hypereosinophilic syndrome Hodgkin's disease
Features of Felty’s syndrome
RA
Leukopaenia
Hypersplenism
Causes of thrombocytopaenia
Low platelets
Decreased production
- Bone marrow failure
- Aplastic anaemia
- megaloblastic anaemia
- myelosuppression
increased destruction or consumption
- DIC
- Thrombotic thrombocytopenic purpura
- Haemolytic uraemic syndrome
- Sequestration
- SLE
- CLL
Define megaloblastic anaemia
Abnormality of erythoblasts in bone marrow in which maturation of the nucleus is delayed relative to the cytoplasm
Results from defective DNA synthesis
Large immature RBCs (megaloblasts) and hypersegmented neutrophils are in circulation
Epidemiology of megaloblastic anaemia
More common in women
peak age = 60
FHx
Aetiology of megaloblastic anaemia
B12 or folate deficiency
- 80% is pernicious anaemia
B12 deficiency
- Gastrectomy, gastric resection, gastritis, H. pylori, congenital intrinsic factor deficiency
- Inadequate dietary intake
- Malabsorption, ileal resection, Crohn’s of ileum, chronic tropical sprue, HIV
- Drugs: colchicine, neomycin, metformin
- Long term PPI
B12 deficiency takes 4-5 years due to abundant liver stores
Folate def
- Dietary deficiency
- Malabsorption
- increased demand: haemolysis, leukaemia, pregnancy
- Increased urinary excretion: HF, acute hepatitis, dialysis
- Drug induced: alcohol, methotrexate, anticonvulsants, sulfasalazine, trimethoprim
Causes of non-megaloblastic macrocytosis
(not B12 or folate deficiency)
Alcohol abuse Liver disease Severe hypothyroidism Reticulocytosis Aplastic anaemia Red cell aplasia Myelodysplastic syndromes Myeloid leukaemia Azathioprine
Presentation of megaloblastic anaemia
SOB on exertion
Fatigue
Palpitations
Exacerbations of angina
Conditions associated with pernicious anaemia
Vitiligo Primary hypothyroidism Hashimoto's disease Addison's disease Diabetes Hypoparathyroidism
Investigations for megaloblastic anaemia
FBC (raised MCV, low Hb, raised reticulocytes)
Blood film (macrocytic red cells, neutrophils with hypersegmented nuclei, Howell-Jolly bodies)
Serum folate
Serum B12
LFTs - raised unconjugated bilirubin if increased breakdown of RBC precursors
Urinalysis
Coomb’s test for haemolytic anaemia
Bone marrow exam only if ? haematological malignancy
Autoantibody screen: intrinsic factor antibodies (only found in 27% of pernicious anaemia, but are 100% diagnostic)
Gastric parietal antibodies (more sensitive but less specific)
Schilling’s test - measures absorption of B12 by measuring radioactivity after oral B12 radioisotope (rarely used)
When are Howell-Jolly bodies seem
Asplenia
- Hereditary spherocytosis
- Trauma
- Autosplenectomy (sickle cell)
Radiation therapy e.g. Hodgkin's lymphoma Amyloidosis Severe haemolytic anaemia Megaloblastic anaemia Hereditary spherocytosis Myelodysplastic syndrome
management of megaloblastic anaemia
A cause must be found - not a final diagnosis
- Correct defieicny
- Treat underlying condition
Management of pernicious anaemia
6 injections of hydroxycobalamin every 2-4 days
Then every 3 months
If neurological involvement then every other day then every 2 months
If both B12 and folate deficient - treat the B12 first or it can precipitate subacute degeneration of the spinal cord
WHO pain ladder
- non-opioid including NSAIDs and Paracetamol
+/- adjuvant analgesia (including steroids and antidepressants) - Opioid for mild-moderate pain
+/- non opioid agent
+/- adjuvant analgesia - opioid for moderate severe pain + 1 + 2
Management of mild to moderate pain
- Paracetamol max dose
- Substitute Paracetamol for NSAID (ibuprofen)
- Add Paracetamol to 2
- Paracetamol + naproxen
- Full therapeutic dose of weak opioid (codeine)
Drugs used for neuropathic pain
Amitriptyline
Gabapentin
Pregabalin
Duloxetine
Tramadol only as acute rescue therapy
Epidemiology of pancreatic cancer
Age: peaks in 70s and 80s Increased in men 2% of all cancers Very poor prognosis Fhx - 5-10% have inherited component
RFs Smoking Hereditary cancer syndromes Hereditary pancreatitis Chronic sporadic pancreatitis Diabetes mellitus Obesity Dietary factors (high red meat) IBD, peptic ulcer disease
- Peutz-Jeghers syndrome
- BRCA1 or 2
- HNPCC (Lynch’s syndrome)
Pathophysiology of pancreatic cancer
Linear progression from 3 precursor lesions to invasive ductal adenocarcinoma
Accumulation of multiple genetic alterations
65% head of pancreas
15% body
10% tail
10% multifocal
Spread to liver, lung, skin, brain
Symptoms of pancreatic cancer
Painless, progressive, obstructive jaundice
- Pale stools, dark urine
Abdominal pain - epigastric, radiating to the back, worse when supine, eased sitting forward
Non-specific upper abdominal pain or discomfort
Weight loss
Anorexia
Steatorrhoea
Thirst, polyuria, nocturia
Nausea and vomiting
Bruising
Haematemesis, melena
Signs of pancreatic cancer
Epigastric mass Iron deficiency anaemia (pallor) Enlarged supraclavicular node Petechia, purpura Jaundice Courvoiser's sign POSITIVE - palpable gall bladder, painless Trousseau's sign Hepatomegaly
Courvosier’s sign
palpable gall bladder, painless jaundice
Pancreatic cancer
Trousseau’s sign
HYPOCALCAEMIA BP cuff around the arm. Leave in place for 3 minutes Spasms of the hand and forearm indicate hypocalcaemia Flexion of wrist, MCP joints Extension of DIP and PIP
Investigations for pancreatic cancer
FBC - normocytic normochromic anaemia
LFTs - raised bilirubin, raised ALP and GGT
Hyperglycaemia
Tumour marker - CA19-9
US liver, bile duct and pancreas
Abdominal CT for staging
Endoscopic US for tumour biopsy and histological analysis
MRA - MR angiography - delineates tumour and vascular supply
Management of pancreatic cancer
10% resectable
- proximal pancreatic duodenectomy + antrectomy (Whipple’s procedure)
- adjuvant chemotherapy with GEMCITABINE
90% unresectable
- Stenting of bile duct or duodenum to relieve itch and jaundice
- Palliative chemotherapy if reasonable performance status
- Pain relief
- Coeliac plexus block
- Chemoraditation for severe pain
- Pancreatic enzyme supplements for weight maintenance
Prognosis of pancreatic cancer
Very poor
Stage 1 A has medial survival or 24 months
Stage 4 - 4 months
Primary liver cancers
90% are hepatocellular carcinoma
Other
- hepatoblastoma (more common in children)
- cholangiocarcinoma
Epidemiology of liver cancers
Prevalence follows rates of Hep B and C infection
Highest in Asia and Sub-Saharan Africa
Onset generally 20-30 years after insult
Risk increases with age
More common in men (4-8x)
FHx YES
RFs Alcohol Cirrhosis NAFLD Metabolic syndrome Primary sclerosing cholangitis Cholecystectomy Smoking Hep B and C COCP Diabetes HIB Alpha 1 antitrypsin deficiency High BMI Primary biliary cirrhosis SLE Parasitic flat worm infection Aflatoxins
Aetiology of hepatocellular carcinoma
Patients with cirrhosis have the highest risk of developing HCC
90-95% have underlying cirrhosis
Causes of cirrhosis
- Hep B or Hep C
- alcoholism
- Genetic haemachromatosis
- Primary biliary cirrhosis
- Aflatoxins (myotoxins produced by Aspergillus)
- Metabolic syndrome, diabetes, smoking
Pathophysiology of hepatocellular carcinoma
Acquisition of Hpe B in early life can cause chronic inflammation and cirrhosis
Hep B is a direct carcinogen and causes methylation of p16 gene causing HCC
Chronic Hep B, Hep C and metabolic disorder can lead to p53 damage
Aflatoxins from aspergillus (found in contaminated soya beans) causes mutations in p53
HCC from the development of dysplastic nodules
Spreads to lymph, bone and lungs
Aflatoxins
Mycotoxin produced from Aspergillus
Found in contaminated soya beans
Symptoms of liver cancer
Pruritus Confusion (hepatic encephalopathy) Weight loss Abdominal distension (ascites) Jaundice RUQ pain
Signs of liver cancer
Splenomegaly Jaundice Hepatomegaly Bleeding oesophageal varices Palmar erythema Early satiety Ascites Spider naevi Peripheral oedema Anaemia Asterixis Periumbilical collateral veins
Investigations for liver cancer
FBC - microcytic anaemia, thrombocytopaenia
CRP - may be raised
U&Es - hyponatraemia, raised urea
LFTs - deranged - high IR or PT. Low albumin
AFP - tumour marker for HCC
Liver US - mass over 2cm + raised AFP is diagnostic
FNA +/- biopsy
Staging CT TAP
Screening for liver cancer
HBV carriers
High HBV DNA
Hep C
Alcoholic cirrhosis
Surveillance = 6-12 monthly US and AFP
Management of liver cancer
Liver transplant - minority are suitable.
Solitary tumour under 5cm
Tumour resection
- Preferred choice if no cirrhosis
- Higher recurrence rate than transplant
- Only if no extrahepatic spread and adequate liver function
Ablative therapy
- Alcohol/ethanol injection
- Radiofrequency ablation: high frequency US produces tumour necrosis,. Useful if resection not possible.
- Microwave ablation: destroys tumour cells with heat and induces tissue necrosis
- Chemoembolistion: high concentration chemo via hepatic artery
- Systemic chemotherapy in advanced disease (HCC is relatively chemo resistant)
- Selective internal radiation therapy
Prognosis of liver cancer
Depends on extent of underlying cirrhosis
median survival 6 months.
Liver failure can occur with death due to:
- Cachexia
- Variceal bleeding
- Tumour rupture with peritoneal bleeding
Types of ovarian cancers
Epithelial tumours (85-90%)
- Arise from epithelial cells
- Serous (40-50%) in 40-60 years
- Endometroid (10-20%) in 50-70 years
- Clear cell (5-6%) in 40-80 year associated with endometriosis
- Mucinous (10%)
Germ cell tumours (2-10%)
- Derived from primitive germ cells of gonas
- Women under 35
- Curable with high survival rates
- Rapidly enlarging abdominal mass with pain
Sex cord-stromal tumours <5%
- from connective tissue cells
- fibroma/fibrosarcoma/granulosa cell
Borderline tumours
- Low malignant potential
- Do not respond well to chemo
Epidemiology of ovarian cancer
5th most common cancer in women 2% lifetime risk Increases with age, peak at 70 Increased in Caucasians Fhx yes - BRCA1/2
RFs Smoking Obesity Nulliparous Decreased exercise Early menarche Late menopause Asbestos Endometriosis HT Hx of infertility or infertility treatments e.g. clomifene
Protective factors for ovarian cancer
COCP
Child bearing
Breast feeding
Early menopause
Met sites for ovarian cancer
Pelvic and peri-aortic lymph nodes
Over abdominal peritoneum
Bowel mesentery
Liver capsule
Peritoneal cavity
Presentation of ovarian cancer
75% present with stage 3 or 4.
Insidious onset
Abdominal discomfort Abdominal distension Bloating Urinary frequency Dyspepsia Weight loss Fatigue Anorexia Depression Pelvic or abdominal mass Abnormal uterine bleeding Ascites or pleural effusion Abdominal, pelvic or back pain is a later sign
Investigations for ovarian cancer
Organise CA125 If raised - pelvic and abdo US If both raised = suspicious CT abdo pelvis for assessment Use Risk Malignancy Index 1 to assess likelihood of malignancy. Refer if >250
Alpha fetoprotein can be used to exclude endodermal sinus tumours
Beta hCG can be used for dysgerminomas, embryal carcinomas or choriocarcinomas
Tissue sampling and histopathology
Management of ovarian cancer
Exploratory laparotomy with standard TAH + BSO + lymph node biopsy
Surgery, usually with adjuvant chemotherapy
- Conservative if young and still want children
Chemotherapy for all those stage 2 and above.
Paclitaxel and carboplatin
Can use intraperitoneal chemo
Radiotherapy only in early disease
CA125 can be used for monitoring efficacy and recurrence
Cancers curable with chemotherapy
Teratoma Seminoma High grade Hodgkin's lymphoma Wilm's Myeloma
Cancers with no gain for chemotherapy
Melanoma
Renal
Cholangiocarcinoma
MOA of cytotoxics
Antimetabolites: 5FU, gemcitabine, capectiabine
Alkylating agents - cyclophosphamide, cisplatin, carboplastin
Mitotic spindle poison - vincristine
Taxanes - paclitaxel, docetaxel
Modify tertiary structure of DNS - etoposide
Short term side effects of chemotherapy
Nausea and vomiting Anorexia Weight loss Alopecia Bone marrow suppression - neutropaenia, anaemia, thrombocytopaenia Infective symptoms Fatigue Liver and renal toxicity Mucositis peripheral sensory neuropathy Ototoxcity Acute cardiomyopathy
Long term side effects of chemotherapy
Cardiomyopathy Pulmonary fibrosis Increased risk of secondary cancers, particularly Hodgkin's, acute leukaemia, testicular cancer Subfertility/infertility Renal insufficiency
Why are brain tumours hard to treat with chemotherapy
Chemotherapy is a large molecular with low solubility
BBB is lipid soluble and small molecules
Can’t cross the BBB to treat
Brain tumours also poorly irrigated
When chemotherapy can be given?
Primary chemotherapy - sole anti cancer treatment if highly sensitive tumour types
Adjuvant - given after surgery to mop up microscopic disease
Neo-adjuvant - given pre-surgery to shrink the tumour
Concurrent - given with radiation
Hormonal chemotherapy therapies
Usually reserved for breast and prostate cancer.
Highly effective and relatively non-toxic
Breast cancer
- If oestrogen receptor positive, oestrogen binds to cells to increase growth
- Tamoxifen (SERM) competes for this binding to stop growth
- Aromatase inhibitors prevent precursors being converted into oestrogen
Prostate cancer
- androgens are a critical growth factor for prostate cancer
- Goserelin - LHRH agonist - reduces pituitary production of LH and FSH
- Flutamide anti-androgen, competitive androgen receptor inhibitor
Resistance will eventually develop
Biological chemotherapy agents
Work differently depending on the target cell
Recognise and attach to specific proteins produced by cells
- Breast cancer: Trastuzumab (Herceptin) if HER2 +
- Lymphoma: Rituximab (anti CD20)
- Colorectal cancer: Cetuximab (EGF receptor)
- Colorectal, lung and breast: bevactzumab (VEGF)
- CLL: Alemtuzumab (CD52)
- Lung cancer: Erlotinib (EGFR-TK mutation)
Normal bone marrow
Contains a matrix of sinusoids lined with epithelial cells interspaced with islands of erythropoeitic cells encapsulated by reticulin cells
Composed of red marrow and inactive adipose tissue (yellow marrow)
Found in pelvic, ribs and end of axial long bones
At birth 100% red marrow, decreases with age
Causes of bone marrow failure
Haemopoietic cell damage causing hypo/aplastic anaemia
- Congenital: Fanconi’s anaemia, Diamond Blackfan anaemia
- Acquired: Hep B, EBV, parvovirus 19, autoimmunity, radiation, drugs, poisons (benzene), paroxysmal nocturnal haemaglobinuria
- Abnormal or hostile marrow microenvironment
- Immunological suppression of haematopoesis
Maturation defects - B12 or folate deficiency
Differentiation defects - myelodysplasia
Bone marrow infiltration
- Lymphoma
- Myeloma
- Carcinoma
- Hairy cell leukaemia
Fanconi’s anaemia
Autosomal recessive Causes bone marrow failure by 40 Significant risk of AML Increased in Jewish population Genetic defect resulting in failure of DNA repair
Short stature Café au lait spots petechial, bruises Fatigue Pale
Presentation of bone marrow failure
Anaemia - fatigue, weakness, pallor, SOB, tachycardia
Neutropaenia - recurrent or severe bacterial infections. sepsis. pneumonia. cellulitis
Thrombocytopaenia - easy bruising, petechiae, bleeding from nose/gums, heavy periods, melaena, haematuria, haematemesis, severe headaches, dizziness
If hepatomegaly, splenomegaly or lymphadenopathy - suggests leukaemia
Investigations for bone marrow failure
FBC - normocytic normochromic anaemia, low reticulocyte count. Agranulocytosis, thrombocytopaenia
Ham test / sucrose haemolysis test
- Positive in paroxysmal nocturnal haemoglobinuria
Falconi anaemia screening
- in all children with aplastic anaemia
Bone marrow biopsy and aspiration
- histology may provide cause of the failure
- Marrow replaced with fat cells
- Very few haematopoietic cells
- Hypoplastic in non-leukaemic causes
Imaging - PET or MRI
Paroxysmal nocturnal haemoglobinuria
Rare acquired, life threatening disease
Destruction of red blood cells by the complement system
Only ACQUIRED haemolytic anaemia
- Defect in cell membrane (glycophosphatidylinositol)
Haematuria- more noticeable in the morning
Management of bone marrow failure
Transfusions of RBCs and platelets as required
Severe cases - bone marrow transplant - only if under 55, with severe disease and a match
If transplant not an option - intensive immunosuppressive therapy with haematopoietic growth factors: ciclosporin
White blood cell stimulating agents: filgrastrim
EPO
Subtypes of nausea associated with chemotherapy
Acute - within 24 hours of chemo
Delayed - between 24 hours and 5 days
Breakthrough - occurs despite prophylactic treatment
Anticipatory - triggered by surroundings or anxiety for chemotherapy
Refractory - occurs with failed antiemetic use
Chemotherapy that has high chance of nausea and vomiting
Cisplatin
Dacarbazine
Doxorubicin
Cyclophosphamide
Carboplatin
Irinotecan
Oxaloplatin
Risk factors for N&V with chemotherapy
Female Under 55 N&V during pregnancy Hx of motion sickness Anxiety or depression
Management of nausea and vomiting in chemotherapy
Acute
- Dexamethasone
- Add 5HT3 if severe
Delayed
- Domperidone
- Add dexamethasone if severe
Managing alopecia with chemotherapy
Always reversible Can be reduced by scalp cooling during chemotherapy Cut hair short. Wigs Wear sun cream
Neuropathy and chemotherapy
More common with paclitaxel and docetaxel
Can start anytime after treatment and worsens as treatment continues
Starts in toes
- Protect feet from injury
- Use walking aids
- Check water temperature
MOA of radiotherapy
X-rays
Collide with orbiting electrons in tissues to eject fast electrons - damages DNA through direct action
More commonly collides with water producing hydroxyl radicals that damage DNA through indirect action (2/3)
When is radiotherapy given in cancer?
Radically +/- chemotherapy as a curative treatment
Adjuvant with surgery
In palliation - to increase survival and increase quality of life
What causes increase cell sensitivity to radiotherapy?
Cells in G2 or M Increased cell oxygenation Highly active metabolically Well nourished and rapidly dividing Lymphocytes and oocytes
Immediate effects of radiotherapy
Depends on site
Lethargy Skin redness Local discomfort Nausea Mucositis, diarrhoea hair loss Decrease taste Blood changes Flu like symptoms Decreased libido Sore throat
Long term effects of radiotherapy
Change in skin colour Fibrosis Delayed wound healing Breathing problems Impotence Dry mouth Infertility bowel changes - diarrhoea 2y cancer from radiation long term pain Lung classically has delayed response - pneumonitis
Types of radiotherapy
External beam radiation therapy
- 3D conformal radiation therapy
- Intensity modulated radiation therapy - collimators, allows different areas to get different doses
- Image guided: repeat scans during treatemtn to detect change in tumour and alter raditation
- Steterotactic radiotherapy - high dose radiation to small tumour, extremely accurate and image guided
- Proton therapy
Internal radiation therapy
- Brachytherapy - radiation delivered from sources placed inside the body
Systemic
- patient swallows or is injected with radioactive substance that can be bound to monoclonal antibodies
- 131 I used in thyroid
Congenital breast disease
1-5% of the population have accessory nipples (less common = accessory breast)
Usually develops along the milk line
Most common site for extra nipple is below the breast
Most common site for extra breast in in axilla
Treatment only for cosmetic purposes
Subject to the same disease as normal breast tissue
Cystic breast mass
MOST COMMON
- Common cause of dominant breast mass
- May occur at any age
- Uncommon in post-menopausal
- Fluctuates with menstrual cycle
- Firm and mobile
- Well demarcated from surrounding tissue
- Not as smooth and mobile as fibroadenoma
- Difficult to distinguish from solid mass
Treatment = aspiration
Fibroadenoma
2nd most common
- Benign solid tumours containing glandular and fibrous tissue
- Well defined, mobile mass
- Breast mouse
- Women between 15 and 35
- Cause unknown
- Needs core biopsy
- Increases in size with pregnancy or oestrogen therapy
- Excise if >3cm, rapidly enlarging or patients wishes
- Giant = 10cm
Phylloides tumour
Rapidly growing 25% malignant 10% metastasise Bulky tumours that distort the breast May ulcerate through the skin due to pressure necrosis Treatment = wide excision
Fat necrosis
Rare
Secondary to trauma, often not remembered
Tender
Ill defined mass
Occasional skin retraction
Biopsy and clinical follow up to ensure decreasing size
Can mimic cancer
Galactocoele
Milk filled cyst from over distension of lactiferous duct
Firm, non-tender mass in breast
Common in upper quadrants, beyond areola
Diagnostic aspiration is usually curative
Duct ectasia
Usually in older women
Dilation of subareolar ducts can occur
Palpable retroareolar mass
Nipple discharge or retraction
Treatment = biopsy or excision
Gynaecomastia
Benign growth of glandular tissue of the male breast
Due to imbalance of oestrogen and androgens
Unilateral or bilateral
Physiological and common in infancy, adolescence and adults
Causes: testicular tumours, drugs (cannabis, steroids, spironolactone), idiopathic, chronic disease
No treatment
Paget’s disease of the breast
Cancerous Appearance of eczema Skin changes involving the nipple of the breast 2% of all breast cancers Areolar itchy and inflamed Skin may become flaky Discharge: straw coloured or bloody Burning sensation inverted nipple No lump as such
Nipple discharge
Majority of cases are benign
Most common cause is lactational
Other causes: over stimulation, prolactin secreting tumours, hypothyroidism, drugs
Unilateral spontaneous bloody discharge is suspicious
Mastitis
Most common in lactating female
Dry cracked fissured areola or nipple is portal for infection
Usually caused by Staph or Strep
Treat with HEAT, continued breast feeding and antibiotics
Rule out malignancy
Breast abscess
May present with breast swelling, tenderness and fever
Breast tender, warm and fluctuant
May also have purulent discharge and/or systemic symptoms
Treated by US guided aspiration and Abx
Surgical drainage only is skin necrosis
Normal range of blood calcium
2.25-2.5mmol/L
Blood calcium circulation
Calcium is protein bound
Must take consideration of albumin levels to interpret blood calcium
In hypercalcaemia, over half of circulating calcium is protein bound
Levels from labs can be corrected or uncorrected (allowing for albumin)
Only the unbound ionised calcium is physiologically important
Aetiology of hypercalcaemia
90% of cases:
- Primary hyperparathyroidism
- Malignancy
- Primary malignancy
- Metastasis
- Myeloma
Others:
- Granulomatous conditions: sarcoidosis, TB
- Renal failure
- Endocrine: thyrotoxicosis, phaechromocytoma, primary adrenal insufficiency
- Drugs: thiazide diuretics, vitamin D and A
- Familial hypocalciuric hypercalcaemia
- Prolonged immbolisation
- Calcium alkali syndrome
- AIDS
- Paget’s disease
Presentation of hypercalcaemia
- 5-2.8
- Polyuria and polydipsia
- Dyspepsia
- Depression
- mild cognitive impairment
2.8-3.5 \+ muscle weakness \+ constipation \+ anorexia \+ fatigue
>3.5 \+ abdominal pain \+ vomiting \+ lethargy \+ shortened QT interval \+ coma \+ pancreatitis
stones, bones, thrones, abdominal moans, and psychic overtones
- Renal or biliary stones
- Bone pain
- Abdominal pain and nausea and vomiting
- Thrones : polyuria
- depression/cognitive dysfunction/coma
Investigations for hypercalcaemia
Calcium levels
Hypercalcaemia PLUS
- Raised albumin and raised urea = dehydration
- Normal ALP = myeloma, calcium alkali syndrome, thyrotoxicosis, sarcoidosis
- Raised ALP - bony mets, sarcoidosis, thyrotoxicosis
- Raised calcitonin = B cell lymphoma
PTH levels
ALP
Phosphate
X-rays
US for stones
CT for bony abnormality
Pathophysiology of hypercalcaemia
Causes dehydration by inducing renal resistance to vasopressin - nephrogenic diabetes insipidus
Dehydration leads to further increase in calcium
Damages excitable membranes leading to muscle fatigue
Raised calcium exceeds capacity for renal absorption and so it enters urine = stones
Acute Management of hypercalcaemia
Increased fluids - 0.9% NaCl (increases urine output and decreases calcium)
Loop diuretic (furosemide)
IV bisphosphonates (after hydration) to decrease bone turnover
Glucocorticoids - if vitamin D toxicity, lymphoma or sarcoidosis
Iv gadolinium - if not responding to bisphosphates
Denosumab - RANKL inhibitor to prevent calcium removal from bones in reponse to PTH stimulation
If severe or renal failure then haemodialysis
Management of chronic hypercalcaemia
Regular monitoring
Decreased dietary calcium - dairy and leafy green veg
Mobilisation
Important side effect of bisphosphonates
Osteonecrosis of the jaw
Also, oesophagitis if not taken correctly
Define cauda equina syndrome
Cauda equina is formed by nerve roots caudal to the level of the spinal cord termination
The syndrome is caused by compression of these nerves
Medical emergency
Causes of cauda equina
Herniation of intervertebral disc (usually lumbar) Tumours, mets, lymphomas, spinal tumours Trauma Infection Congenital spinal stenosis Spina bifida Spondylolisthesis Late stage anklylosing spondylitis Post-op haematoma Sarcoidosis
Presentation of cauda equina syndrome
Low back pain, pain into legs
Lower limb weakness and sensory deficit
Bowel dysfunction: faecal incontinence, constipation, loss of anal tone and sensation
Bladder dysfunction: urinary retention, difficulty starting or stopping stream, overflow incontinence, decreased urethral and bladder sensation
Saddle and perineal anaesthesia
Sexual dysfunction
Decreased reflexes below the level (LMN)
Presentation of spinal cord compression
Neurological symptoms - Abnormal gait, clumsy or weak limbs Loss of sexual, bladder and bowel function Sensory changes variable Reflexes are - increased below the level of the compression - Absent at the level of compression - Normal above compression
Symptoms of spinal mets in a cancer patient
Pain in thoracic or cervical spine Progressive lumbar spinal pain Severe unremitting lower spinal pain Spinal pain aggravated by straining (stool, cough, sneeze) Localised spinal tenderness Noctural spinal pain preventing sleep
Investigations in suspected cauda equina
EMERGENCY
MRI of whole spine ASAP
Treatment of spinal metastases
Analgesia as required
Bisphosphonates if breast cancer or myeloma to decrease pain and risk of metastatic spinal cord compression (MSCC)
Radiotherapy - palliative for pain
Consider vertebroplasty if mechanical pain or vertebral body collapse
Consider surgery to stabilise the spine and prevent MSCC
If MSCC and pain and not suitable for surgery offer halo vest or external orthosis
Denosumab to prevent MSCC
Treatment of threatened spinal cord in metastatic spinal cord compression
Nurrse flat with neural spine and slowly progress to gradual movements
Loading dose dexamethasone ASAP (16mg)
Start treatment within 24 hours
Stage tumour and establish primary histology
If surgery - spinal cord decompression and spinal column stabilisation
Only offered in para/tetra plegic after 24 hours if for pain
Radiotherapy if not surgery within 24 hours unless, >24 hours with permanent disability and pain free or overall prognosis too poor.
Supportive therapy for spinal cord compression post event
Thromboprophylaxis Regular turning to decrease pressure sores Urinary catheter Faecal incontinence Rehab Social support
Methods of treating cancer bone pain
Depends on the type of cancer and patients wishes
- Radiotherapy - MOST COMMON, can relieve pain and swelling. Generally external
- Hormonal therapy
- Chemotherapy
- Targeted therapies
- Surgery
Remove affected area, replace with prosthesis
Bone support if weak and open to fracture
Joint replacement
Cementoplasty
Analgesics
Bisphosphonates if breast or myeloma
Massage
Heat
Aetiology of haemolytic anaemia
Genetic
- Red cell membrane abnormalities: hereditary spherocytosis, elliptocytosis
- Haemoglobin abnormality: sickle cell, thalassaemia
- Enzyme deficit: G6PD deficiency, pyruvate kinase deficiency
Acquired
- Immune: haemolytic disease of the newborn, blood transfusion reaction
- Autoimmune
WARM - + Coomb’s - idiopathic, SLE, lymphoma, CLL, Evan’s syndrome
COLD - cold haemogluttin disease, paroxysmal cold haemoglobinuria, mycoplasma pneumonia, lymphoma, infectious mononucleosis
Non-immune
- Trauma: cardiac haemolysis, haemolytic uraemic syndrome, thrombocytic thrombocytopaenia purpura
- Infection: malaria, sepsis, leishmaniasis
- hypersplenism
- paroxysmal nocturnal haemoglobinuria
- liver disease
Hereditary spherocytosis
Autosomal dominant
Abnormality of erythrocytes
Sphere shaped RBCs
More prone to rupture, less flexible to travel through arteries
Anaemia Jaundice Splenomegaly Fatigue Howell-Jolly bodies
Blood smear: red blood cells appear small and lack central pale area
Elevated reticulocytes
Increased mean cell haemoglobin concentration
G6PD deficiency
Glucose 6 phosphate dehydrogenase deficiency
X linked recessive inborn error of metabolism
Predisposes to haemolysis and jaundice after a number of triggers.
- Illness, especially infection
- Drugs (quinine)
- Foods (fava beans/ broad beans)
- Certain chemicals
Can present with DKA, haemolytic crisis, prolonged jaundice in neonate, AKI
Increased in Mediterranean and African
Most common human enzyme condition,
Heinz bodies are present
Coomb’s test negative (not immune mediated)
Beulter fluorescent spot test - positive
Pyruvate kinase deficiency
Inherited metabolic disorder of the enzyme pyruvate kinase which affects survival of red blood cells
autosomal recessive
- Symptoms most severe in childhood
- Haemolytic anaemia
- Cholecystolithiasis
- Gallstones
- Tachycardia
- haemochromatosis
- Splenomegaly
- Jaundice
Haemolytic disease of the newborn
Alloimmune condition that develops in a foetus when IgG produced by the mother pass through placenta.
Some attack antigens on RBCs in foetal circulation causing haemolysis
Develops reticulocytosis and anaemia
Positive Coomb’s test
Elevated cord bilirubin
Haemolytic anaemia
Jaundice
Causes:
- foetal maternal haemorrhage
- ABO incompatibility in transfusion
- ABO haemolytic disease of the newborn
- Rhesus D haemolytic disease of newborn
Pathophysiology of haemolytic anaemia
Normal RBC has lifespan of 120 days
Shorted in haemolytic anaemia
It can occur by 2 mechanisms:
- Intravascular: RBC destroyed in circulation due to complement fixation, trauma or other intrinsic factors:
Raised Hb, haemosidinuria, decrease haptoglobulins, positive Schumm’s test - Extravascular - most common
RBC removed from circulation of mononuclear phagocytic system as they are intrinsically defective or have immunoglobulins on their surface
Signs and symptoms of haemolytic anaemia
Can be caused by anaemia and underlying disease
- Severe anaemia: tachycardia, SOB, angina
- Gallstones (raised bilirubin)
- Haemoglobinuria (in intravascular)
- Pallor, pale conjunctiva
- Hypotension (if severe)
- Mild jaundice
- Splenomegaly (CLL, SLE, lymphoma, hereditary spherocytosis)
- leg ulcers (sickle cell)
- Bleeding and petechiae - Evan’s syndrome or TTP
Investigations for haemolytic anaemia
FBC
- Low Hb
- Usually normal MCV or MCH
- Platelets normal (high in CLL, SLE or haemolytic uraemic syndrome)
- Coomb’s test (positive if immune mediated)
- Cold agglutinins
High anti-I antibody = infectious mononucleosis, mycoplasma
High anti-p antibody = paroxysmal cold haemoglobinuria
US for spleen size
Blood tests in haemolytic anaemia due to increased RBC breakdown
Low Hb High bilirubin High urobilinogen Raised LDH Decreased haptoglobin Positive urinary haemosiderin
Causes of positive Coomb’s test
Drugs: methyldopa, quinine, NSAIDs, interferon, ribavirin
Autoimmune:
- Haemolytic disease of newborn
- Transfusion reaction
- SLE
- Evan’s syndrome
- Waldenstrom’s
- Infectious mononucleosis
- Paroxysmal cold haemoglobinuria
Causes of spherocytes on blood film with negative Coomb’s test
Hereditary spherocytosis
Malaria
Causes of bite cells, blister cells of Heinz bodies on blood smear
G6PD deficiency
Pyruvate kinase deficiency
Pyrimide 5’ nucleotidase deficiency
Causes of fragmentation on blood smear
Microangiopathic haemolytic anaemia
- Eclampsia
- Haemolytic uraemic syndrome
- DIC
- TTP
Haemolytic uraemic syndrome
TRIAD
- Haemolytic anaemia
- AKI (uraemia)
- Thrombocytopaenia
In children
Generally preceded by E. Coli O157
- Schisocytes
- Anaemia
- Elevated LDH
- Low platelets
- Confusion
- Fatigue,
- Oedema
Management of haemolytic anaemia
Mainly supportive Folic acid as haemolysis can cause folate deficiency Discontinue any aggravating medications Avoids transfusions unless necessary Corticosteroids Splenectomy Rituximab (anti CD20)
Beta thalassaemia
Normally haemoglobin in 2 alpha and 2 beta chains
In beta thalassaemia - either none or reduced beta chains formed.
Increased alpha chains precipitate causing ineffective erythropoiesis and haemolysis
Increase HbA2 (alpha 2 delta 2)
Increased HbF (alpha 2, gamma 2)
- Major require regular transfusions. Severe.
- Minor (trait) asymptomatic
Alpha thalassaemia
Caused by gene deletions
4 deletions = Bart’s (not compatible with life) no alpha, Hb gamma 4
3 = HbH (beta 4) severe anaemia
2 = HbA, some HbH
1 = HbA
Sickle cell pathology
HbS results from a single base mutation of adenine to thymine which changes glutamic acid to valine on the beta chain.
HbSS - sickle cell (both genes abnormal)
HbAS - sickle trait
It does not manifest until HbF decreases to adult levels at 3-6 months
Increased prevalence in African populations.
Deoxygenated HbS is insoluble and polymerises
Decreased flexibility, rigid and sickle. After time does not return to normal when oxygenated.
Sickling produces
- Decreased RBC survival
- Impaired passage of cells through microcirculation
- Obstruction and infarction
- Precipitated by: infection, dehydration, cold, acidosis, hypoxia
HbS releases oxygen more readily than HbA so feel well despite the anaemia
Presentation of sickle cell anaemia
Anaemia Jaundice Pallor Lethargy Growth restriction Weakness
Veno-occulsive crisis
- Acute severe bone/hand/feet pain due to occlusion of small vessels
- Fever accompanies pain
Pulmonary hypertension (increased free Hb, decrease NO, endothelial dysfunction)
Acute chest syndrome
- 30%. Chronic lung disease and pulmonary hypertension is most common cause of death in sickle cell
- Caused by infection, fat embolism from necrotic bone marrow, pulmonary infarction from sequestration
- SOB, chest pain, consolidation of chest
Anaemia (60-60)
Splenic sequestration - splenomegaly. Splenic pooling of RBCs and hypovolaemia can cause shock
Bone marrow aplasia (after erythrovirus B19)
Long term problems associated with sickle cell disease
Abnormal growth and development
- Delayed sexual maturation, decreased weight, normal height by adulthood
- Compression and shortening of bones from vaso occlusion
- Increased osteomyelitis
- Increased infections: especially bones, kidneys and lungs
- Leg ulcers over malleoli
- Cardiac issues: cardiomegaly, arrhythmia
- Neuro: TIA, seizure, stroke, coma
- Gall stones, hepatomegaly, priaprism, retinopathy, spontaneous abortion
Investigations in sickle cell
FBC - Hb 60-80, high reticulocytes
Blood film: sickling
Sickle solubility test
Hb electrophoresis - no HbA, 90% HBSS, 10% HbF
General management of sickle cell
Prophylactic 500mg penicillin daily
Pneumococcal and annual influenza vaccine
Folic acid of haemolysis
Blood transfusions if required
Hydroxycarbamide - increased HbF concentration to decreased crises
Stem cell transplant
Counselling
Stroke prevention
Contraception - not IUDs as infection risk
Management of acute painful sickle crisis
Avoid exposure to cold and dehydration
Morphine IV/SC until pain controlled (PCA)
Adjuvant oral analgesia - Paracetamol + ibuprofen/diclofenac
Laxatives
Antipruritics, antiemetics, anxiolytic as required.
Prognosis of sickle cell
Median life expectancy 40-60
Most common cause of death in first 2 years = infection
In adults = cerebrovascular disease, sepsis, acute chest syndrome or pulmonary hypertension
4 main subtypes of leukaemia
Acute Myeloid Leukaemia (AML)
Acute lymphoblastic leukaemia (ALL)
Chronic Myeloid Leukaemia (CML)
Chronic Lymphocytic Leukaemia (CLL)
AML
Acute myeloid leukaemia
Malignant disease of bone marrow in which precursors of blood cells are arrested in an early stage of development
- Most AML shows > 30% blasts of myeloid lineage
- Maturational arrest of bone marrow cells in 1st stage of development
- Activation of abnormal genes through chromosomal translocation
- Decreased number of blood cells
- Failures of apoptosis leads to increased accumulation in liver and spleen
Types of AML
AML with characteristic gene abnormalities - better prognosis
AML with multilineage dysplasia - prior MDS or myeloproliferative disease
AML therapy related - post chemo or radiotherapy
AML otherwise not characterised
Epidemiology of AML
5 per 100,00
Most common acute leukaemia in adults
Incidence increases with age - median age 67
RFs
- Predisposing haematological disorders: MDS, aplastic anaemia, myelofibrosis, paroxysmal nocturnal haemoglobinuria, polycythaemia, ruba vera
- Radiation
- Congenital disorders: Bloom’s syndrome, Down’s, congenital neutropaenia, Fanconi’s anaemia, neurofibromatosis
- Autosomal DOMINANT - presents in 60s
- Previous cancer chemotherapy
Symptoms of AML
Children - acute symptoms over days to weeks
Adults - fatigue over weeks to months
Dizziness SOB on exertion MI or angina Fever (high WBC, low neutrophils) Easy bleeding or bruising Haemorrhage in lungs, GI tract or CNS Fullness in LUQ and early satiety Leukostasis with respiratory distress and altered mental status Bone pain
Signs of AML
Hepatomegaly Splenomegaly Lymphadenopathy Testicular enlargement Mediastinal mass SVCO Pallor Signs of infection Leukostasis - hypoxia, low GCS, retinal vein dilation, papilloedema, fundal haemorrhage Petechiae, purpura, ecchymoses Gingivitis
Investigations for AML
FBC
- Thrombocytopaenia
- Anaemia (macrocytic)
- WCC can be high, low or normal
- Low neutrophils
- Raised blast cells
Clotting - DIC is common, raised PT, low fibrinogen
LFTs and U&Es
High LDH
High lactic acid
Both from increased cell turnover
Peripheral blood film - blast cells
Bone marrow aspiration - DIAGNOSTIC
- Hypercellular with replacement of normal elements with blast cells
- AUER rods
- HLA typing and family for stem cell transplant
Cytochemical stains for classification
If child chromosomal analysis
Check heart function as treatment cardio toxic
Management of AML
Criteria of response =
Blast cell clearance in bone marrow <5% of all nucleated cells, normal haematopoiesis and normal blood counts.
Treatment given in 2 phases:
- Induction (to achieve remission): cytarabine and daunorubicin. Severe bone marrow hypoplasia
- Post remission consolidation: only if remission achieved.
- Can use stem cell transplant in moderate to high risk (not low)
- Blood product replacement
- Antibiotics for infection ? potential antibiotic prophylaxis
- Aciclovir for reactivation of herpes simplex or zoster
- Allopurinol to lower uric acid levels
Prognosis of AML
13% will get 2y malignancy
In children 80% achieve remission
Adults:
- Young patients 80% remission, 5 year survival = 40%
- Older patients: 60% remission, median survival 5-10 months
Poor prognosis: failure to respond to 1 or 2 induction rounds, previous MDS or chemo, co-morbidities, increasing age
ALL
Acute lymphoblastic leukaemia
Malignant transformation of a clone cell from lymphoid progenitor cells.
The majority are B cell in origin but some are from T cell precursors.
- Lymphoid precursors proliferate and replace normal cells of the bone marrow. Blast cells spill into peripheral circulation
- Immunophenotyping distinguished from other lymphoid malignancies
Epidemiology of ALL
Most common cancer in children 3 per 100,000 12% leukaemias but 80% in children Peak incidence 2-4 years Smaller peak in 50s
RFs
- Genetic (25% twin concordance)
- Trisomy 21
- Fragile chromosomes: Fanconi’s anaemia
- Increased radiation dose
- Smoking, alcohol, pesticides, illicit drug use (all weak associations)
Symptoms of ALL
Fatigue, dizziness, palpitations
Sever or unusual bone or joint pain
Recurrent and severe infections
Fever without obvious infection
LUQ fullness and early satiety (splenomegaly)
SOB
Headache, irritability, altered mental status
Haemorrhagic or thrombotic complications - DIC
Bone pain
Sanctuary sites for ALL
Testicles
Meningeal
Signs of ALL
Pallor Non specific signs of infection Tachycardia Flow murmur Petechiae -> purpura -> echymoses Hepato and splenomegaly Lymphadenopathy Testicular enlargement Gum hypertrophy Cranial nerve palsy 3,4,6,8 Renal stones, AKI (raised uric acid)
Investigations of ALL
FBC
- Anaemia
- Thrombocytopaenia
- WCC high, low or normal
- Neutropaenia (usually)
- Will not always be abnormal if no bone marrow suppression yet
Blood film
- Blast cells (may be absent if just confined to marrow)
Clotting - DIC can occur, raised PT, low fibrinogen
Raised LDH and raised uric acid
Check LFTs and U&Es prior to treatment
CXR - lytic bone lesions or mediastinal mass
ECG or echo due to cardio toxic drugs
Bone marrow biopsy > 20% blasts in marrow or peripheral blood
Flow cytometric demonstration of lymphoid antigens to confirm lymphoid and not myeloid
Cytogenetics - Philidelphia chromosome
Negative MYELOPEROXIDASE screen is diagnostic
Classifications of ALL
B cell ALL
- Early pre-B ALL - 10%
- Common ALL - 50%
- Pre -B ALL - 10%
- Mature B ALL (Burkitt’s) - 4%
T cells ALL
- Pre-T cell ALL - 5-10%
- Mature T ALL - 15-20%
Management of ALL
Mature B cell ALL get short term intensive chemo (30-40% remission rate)
Others:
- Remission induction
- Consolidation/intensification
- Maintenance
Remission induction
- Eliminates 90% of leukaemic cells to restore haemtopoeisis
- Remission rate in children 98%, adults 85%
- Quadruple therapy for 4-6 weeks: prednisolone, vincristine, anthracyclines, crisantaspase
Consolidation
- Starts once normal haematopoiesis
- Methotrexate + mercaptopurine or aspraginase
- Done if high or very high risk of relapse
Maintenance
- For 2 years
- weekly methotrexate + daily mercaptopurine
General supportive
- Replacement blood products
- Growth factors can alleviate myelosuppression (GCSF)
- Antibiotics and antifungals for opportunistic infection
- Allopurinol for high uric acid levels
- Hickman line
CNS prophylaxis
- ALL patients often have meningeal leukaemia at relapse
- Intrathecal and high dose chemotherapy
Stem cell transplant allows intensification of chemo and radiotherapy by replacing damaged stem cells
Relapse has very poor prognosis
Complications of ALL
Susceptible to pneucystis jirovecii
Impaired growth
Secondary malignancy
Cardiac or pulmonary disease
Most complications are iatrogenic
- Haemorrhage, anaemia infection
- Hair loss, rash
- N&V. Diarrhoea. Constipation
- Mucositis
- Electrolyte disturbance
- Nephro and hepatotoxicity
- Peripheral neuropathy
- Stroke
- Graft vs host disease
- Tumour lysis syndrome
Tumour lysis syndrome
Most commonly after treatment for leukaemias and lymphomas due to increased cell lysis.
Raised uric acid Raised phosphate Raised potassium Low calcium Raised blood urea nitrogen
Prognosis of ALL
Better in children than adults
85% long term survival rate in children
Adults have more cytogenic abnormalities and less likely to tolerate treatment
Poor prognosis with: <12 months, > 10 years, male, adverse cytogenetics, CNS involvement, very high leukocyte count at presentation,
Define CML
Myeloproliferative disorder of pluripotent haematopoietic stem cells affecting one or all cell lines
- erythroid
- platelet
- myeloid
Over time the leukaemic cells proliferate due to stepped up production and failed apoptosis
Stages of CML
3 stages
CHRONIC
- Immune system is competent and patients are asymptomatic for prolonged periods
- 4-5 years
- More than 90% are diagnosed in chronic phase
ACCELERATED PHASE
- Defined by 15-30% blasts in the blood or bone marrow OR, >20% basophils in blood, thrombocytosis, thrombocytopaenia
- In 2/3 chronic transforms into accelerated
- Increased blasts, low Hb, Low platelets
- Progressive maturation arrest
- Increased symptoms, splenomegaly
BLAST CRISIS
- 1/3 straight from chronic to blast
- > 30% blasts in blood or bone marrow or extramedually blastic infiltration
- Severe symptoms due to tumour burden: weight loss, fever, night sweats, bone pain, bleeding, infection
- Aggressive acute leukaemia with marrow exhaustion is rapidly fatal and refractory to chemotherapy
Epidemiology of CML
1 per 100,000
15% of adult leukaemias
Median age 60-65
Can be caused by PHILADEPHIA CHROMOSOME
Translocation 9 to 22
places ABL from long arm of 9 to long arm of 22 in BCR region
BCR-ABL encodes fro a protein with strong tyrosine kinase activity and results in CML
Presentation of CML - Symptoms
Can be insidious in onset Fatigue Weight loss Night sweats Abdo fullness/ abdominal distension LUQ pain if splenic infarction
Signs of CML
Splenomegaly hepatomegaly Lymphadenopathy Anaemia Easy bruising Fever Gout due to rapid cell turnover Hyperviscosity syndrome
Hyperviscosity syndrome
Due to leucocytosis
- Visual disturbance (papilloedema, venous obstruction, retinal haemorrhage)
- Priaprism
- Cerebrovascular event
- Confusion
Treat with leukocytophoresis, prednisolone, chemotherapy and allopurinol
Avoid blood transfusions as can worsen
Investigations for CML
FBC
- normochromic normocytic anaemia
- Leukocytosis
- Granulocytes at all development stages
- Increased eosinophils and basophils
- Platelets: high low or normal
Peripheral blood smear
- All stages of maturation seen
- Often resembles a bone marrow aspiration
U&E
- Normal - can have high LDH and urate
Bone marrow aspiration
- Quantify % blast cells and basophils
- Assess degree of fibrosis and obtain material for cytogenetics
Cytogenetics - FISH or PCR for Philadelphia chromosome
HLA typing if considering transplantation
Management of CML
Aim:
- haematological remission (normal FBC and exam)
- Cytogenetic remission (no Philadelphia chromosome)
- Molecular remission (no BCR-ABL)
- Tyrosine kinase inhibitor (IMATINIB)
- 70% have cytogenetic response in 12 months
Transplant
- Most common indication for transplant
- Should be done in chronic phase
- Preferable if HLA matched sibling
Risks of bone marrow transplant
Graft vs host disease Veno occlusive disease Life threatening infections Risk of 2y malignancies Decreased QoL
Prognosis of CML
Increasing survival
Estimated 90% survival at 5 years
Define chronic lymphoid leukaemia
CLL
Malignant monoclonal expansion of B lymphocytes
Accumulation of abnormal lymphocytes in blood, bone marrow, spleen, liver and lymph nodes
Normal appearance but are immature and non-reactive resulting in immunological compromise
25% of all leukaemias
Disease of the elderly
Diagnostic criteria for CLL
Presence in peripheral blood of > 5000 B lymphocytes for over 3 months
Leukaemic cells in blood smear - small mature lymphocytes, narrow border of cytoplasm, dense nuclei, no nucleoli and partially aggregated chromatin.
Epidemiology of CLL
Most common leukaemia (25%) Increases with age 4.2 per 100,000 Increase in males FHx rare
Symptoms of CLL
Insidious onset
90% are asymptomatic at diagnosis - detected on routine blood tests
- Susceptibility to infection (zoster/simplex/pneumonia)
- Symmetrically enlarged lymph nodes
- Abdominal discomfort from enlarged spleen
- bleeding / petechiae from skin/mucus membrane
- Fatigue
Signs of CLL
Lymphadenopathy Splenomegaly Heptatomegaly Petechiae Tonsillar enlargement pallor (rare = skin infiltration or involvement of lacrimal glands or salivary glands)
Investigations in CLL
FBC
- Normocytic normochromic anaemia
- Clonal B cell lymphocytosis
Blood film
- Lymphocytosis and SMUDGE cells
Coomb’s test
- before any treatment to determine if there is any autoimmune haemolytic anaemia
Bone marrow aspirate
- Lymphocytic replacement of normal marrow elements
Lymph node biopsy
- If lymph nodes enlarge rapidly then can transform into high grade lymphoma
- If transformation = Richter’s syndrome
Immunophenotyping - peripheral blood flow cytometry confirms CLL and shows clonal B lymphocytes expressing CD5, CD19, CD20 and CD23
Richter’s syndrome
Transformation of CLL to high grade lymphoma
+ fever
+ weight loss
+ pain
Staging of CLL
Binet system
A, Hb>10, Platelets > 100, < 3 lymph nodes involved
B Hb and platelets as A but with 3+ lymph nodes involved
C - Hb< 10, platelets less 100 or both
Management of CLL
No curative treatments Current treatments do not prolong survival If early disease = watch and wait - blood counts every 3- 12 months Chemotherapy only with active symptoms - Weight loss > 10% - Fatigue - Fever - Night sweats - Autoimmune haemolytic anaemia - Lymphadenopathy - Splenomegaly
Typically cyclophosphamide in combinations
Rituximab (anti CD20)
Steroids for autoimmune complications
Stem cell transplant is only curative treatment but most paitents are elderly with increased morbidity and mortality so rarely justified
Splenectomy
Palliative radiotherapy for large spleen/lymph nodes
Complications of CLL
Susceptible to infection
- Antibiotic prophylaxis
- Up to date with immunisations
Autoimmune cytopaenia
AUTOIMMUEN HAEMOLYTIC ANAEMIA (common)
Hyperviscosity syndrome due to raised WCC
Lymphatomous transformation - Richter’s syndrome in 5%
increased risk of 2y malignancy
Types of lymphoma
Hodgkin’s
Non-Hodgkin’s
Define Hodgkin’s lymphoma
Uncommon haematological malignancy arising from MATURE B CELLS
Characterised by presence of REED-STERNBREG CELLS
Epidemiology of Hodgkin’s lymphoma
3 per 100,000
2 age peaks - young adult 20-25 and 50-60
Nodular sclerosis type increased in young females (better prognosis)
Increased in Caucasians
Overall no gender difference
RFs
5% familial
Past EBV/infectious mononucleosis
Higher socio-economic class
Aetiology of Hodgkin’s lymphoma & pathophysiology
Unknown
Probably multi factorial
Could be infectious as EBV is often harboured in Reed-Sternberg cells
Unknown pathophysiology
Immunoglobulin expression in ABSENT
Classification of Hodgkin’s lymphoma
Nodular sclerosis 70%
Mixed cellularity 25%
Lymphocyte rich 5%
Lymphocyte depleted <1%
Presentation of Hodgkin’s lymphoma
Painless lymphadenopathy - usually in the head, neck, mediastinum
Itching
Eosinophilia
Unexplained fever Night sweats Weight loss Cough Dyspnoea Chest pain SVCO Abdominal pain Tonsillar enlargement Hepatomegaly Splenomegaly
Investigations for Hodgkin’s lymphoma
FBC
- Low Hb - normochromic normocytic anaemia
- Low platelets
- Increased/decreased/normal WCC
- EOSINOPHILIA
Raised CRP/ ESR and LDH
CXR: mediastinal mass, large mediastinal adenopathy
PET/CT for staging - can use full body CT
Excisional lymph node biopsy - REED-STERNBERG CELLS
Immunohistochemical studies
- CD30, CD15, CD20
Bone marrow biopsy
TFTs can become abnormal after neck radiation
Staging in Hodgkin’s lymphoma
Ann Arbour system
I - single lymph node area
II - 2+ lymph node regions on same side of diaphragm
III - Involvement on both sides of diaphragm
IV - Involvement of extranodal sites
A - no systemic symptoms
B - symptoms (>10% weight loss, sweats, fever)
Letter and number!
Management of Hodgkin’s lymphoma
If stage I then radiotherapy and chemotherapy
ABVD - Doxorubicin, bleomycin, vinblastine and dacarbasine
Staging PET pre chemo and after 2 cycles
Response PET predicts overall survival - 95% of Hodgkin’s is PET active
Chemo treatment = cardiac and respiratory toxic to test first
If the disease relapses then autologous transplant (stem cells)
Prognosis of Hodgkin’s lymphoma
90% of early stage achieve remission
In advanced 50-70% can be cured
Hasenclever prognostic index
Predicts 5 year freedom from progressive and 5y survival
Autologous stem cell transplant
Used in relapsed lymphomas and myelomas
Always remove cells peripherally
To gather cells - One round of chemo, GCSF given during chemo recovery. Chemo helps to release stem cells to peripheral blood
Allows for stronger chemotherapy treatment that would otherwise wipe out the bone marrow
Give own cells back to repopulate the bone marrow and allow recovery
Define Non-Hodgkin’s lymphoma
Group of lymphoproliferative malignancies with differing patterns of behaviour and response
Greater tendency to disseminate to extranodal sites
Low grade - not curable in advanced stages. Not responsive to treatment. low proliferation rate
High grade - rapid proliferative rate. More responsive the intensive chemotherapy
Classification of Non-Hodgkin’s lymphoma
Can transform from low to high
- Precursor B cell lymphoma
Mature B cell High grade - Diffuse large B cell lymphoma (DLBCL) 30-60% - Burkitt's lymphoma - Mediastinal large B cell Low grade - Follicular (20-25%) - marginal zone/Waldenstrom's - MALT lymphoma - Mantle cell (poor prognosis)
Precursor T cell lymphoma
Mature T cell neoplasms
Mature B cell Non-Hodgkin’s lymphomas
High grade
- Diffuse large B cell lymphoma (DLBCL)
- Burkitt’s
- Mediastinal large B cell
Low grade
- Follicular
- Marginal zone/Waldenstrom’s
- MALT lymphoma
- Mantle cell
Epidemiology of Non-Hodgkin’s lymphoma
5x more common than Hodgkin's Increased in Caucasian 12 per 100,000 Increased with age 60-70 Slightly more common in men Low grade are very rare in children
2 most common; DLBCL and follicular
RFs
- EBV (Burkitt’s)
- Autoimmune disorders (Sjorgens, Hashimoto’s)
- H.pylori for GI lymphoma
- Hep B and HIV for Karposi’s sarcoma
Presentation of Non-Hodgkin’s lymphoma
Depends on stage and subtype
Can occur anywhere
Gives site specific symptoms
LYMPHADENOPATHY
B symptoms: lethargy, fevers, night sweats, weight loss, loss of appetite
Systemic: GI tract, skin, bone marrow, sinus, GU tract, thyroid, CNS
Tumour lysis syndrome is common with chemo - occurs in Burkitt’s without treatment
Tumour lysis syndrome
Raised uric acid
Raised phosphate
Raised K+
Hypocalcaemia
Due to high cell lysis after treatment of lymphoma and leukaemia
Causes:
- Nausea and vomiting
- Acute uric acid nephropathy
- AKI
- Seizures
- Arrhythmias
- Death
Treat with allopurinol
Investigations for Non-Hodgkin’s lymphoma
FBC
- Anaemia (marrow failure of autoimmune haemolytic anaemia)
- Thrombocytopaenia /cytosis
- High or low neutrophils
U&Es for nephropathy or hypercalcaemia
Uric acid
CXR - mediastinal adenopathy, pleural or cardiac effusions
PET/CT
Biopsy of lymph node/ mass
Bone marrow biopsy
CT TAP for lymph nodes
Staging of Non-Hodgkin’s lymphoma
Ann Arbour system
I - single lymph node area
II - 2+ lymph node regions on same side of diaphragm
III - Involvement on both sides of diaphragm
IV - Involvement of extranodal sites
A - no systemic symptoms
B - symptoms (>10% weight loss, sweats, fever)
Letter and number!
Management of Non-Hodgkin’s lymphoma
All have steroids during treatment
LOW GRADE
- Asymptomatic may not require therapy
- Treat with marked systemic symptoms, lymphadenopathy causing disfigurement, bone marrow failure, compression syndrome
- Low intensity chemo
- Rituximab often used
HIGH GRADE
- Treat at presentation
- RCHOP - Rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone
- If relapse the autologous stem cell transplant
Complications of Non-Hodgkin’s lymphoma
Pancytopaenia (due to marrow infiltration) Depends on location - SVCO - Spinal compression - GI obstruction
Tumour lysis syndrome
Prognosis of Non-Hodgkin’s lymphoma
Low grade = better prognosis but not curable
Transformed has worse prognosis
most relapse in the first 2 years
High grade = aggressive but responds to chemo
Define myeloma
Malignancy of memory B cells (PLASMA CELLS)
When they are healthy they should only be found in the bone marrow
Epidemiology of myeloma
2nd most common haematological cancer
15-20% of haematological cancer deaths
4 per 100,000
Increases with age - median = 70
Increased in Blacks
Increased in men
Aetiology and pathophysiology of myeloma
Malignant proliferation of plasma cells (memory B cells)
They accumulation in the bone marrow and produce monoclonal protein that causes organ and tissue impairment.
It arises from genetic changes during terminal differentiation of B cell lymphocytes to plasma cells
In half of cases: chromosomal translocation of oncogene onto chromosome 14
Imbalanced bone remodelling = increased osteoclasts
Causing unopposed osteolysis and hypercalcaemia
Plasma cells produce variable amounts of monoclonal free light chains
when in urine = Bence Jones proteins
When light chain load > absorptive capacity they precipitate as casts in the distal tubule
Causes tubular obstruction, tubulointerstiial inflammation and AKI
Presentation of myeloma
It can present with a wide variety of symptoms including those due to hypercalcaemia, anaemia, renal impairment and osteolysis
- Bone pain (especially back pain)
- Pathological fractures
- Spinal cord compression
- Lethargy
- Anorexia
- Dehydration (due to proximal tubule dysfunction_
- Recurrent bacterial infection)
- Bruising or bleeding
- Features of amyloidosis - cardiac failure, nephrotic syndrome
- Features of hypercalcaemia - thirst, polyuria, constipation, nausea, confusion
- Hyperviscosity - dizziness, confusion, blurred vision, headache, epistaxis, stroke
Investigations for myeloma
FBC
- normocytic normochromic anaemia
- Leukopaenia
- Thrombocytopaenia
- High plasma viscosity
U&E
- Hypercalcaemia
- Decreased renal function
Raised CRP and ESR
Raised uric acid
Urine protein electrophoresis - Bence Jones Proteins
Bone marrow aspirate and plasma cell phenotype
Immunofixation of the paraprotein
Skeletal survey - plan x-ray of long bones (humerus and femur), pelvis, spine and skull
If an abnormality is found then spinal MRI
Bone scan will be negative as it looks for active disease
Diagnostic criteria for myeloma
SYMPTOMATIC
All 3
1. Monoclonal plasma cells in marrow > 10%
2. Monoclonal paraprotein in serum or urine
3. Evidence of myeloma related organ or tissue impairement
- Hypercalcaemia
- Decreased renal function
- Anaemia
- Lytic bone lesions
- Osteoporosis
- Pathological fracture
ASYMPTOMATIC 1 or 2 only
Early stage myeloma
Monoclonal gammopathy of undetermined significance
Management of myeloma
Currently incurable
It is chronic, relapsing and remitting
Only treat if symptomatic
Elderly
- Thalidomide + alkylating agent + corticosteroid
Younger
- Induction + high dose chemo + autologous stem cell transplant
Treatment of relapsed or refractory disease depends on age, performance status, co-morbidities and tolerance of past treatments
Pain control
- Analgesia
- Amitriptyline, carbamazepine, gabapentin
- Corticosteroids
- Radiotherapy
- Surgery to stabilise #
- Chemotherapy as treatment
Complications of myeloma and their treatment
Hypercalcaemia
- Rehydration, IV fluids, bisphosphonates
Renal impairment
- caused by light chain damage to proximal tubules
- increased fluids, avoid nephrotoxins
Anaemia
- consider EPO if symptomatic
- red cell transfusion risks worsening hyperviscosity
Infection
- treat any fever with broad spec abx
- prophylactic trimethoprim during chemo
- vaccinations up to date
Cord compression
- Dexamethasone and local radiotherapy
Hyperviscosity
-plasma exchange, venesection, chemotherapy
Prognosis of myeloma
5 year survival average
If presents as an emergency = poor prognosis
Epidemiology of testicular cancer
Relatively rare cancer
1 in 200 lifetime risk
Most common between 15 and 40
Testicular cancer is the most common cancer between 20 and 35
RFs
- Cryptochidism or testicular maldescent
- Klinefelter’s syndrome
- FHx
- Male infertility (x3)
- Infantile hernia
- Taller men (germ cell tumours
- Testicular microlithiasis (small calcifications)
Seminoma is the most common testicular tumour in over 60s, rare in under 10s
Classification of testicular tumours
95% of them arise from germ cells
Germ cell tumours
- 50% Seminoma
- 50 % Non-seminomas
- Seminomas
- Teratomas
- Yolk sac tumours (also known as endodermal sinus tumours)
Most common prepubertal
Aggressive natural but overall prognosis excellent
Genes involved in testicular cancer
Testicular germ cell tumour on X chromosome
Virtually all testicular tumours show an abnormality on chromosome 12
Symptoms of testicular cacer
95% present with a lump
Painless
Testicular pain and/or abdominal pain can be present
Dragging sensation
Recent history of trauma- may then examine self (not a cause)
Hydrocoele
Gynaecomastia (raised B-hCG)
Metastasise sites of testicular cancer
Seminoma –> para-aortic nodes & back pain
Teratoma –> blood born spread to liver, lung, bone and brain
Investigations for testicular cancer
Diagnosis usually confirmed by US
Tumour markers
- AFP in yolk sac tumours (endodermal sinus tumours)
- Beta hCG raised in teratoma and seminoma
Tissue histology post orchidectomy
Staging with CT thorax and abdomen
Staging of testicular cancer
Royal Marsden Staging 1 - no disease outside testes 2 - Infradiaphragmatic nodal involvement 3 - supradiaphragmatic nodal involvement 4 - mets
Management of testicular cancer
90% achieve remission
Radical orchidectomy - offer testicular prosthesis to all
If appropriate offer sperm storage if chemotherapy or radiotherapy
Chemotherapy if required
Epidemiology of bladder cancer
7th most common cancer in the UK (4th most common in men, 11th in women) 11 per 100,000 Most patients are over 60 Increased in men (3:1) Women have a poorer prognosis
RF
- 50% due to SMOKING
- Aromatic amines, hydrocarbons (industrial plant chemicals)
- Radiation to pelvis
- Cyclophosphamide
- Squamous can follow stones
- In developing countries Schistosomiasis
Bladder cancer types
90% are Transitional cell carcinomas
10% Squamous cells
Transitional from mucosal urothelium may present as non-invasive papillary tumour or as a solid tumour that invades bladder wall and metastasises.
Presentation of bladder cancer
Painless GROSS haematuria in 90%
- Painless haematuria must be treated as malignancy of urinary tract until proven otherwise
No abnormality on physical examination
Advanced disease can cause
- Voiding symptoms
Only 5% have mets at presentation
- Goes to lung, lymph, liver, bone and CNS
