Essential Notes for MRCS - Book 2(B)

Wound infection
Clean wounds: flucloxacillin (to cover skin flora) • Traumatic or abdominal surgical wounds: intravenous
cefuroxime 1.5 g three times daily and metronidazole 400 mg three times daily • Animal bites: co-
amoxiclav

If considering necrotising fasciitis (sepsis, delirium, rapidly progressive pain, systemic upset out of
keeping with erythema) seek microbiological advice because this is commonly group A streptococci –
give cefuroxime (or clindamycin) and gentamicin.

Cellulitis
Most likely organisms are staphylococci and streptococci.
If not systemically unwell consider oral clindamycin 300 mg four times daily (oral flucloxacillin is not
very effective) • If systemically unwell consider intravenous flucloxacillin 2 g four times daily

Management of ulceration should include imaging to exclude bony involvement. If systemically unwell
can consider intravenous cefuroxime 1.5 g three times daily and metronidazole 400 mg three times daily.

Intra-abdominal sepsis

Most intra-abdominal organisms will be covered by intravenous cefuroxime 1.5 g three times daily and
metronidazole 400 mg three times daily. If there is a history of rigors, hypotension or suspected
cholangitis then you should also consider a one-off single dose of gentamicin (5 mg/kg – but check renal
function is normal).

Pneumonia

Community-acquired pneumonia
Treatment should be guided by severity. The CURB criteria are a useful guide:
Confusion
Urea
Respiratory rate
Blood pressure

For mild pneumonia give oral amoxicillin 500 mg three times daily. For moderate pneumonia (one or two
criteria) give oral amoxicillin 500 mg three times daily and oral erythromycin 500 mg four times daily.
For severe pneumonia (more than two criteria) give intravenous cefuroxime 1.5 g three times daily and
oral erythromycin 1 g four times daily.

Hospital-acquired pneumonia
Usually treated with intravenous cefuroxime 1.5 g three times daily. If there is worsening of respiratory
function or fever on cefuroxime, then consult microbiology (commonly change to intravenous meropenem
500 mg four times daily or Tazocin 4.5 g three times daily).

Urinary tract infection

Simple UTI
If there is no systemic upset then consider 3 days of oral treatment. The choice depends on local policy
(which reflects resistance patterns):
Nitrofurantoin 50 mg four times daily
Trimethoprim 200 mg twice daily
Ciprofloxacin 100 mg twice daily

Complicated UTI
UTI involving urosepsis or pyelonephritis generally presents with rigors and loin pain. Generally best
treated with intravenous cefuroxime 1.5 g three times daily plus a single dose of gentamicin (5 mg/kg –
but check renal function is normal).

Catheter-related sepsis
Treatment is not required for asymptomatic bacterial colonisation. Indications for treatment include
urinary symptoms, fever, signs of sepsis or high WCC. When changing long-term indwelling catheters it is
advisable to give 1.5 mg gentamicin as a single dose (check renal function is normal) or oral
ciprofloxacin 500 mg 1 hour before the procedure.

Diarrhoea

Diarrhoea after antibiotic therapy
Send stool for CDT. Treat with metronidazole 400 mg three times daily (commonly for 2 weeks). Failure
to respond to metronidazole – can give oral vancomycin 125 mg four times daily.

Diarrhoea after food poisoning
May not require treatment. Traveller’s diarrhoea (with associated pyrexia) or after food poisoning may
respond to oral ciprofloxacin 500 mg twice daily.

Septic arthritis

Obtain an aspirate to guide treatment. It is likely to require joint wash-out. Give empirical treatment with
intravenous cefuroxime 1.5 g three times daily.

Meningitis

Uncommon unless in neurosurgical setting. Should give intravenous ceftriaxone 2 g twice daily (dose
before lumbar puncture). Guidelines now also give consideration to dexamethasone administration. If the
patient is elderly, immunocompromised or pregnant then consider intravenous ceftriaxone 2 g twice daily
with amoxicillin 2 g four times daily (to cover Listeria spp.) ± steroids.

6.3 Antibiotic prophylaxis



In a nutshell ...

Prophylactic antibiotics
Reduce surgical site infection
Should be given early (before or just after anaesthetic) • Can be given as a single dose at therapeutic

concentration • Must be broad spectrum and appropriate to probable organisms

The most important aspect of good antibiotic prophylaxis is to obtain high levels of systemic antibiotics at
the time of the procedure and to maintain this for the duration of surgery. Prophylactic antibiotics should
not be continued beyond this. This measure aims to reduce the incidence of surgical site infection,
particularly during implantation of prosthetic material. The aim of antibiotic prophylaxis is to prevent
bacteria from multiplying without altering normal flora.

Prophylaxis should be started preoperatively, ideally within 30 minutes of anaesthesia, and antibiotics
should be given intravenously. Early administration of the antibiotic allows time for levels to accumulate
in the tissues before they are disrupted by surgery (eg application of tourniquets, opening hollow organs).

A single dose of the correct antibiotic at its therapeutic concentration is sufficient for most purposes.
Prophylaxis may be continued for a set duration (eg 24 hours) as a matter of policy in certain
circumstances but it should not be inappropriately prolonged.

Choice of antibiotic may be set by hospital policy or surgeon preference, but the prophylaxis chosen must
be broad spectrum and cover the organisms likely to be encountered. Policies for surgical prophylaxis
that recommend β-lactam antibiotics as first-line agents should also recommend an alternative for patients
with allergy to penicillins or cephalosporins.

Issues for consideration
Is it needed?
For what pathogen and where?
Which route of administration?
Is the patient immunocompromised?

Indications for antibiotic prophylaxis

Where procedure commonly leads to infection (eg colectomy) • In reducing postop infections from
endogenous sources (proven value) • Where results of sepsis would be devastating, despite low risk of
occurrence (eg vascular or other prostheses)
It has no value in clean procedures where the risk of sepsis from an exogenous source is <2%.

Administration of antibiotic prophylaxis

Choice of antibiotic: bacteriostatic or bactericidal (if immunocompromised) • Give short courses <24
hours
Dosage:
• Single dose (used if 3–6% postop infection rate) or • Multiple dose (used if 6% postop infection rate) •
Timing of administration:
• Within 1 hour preoperatively or at induction (15–20 minutes before skin incision or tourniquet inflation)
• Second dose if operation >4 hours to maintain adequate tissue levels
Note: beware of the following when giving antibiotic prophylaxis:
Toxicity
Side effects
Routes of excretion
Allergies

Examples of antibiotic prophylaxis

Upper GI surgery: cefuroxime and metronidazole; ciprofloxacin • Lower GI surgery: cefuroxime and
metronidazole • Orthopaedic surgery:
• Open fractures: first-generation cephalosporin plus benzylpenicillin (plus gentamicin if grade III or very
heavily contaminated) • Joint replacement: cefuroxime
Vascular surgery: cefuroxime, gentamicin and metronidazole • Cardiothoracic surgery: flucloxacillin and
gentamicin

6.4 Microbial resistance



In a nutshell ...

Hospital-acquired (nosocomial) infection is increasing in incidence (sicker patients, rapid patient
turnover, etc) • Antibiotic resistance is increasing, acquired by spontaneous mutation, transformation
and plasmid transfer • There are clinical measures to help reduce the acquisition of both nosocomial

infection and antibiotic resistance

Bacterial antibiotic resistance and multiresistant organisms

Bacterial resistance is increasing. Data from the USA show that in intensive therapy unit (ITU) patients up
to 30% of hospital-acquired infections are resistant to the preferred antibiotic for treatment. Increasing
MRSA incidence has been documented (and use of vancomycin results in emerging S. aureus resistance to
vancomycin). Resistance results from selective survival pressure on bacteria.

Mechanisms of resistance

Resistance may occur by:
Alteration of bacterial cell-wall proteins to prevent antibiotic binding (eg penicillin resistance) •
Alteration of ribosome structure to prevent antibiotic binding (eg erythromycin, tetracycline, gentamicin) •
Production of antibiotic-destroying proteins

Resistance is passed on to all subsequent bacterial progeny. Resistance may be conferred against multiple
antibiotics.



Bacteria acquire resistance genes by three mechanisms
Spontaneous mutation: rapid replication times cause spontaneous mutations to arise in bacterial DNA;

some of these mutations may confer resistance
Transformation: one bacterium takes up DNA from another and splices it into its genome using enzymes

called integrases, allowing passage of resistance genes against antibiotics, disinfectants and pollutants
• Plasmids: these are small circles of DNA (similar to small chromosomes) which can be transmitted
from bacterium to bacterium and cross bacterial phylogeny

Potential causes of resistance

Inappropriate prescription
Failure to finish the course of antibiotics: microbes that are relatively drug-resistant will not be killed in
the first few days and will become preferentially selected
Addition of antibiotics to agricultural feed (entry into the food chain) • Extensive use of antibiotics in sick
patients with multiple organisms may promote resistance and transmission between individuals • Natural
evolution of bacteria

Meticillin-resistant S. aureus

During the last 20 years the prevalence of MRSA in hospitals has fluctuated – it is now nearly 50% in UK
hospitals. Beta-lactam antibiotics inhibit bacterial cell-wall synthesis by inactivating penicillin-binding
proteins (PBPs); MRSA strains produce an alternative PBP (mecA gene) that allows continued cell-wall
synthesis.

Prevention of MRSA transmission
Use of preventive measures (handwashing, alcohol gels, etc) • Patient screening (especially important if
having elective surgery with prosthetic implants) • Isolation of carrier or infected patients (barrier
nursing) • Removal of any colonised catheters
Eradication of carriage (nasal: mupirocin; chlorhexidine hair and body wash; hexachlorophene powder)

Systemic MRSA infections
May require appropriate antibiotics if isolated from sterile site (eg MRSA detected in abdominal cavity
or in blood cultures). An antibiotic regimen that includes intravenous vancomycin 1 g twice daily should
be considered. If the patient is systemically unwell a single dose of gentamicin 5 mg/kg should act as a
holding measure until further cultures are back.

Vancomycin-resistant enterococcus

There are two types of vancomycin resistance in enterococci:
Low-level intrinsic resistance (eg Enterococcus gallinarum) • Acquired resistance by transfer of genes
(vanA, vanB, etc) commonly seen in E. faecalis

Vancomycin-resistant enterococci (VREs) can be carried in the gut without disease (colonisation) and can
be picked up by screening.

CHAPTER 5

Principles of Surgical Oncology

Sylvia Brown

Epidemiology of common cancers
1.1 Epidemiology studies
1.2 Cancer registries
1.3 Common cancers

The molecular basis of cancer
2.1 Normal cell growth
2.2 Disorders of cell growth
2.3 Carcinogenesis
2.4 Abnormalities in neoplastic cell behaviour
2.5 Neoplastic progression – invasion and metastasis
2.6 The immune system and neoplasia

Screening Programmes
3.1 Cancer screening
3.2 UK screening programmes

Clinical and pathological grading and staging of cancer
4.1 Tumour grade
4.2 Tumour staging
4.3 Tumour markers

Principles of cancer treatment
5.1 The role of surgery in neoplasia

5.2 Radiotherapy
5.3 Chemotherapy
5.4 Hormonal therapy
5.5 Additional therapies (including immunotherapy)

Palliative care and care of the dying
6.1 The palliative care team
6.2 Symptomatic control in palliative care
6.3 Oncological emergencies
6.4 The psychological effects of surgery
6.5 Communication skills in surgery
6.6 Breaking bad news
6.7 Dealing with death

SECTION 1

Epidemiology of common cancers

1.1 Epidemiology studies



In a nutshell ...

Epidemiology is the study of disease frequency in populations. In cancer epidemiology, useful concepts
include: Measures of frequency
Prevalence: proportion of population with a condition at a given time • Incidence: proportion of
population developing a condition in a given time
Measures of risk
Risk factor: an agent or characteristic predisposing to the development of a condition • Relative risk:
strength of association between risk factor and condition
Measures of outcome
Disease-free survival: an outcome measure in oncology for the time period from completion of
treatment to detection of recurrence
Life table: a calculation predicting the cumulative probability of surviving a given number of years (eg
5-year survival rate) • Survival curve: plot of probability of survival against time (eg Kaplan–Meier
curve)

1.2 Cancer registries



In a nutshell ...

Cancer registries
Monitor levels and changes in different cancers in the population • Collate information from death

certificates about deaths from each cancer type

These registries are set up to monitor the incidence and mortality of various cancers in the population, and
to determine any changes in these parameters.

Information from death certificates is collated by the National Cancer Registry in England and Wales and
is followed up by case-note analysis and postmortem diagnoses, etc. Statistical information from cancer
registries should be viewed with caution due to potential errors arising from differences in accuracy of
data collection, geographical variations, and differences in diagnosis and postmortem rates, for example.

1.3 Common cancers



In a nutshell ...

Cancer is a common disease affecting a third of the population in their lifetime.
There are 250 000 new cases diagnosed per year • 65% of cancer affects the >65 age group
Common cancers are different for different age groups (adults, teenagers and children) • Smoking and

diet are the main environmental aetiological factors (thought to be responsible for a third of cancer
cases each)

Specific clinical information about most common cancers is covered in Book 2.

Cancer incidence by age and gender

Common cancers in adults

Fifty per cent of adult cancer involves the big four – breast, prostate, lung, large bowel.

Remember that the incidence of a cancer is not the same as the death rate from that cancer. Incidence data
can be expressed as the number of new cases per 1000 per year or as a percentage.

There is a different incidence of certain cancers in men and women.

Common cancers in teenagers

Testicular cancer
Brain tumour
Melanoma
Leukaemia

Common cancers in children

The risk of cancer in childhood (<15 years) is 1 in 500 in the UK. For a detailed discussion of oncology
in childhood see the Paediatrics chapter.

Commonly these cancers are:
Haematological: 25% of childhood cancers are acute lymphocytic leukaemia (ALL). Incidence of
Hodgkin’s lymphoma peaks in teenagers
Brain and spinal cord: eg astrocytoma and primitive neuroectodermal tumour • Embryonal tumours:
occur in different parts of the body and are referred to as ‘blastomas’, eg medulloblastoma (brain),
nephroblastoma (Wilms’ tumour), retinoblastoma
Bone tumours: osteosarcoma and Ewing’s sarcoma. Bone tumour incidence peaks at 14–15 years

Cancer incidence by geographical region

Different cancers have different incidences in different countries and in different ethnic groups.

Breast cancer: much less common in the developing than in developed countries. Its incidence is highest
in the West and second-generation immigrants from areas of low incidence (they acquire the elevated risk
of their new country) • Hepatocellular carcinoma: most common where hepatitis B infection is common
(Far East, sub-Saharan Africa) regardless of race. Iron overload and aflatoxin also contribute in these
regions
Stomach cancer: common in Japan and Chile. First-generation immigrants to the West retain this high rate
but second-generation immigrants adopt the lower rate of their new country, which suggests that dietary
factors may be important (eg salt/nitrates) • Colon cancer: westernised countries with low-fibre diets
have increased risks of colon cancer • Prostate cancer: highest in African-Caribbean people and lowest
in Japan • Oesophageal cancer: common in China, former USSR and poor nations. The reasons may be
dietary • Epstein–Barr virus: is ubiquitous around the world, but Burkitt’s lymphoma is an African
disease, and its distribution corresponds to regions where malaria is endemic. Immigrants to Africa are
susceptible, as are the indigenous black people • Skin cancers: (notably melanomas) are most common in
light-skinned people who have heavy sun exposure at low latitudes and/or high altitudes
Cervical cancer: incidence follows that of sexually transmitted infections (STIs) (aetiological agent is
human papillomavirus or HPV). It may be less common in areas where men are circumcised
Squamous cell carcinoma of the bladder: caused by schistosomiasis and so is common in endemic areas
(eg Egypt)

Changes in cancer incidence in Europe

Factors impacting on incidence of cancer

Behavioural factors
Women starting to smoke in the 1940s (increase in lung cancer) • Sunbathing and tanning became
fashionable (increase in melanoma) • Changing fertility patterns (increase in breast cancer)

Environmental exposure
Asbestos: the EU ban on use of asbestos products in 2005 may reduce mesothelioma rates only in around
35 years’ time due to the long latency period after exposure

Diagnostic tests
Introduction of prostate-specific antigen (PSA) as a test for occult and asymptomatic prostate cancer

Screening
Initial increase in incidence often seen (by detection of asymptomatic tumours) • May decrease incidence
(by detection of precursor lesions that can be treated before the tumour develops, eg colorectal polyps,
carcinoma in situ of the cervix)

There is a variable lag period before the effects of changes in behaviour or environmental exposure are
seen. Implementation of new diagnostic tests or screening programmes may have a much more rapid
impact on the incidence figures.

Increasing incidence of cancer in Europe

Data from Europe over the last decade show increasing incidence in the following cancers:
Melanoma (54% and 37% increases in incidence in men and women respectively) • Prostate (60%
increase; note: remember introduction of PSA testing) • Uterus (23% increase in incidence)
Kidney
Non-Hodgkin’s lymphoma
Breast
Leukaemia
Ovary

Decreasing incidence of cancer in Europe

Incidence is decreasing in the following cancers:
Large bowel (6–8% decrease)
Pancreas
Bladder
Stomach (28% decrease)
Lung
Cervix (24% decrease)

For discussion of survival and mortality rates please refer to the clinical sections on individual cancers in
Book 2.

SECTION 2

Molecular basis of cancer

In a nutshell ...

The word ‘tumour’ means ‘swelling.’ The swelling is either physiological or pathological.
Physiological swelling
The pregnant uterus, for example
Pathological swelling
Neoplastic
Non-neoplastic (eg pus, inflammatory, bony callus)
Neoplasia is an abnormal mass of tissue, the growth of which is uncoordinated, exceeds that of the
normal tissues and persists in the same manner after cessation of the stimuli that evoked the change.

Tumours are similar to the organ in which they arose:
They consist of both parenchymal and stromal elements but come from a single ‘cell of origin’ in the parent
tissue (ie they are clonal)
They may continue to perform some of the functions of the parent organ (eg mucin production in colorectal
tumours; hormone production in endocrine tumours; IgG production in myeloma)
Individual cells look similar to the parent cells; the degree of similarity depends on the degree of
differentiation of the tumour

However, they also differ in some ways:
Deranged histological architecture
No controlled functional contribution to the body
Can proliferate rapidly (unlike other differentiated cell groups) • Can develop metastatic potential

2.1 Normal cell growth



In a nutshell ...

Cells fall into several different categories according to their propensity to divide and their degree of

differentiation:
Labile cells: constantly renewed (eg stratified squamous epithelium of the skin) • Stable cells: usually

quiescent but can be stimulated to divide (eg hepatocytes) • Permanent cells: do not undergo mitosis in
postnatal life (eg neurones, skeletal muscle tissues, glomeruli)
Cells divide as they progress through the cell cycle. There are many regulatory points inherent in the
cycle, and disruption of regulatory genes results in uncontrolled replication.

The cell cycle
DNA structure

Deoxyribonucleic acid (DNA) is a strand-like molecule consisting of four building blocks – adenine (A),
thymine (T), cytosine (C) and guanine (G). These are paired (A with T, and C with G) and their affiliation
for each other zips the two strands of DNA into the double helix.
DNA is stored in the cellular nucleus as a folded form called chromatin. This is wrapped around proteins
called histones to form complexes called nucleosomes (which look like a bead on a string). Active genes
unwrap from the histones, opening out the DNA for access by transcriptional proteins. When the cell
divides, the nucleosomes become very tightly folded, condensing into chromosomes.
The nucleus of most human cells contains two sets of chromosomes, one set given by each parent. Each
set has 23 single chromosomes – 22 autosomes and a sex chromosome (X or Y). There are therefore 46
chromosomes in each cell.



Figure 5.1 The ce ll cycle

Phases of the cell cycle

The cell cycle is divided into phases:
G1 Pre-synthetic
S DNA synthesis (chromosome replication)

G2 Premitotic
M Mitotic (cell division)
G0 Quiescent (resting phase)

Mitosis is divided into several phases:
Interphase: this comprises phases G1, S and G2 of the cell cycle when the cell is in preparation for
division. The chromosomes have replicated and there are two copies of each in the cell (ie 92
chromosomes)
Prophase: the chromatin begins to condense and is seen as chromosomes. Centrioles move to opposing
ends of the cell and fibres stretch between them, forming the mitotic spindle
Prometaphase: the nuclear membrane dissolves and the chromosomes start to move towards the centre of
the cell under the control of microtubules
Metaphase: the spindle fibres align with the chromosomes along the metaphase plate (this allows accurate
separation of the paired replicated chromosomes to the two cells)
Anaphase: the paired chromosomes separate and are dragged to the opposite sides of the cell by the
microtubules • Telophase: the chromatids arrive at the opposite poles of the cell and disperse after new
nuclear membranes are formed • Cytokinesis: an actin fibre forms around the centre of the cell and
contracts, pinching it into two daughter cells, each with 23 pairs of chromosomes

Control of the cell cycle

There are regulatory points between the different phases of the cell cycle.

Most adult cells are in G0 (ie outside the cell cycle) and quiescent. The length of the G1 phase is
variable. The length of the S, G2 and M phases are fairly constant because these processes have a limit as
to how quickly they can be performed.

Entry of G0 cells into the cycle and transition from G1 to S phase are the two crucial regulatory points of
the cell cycle. They are controlled by:
Intracellular enzymes: cyclin-dependent kinases (CDKs) cause cells to move from G1 to S and also from
G2 to M. They are: • Upregulated by platelet-derived growth factor (PDGF), epidermal growth factor
(EGF) and insulin-like growth factor 1 (IGF-1) in the serum
• Downregulated by transforming growth factor β (TGF-β)
Protein p53: this protein blocks the cell cycle in G1 phase if DNA is damaged. This allows for DNA
repair or, if the damage is severe, cellular apoptosis. High levels of p53 are seen in damaged cells and
loss of p53 activity by gene mutation or deletion is associated with tumour development

Cellular differentiation

This is a complex and incompletely understood process occurring during development of the fetus and
occurs continuously in certain systems of the body (eg haematopoiesis).

Definitions relating to differentiation

Differentiation: cell specialisation that occurs at the end of the developmental pathway. Selective genes
are activated to produce the differentiated phenotype

Stem cell: a cell from an embryo, fetus or adult that can reproduce itself for long periods of time and can
give rise to specialised cells and tissues
Totipotent cell: a cell capable of expressing any of the genes of the genome (can give rise to any part of
the later embryo or adult). In humans, the fertilised egg is totipotent until the eight-cell stage
Pluripotent cell: a cell with the potential to generate cell types and tissues from all three primary germ
layers of the body • Plasticity: the ability of a stem cell of one tissue type to generate cells from another
tissue type • Progenitor or precursor cell: occurs when a stem cell divides into two partially
differentiated cells, neither of which can replicate itself but which may continue along the path of
differentiation

Process of differentiation

Irreversible transition from stem cell to a predetermined differentiated cell type can take one of two
pathways:
A totipotent or pluripotent stem cell may proliferate and its daughters progress to terminal
differentiation. As this process progresses these cells lose their ability to divide again. Once committed
to this pathway cells cannot change their lineage, resulting in mature differentiated cells that have specific
functions and do not divide (eg cells of the blood)
After trauma some tissues may selectively replicate to replenish tissues. This can occur because the
stimulus causes some of the cells to de-differentiate, re-enter the cell cycle and replicate rapidly

Regulation of differentiation

There is usually an inverse relationship between cell replication and cell differentiation. Differentiation
is complex and is regulated by a number of factors.

Soluble factors
Hormones (eg glucagon, hydrocortisone)
Interferon
Vitamin D
Calcium ions

Cell–cell interactions
Effects of high cell density and proximity
Through gap junctions

Cell–matrix interactions
Matrix attachments may regulate gene expression

These regulators affect gene expression in the differentiating cell. Gene expression is controlled by a
combination of:
DNA methylation: this causes the gene to be silenced • Chromatin structure: regulation of the
acetylation of histones causes changes in chromatin configuration that allow genes to be increasingly or
decreasingly accessible to transcription

2.2 Disorders of cell growth



In a nutshell ...

Disorders of growth can be divided into: Developmental disorders of growth (before an organ
reaches maturity)
Hypoplasia
Agenesis
Atresia
Ectopia
Heteroplasia
Hamartoma
Acquired disorders of growth (after an organ reaches maturity)
Hyperplasia
Hypertrophy
Teratoma
Atrophy
Metaplasia
Dysplasia
Neoplasia
When cells become neoplastic they are referred to as ‘transformed’.

Developmental disorders of cell growth

Hypoplasia: the organ doesn’t reach its full size • Agenesis: vestigial structure only or no development at
all • Atresia: failure of canalisation in a hollow lumen causing congenital obstruction (eg gastrointestinal
[GI] tract) • Ectopia: location of normal differentiated tissue in an abnormal location (eg thyroid tissue
may develop anywhere along the thyroglossal tract)
Heteroplasia: anomalous differentiation of tissues within an organ (eg the presence of sebaceous glands
within the mouth) is referred to as heteroplasia
Hamartoma: overgrowth of mature cells that are usually found within the tissue but with disordered
architecture (eg haemangioma)

Acquired disorders of cell growth

Hyperplasia

Increase in the number of cells.

The cells mature to normal size and shape. This can occur in response to inflammation, increased
workload, excess endocrine drive or increased metabolic demand, eg:
Benign prostatic hyperplasia
Renal hyperplasia (in response to contralateral dysfunction)

Hypertrophy

Increase in cell size but not in number.

This occurs in response to a demand for increased function, eg:
Increased skeletal muscle volume in athletes
Increased cardiac muscle volume in hypertension
Pregnant uterus

Note that hyperplasia and hypertrophy can occur simultaneously.

Teratoma

Growth of cells originating from more than one germline cell.

Teratomas contain a variety of tissues in a variable state of differentiation. They arise in the gonads or the
midline of the body (eg mediastinum, retroperitoneum, base of skull). They can behave in a benign or
malignant manner.

Atrophy

Loss of cell substance causing a reduction in cell size. These are the different types:
Physiological atrophy: shrinkage of a well-differentiated structure when it is no longer required (eg
ductus arteriosus after birth)
Pathological atrophy: occurs with age (eg musculature, brain tissue) • Local atrophy: often due to
reduced blood flow or neurological input (eg nerve damage) to that region • Disuse atrophy: often
musculature, due to trauma, immobility or age

Metaplasia

Reversible replacement of one differentiated cell type with another.

This is an adaptive response and the replacement cells are of the same tissue type. It can be due to chronic
irritation or altered cell function. There is greater susceptibility to neoplastic transformation (via
dysplasia) but it is not inevitable (eg squamous epithelium changing to gastric type in the distal
oesophagus – Barrett’s oesophagus).

Dysplasia

Disordered cellular development characterised by increased mitosis and pleomorphism. This is
frequently preneoplastic and it may follow metaplasia. May also be called carcinoma in situ,
intraepithelial neoplasia, incipient neoplasia or pre-cancer.

Neoplasia

‘Transformed’ is a word that is used to describe the process by which a normal cell becomes neoplastic.
The processes involved are called carcinogenesis. Transformed cells adopt the abnormal growth patterns
consistent with neoplasia (discussed in section 2.4).

2.3 Carcinogenesis



In a nutshell ...

A tumour (neoplasm) is an overgrowth of tissue formed by a clone of cells bearing cumulative genetic
injuries. Each of these genetic injuries confers an additional growth advantage to the clone that
possesses it (Cole and Nowell, 1976).
These mutations can be:
Congenital: already present in the genome (heritable cancers) • Acquired: additional mutations brought
about by exposure to a carcinogen • (sporadic cancers)

The multistage process of carcinogenesis

Carcinogenesis is a generic term for the acquisition of a series of genetic mutations that lead up to the
expression of full malignant potential. As cells undergo carcinogenesis and become neoplastic they
become transformed.

Cole and Nowell described the multistep process of tumorigenesis in their article in Science in 1976.
Essentially:
Neoplasms are monoclonal (they arise from a single cell)
Neoplasms arise due to cumulative genetic injury • Neoplasms may develop more aggressive sub-clones
as genetic injuries accumulate • Genetic injuries confer growth advantages:
• Increased proliferation (failure of control of division)
• Immortalisation (failure of cell senescence)
• Loss of apoptotic control
Genetic injuries may include:
• Point mutations
• Amplifications
• Deletions
• Changes in control regions (eg gene promoters, enhancer sequences) • Translocations of chromosomal
material

Carcinogens



In a nutshell ...

Carcinogens can be divided into three types:
Chemical
Physical
Infectious (oncogenic viruses, bacteria, protozoa)

Chemical carcinogens

Chemical carcinogens may act directly to damage DNA (eg alkylating agents) whereas the majority
require metabolic conversion from a pro-carcinogen state to become activated (eg polycyclic
hydrocarbons [smoke], aromatic amines, amides and azo dyes, natural plant products and nitrosamines).
The carcinogen is often activated by metabolism via the hepatic cytochrome P450 mixed function oxidase
system of the liver.

Chemical carcinogens can be either mutagens (irreversibly directly damage DNA) or non-mutagens
(reversibly promote cell division). Some heavy metals depolymerise DNA.

The process of initiation is exposure to a carcinogen that causes irreversible DNA damage but does not
directly lead to a change in phenotype, which is followed by the process of promotion; this allows
initiated cells to grow into tumours by promoting cell division (eg hormonal influences on tumour
growth).

Chemicals are tested for mutagenicity by a variety of in-vitro and in-vivo procedures:
Production of mutations in bacteria colonies (eg the Ames test), yeast colonies and in cultured mammalian
cells • Charting unexpected DNA synthesis in cultured mammalian cells
Use of higher plants to look at chromosome damage

Physical carcinogens

These consist of a wide range of agents:
Electromagnetic radiation (ultraviolet [UV] light, ionising radiation) • Extremes of temperature
Mechanical trauma
Foreign bodies and implants

The mechanism of carcinogenesis is thought to be centred around long-term inflammation causing
proliferation. There may also be direct DNA damage by radiation. Selection of clones with growth
advantages then leads to neoplasia. There are a few reported cases of sarcomatous change around foreign
bodies and surgical implants (this is very rare).

Infectious carcinogens

Infection causing persistent inflammation may result in neoplastic transformation (eg bladder
schistosomiasis resulting in transitional cell carcinoma [TCC] of the bladder in endemic areas such as
Egypt; malaria and Burkitt’s lymphoma).

Viral infection may also result in neoplastic transformation. This may be caused by insertion of viral
genomic material into the cell (eg Epstein–Barr virus [EBV] incorporation into the genome) or cell lysis
due to viral infection stimulating cell turnover and proliferation (eg hepatitis and cirrhosis leading to
hepatocellular carcinoma [HCC]).


EXAMPLES OF CARCINOGENS (HISTORICAL AND CONTEMPORARY) AND THEIR
EFECTS

Genes involved in carcinogenesis

Four classes of genes can be affected to produce a neoplasm:
Oncogenes
Tumour suppressor genes
Anti-apoptotic genes
DNA mismatch-repair genes

Oncogenes

Normal genes involved in cell division are called proto-oncogenes. These genes may become
permanently activated by point mutation, translocation or an increase in the copy number (amplification).
This results in permanent upregulation. Activation of these genes causes cell division and promotes
growth in a dominant manner (ie the damaged gene over-rides signals from its undamaged normal
counterpart). These genes code for growth factors and their receptors, signal transducing proteins,
transcription factors and cell cycle regulators.

Examples of commonly mutated oncogenes include:
Ras oncogene (over-expression of growth factor p21) • ERB1 and ERB2 (over-expression of growth
factors) • Telomerase (important for cellular immortality)

Tumour suppressor genes (anti-oncogenes)

These are normal genes that tell cells when not to divide. They are downregulated by mutations. They
tend to act in a recessive manner (ie usually the malignant phenotype is expressed only when both copies

are damaged or missing).

Examples of commonly mutated tumour suppressor genes include:
APC (results in familial adenomatous polyposis or FAP) • E-cadherin
TP53 (mutated in up to 50% of tumours)

Anti-apoptotic genes

Normal tissues are subject to genes regulating programmed cell death (apoptosis). Neoplasia is
associated with changes in cell senescence and immortalisation of the cell line. Loss of these normal
controls results in a reduction in cell death. This occurs when the genes controlling apoptosis are
downregulated by mutation.

Commonly affected apoptosis genes include Bcl-2 (inhibits apoptosis).

DNA mismatch-repair genes

After normal cellular replication, there are genes responsible for recognising and excising mutated gene
segments. If these genes themselves undergo mutation they become downregulated, allowing accumulation
of mutations within the cell.

Commonly affected DNA repair genes include MSH-2.

There is also a level of interaction between all these gene products, exemplified by the role of p53. This
protein is upregulated by cellular and DNA damage, and high levels can be identified in damaged cells.
The p53 protein upregulates a CDK inhibitor molecule, causing inhibition of the CDK family. This halts
the cell cycle in G1. In addition p53 upregulates transcription of GADD-45, which is a DNA-repair
enzyme, and the BAX protein, which binds to Bcl-2 allowing apoptosis to occur if the DNA is not
repaired.

Figure 5.2 Ove rvie w of carcinoge ne s is

The Knudson two-hit hypothesis

This hypothesis describes the role of recessive genes in tumorigenesis. Both normal alleles of the Rb gene
on chromosome 13q14 have to be lost before retinoblastoma develops. One may be inherited as a mutated
copy, but the tumour will develop only if the second copy undergoes mutation.



Figure 5.3 The Knuds on two-hit hypothe s is

The Knudson two-hit hypothesis also helps to explain the development of familial cancer.

Familial and sporadic cancers

Familial cancers – congenital mutations

Defective or mutated genes may be inherited via the cell germline. People carrying this defective gene
copy are at high risk of developing a tumour. These genes may be dominant or recessive.

It is estimated that 5–10% of common solid adult tumours may be attributable to an inherited defective
gene. The rest (and therefore the majority) are sporadic.

Clinical aspects of familial tumours

Familial cancers include:
Breast cancer (+ ovarian or ± sarcoma)
Colorectal cancer
Ovarian cancer
Uterine cancer
Multiple endocrine neoplasia (MEN) syndromes



Suspect a familial cancer if:
Multiple family members are affected
Age of onset is early
Multiple primaries are identified within the same individual
Cancer is bilateral
Cancer is rare form

It is helpful to draw a detailed family tree and mark affected members because this can help
identification of transmission patterns.

Management of familial cancers

Referral to a genetics service should be appropriate to the guidelines for your region. For the purposes
of genetics, close relatives are considered to be:
Parent (mother/father)
Sibling (brother/sister)
Child (son/daughter)
Grandparent (grandmother/grandfather)
Aunt/uncle (note not by marriage; only consider siblings of the parents)


GENES RELATED TO FAMILIAL CANCER SYNDROMES
(all are available for genetic testing)

Guidelines for referral to genetics services
Breast cancer

• One relative (aged <40 years at diagnosis)
• One relative with bilateral disease
• One male relative
• Two relatives (aged <60 years at diagnosis)
Ovarian cancer
• Two relatives (any age at diagnosis)
Colorectal cancer
• One relative aged <45 years at diagnosis
• Two relatives aged <70 years at diagnosis
• Three relatives with GI, uterine or ovarian cancers
• Suspected familial adenomatous polyposis (FAP)
Multiple primary tumours in an individual • Three close relatives have had cancers of the GI tract,
breast, ovary, prostate, pancreas, thyroid or melanoma

Patients who test positive for a defective gene may require:
Increased surveillance
Watchful waiting
Screening (eg mammography, colonoscopy, PSA)
Prophylactic measures:
• Lifestyle changes (eg exercise, fat intake)
• Medical prophylaxis (eg drugs)

• Surgical prophylaxis (eg mastectomy for BRCA-1 and BRCA-2; total colectomy for FAP)

Sporadic cancers – acquired mutations

Mutations may accumulate with advancing age and with exposure to an environmental mutagen (a
carcinogen). Carcinogens act by causing additional genetic mutations within the cell that eventually
accumulate sufficiently for the development of neoplasia.

2.4 Abnormalities in neoplastic cell behaviour



In a nutshell ...

Neoplastic cells exhibit different behaviour from normal cells in terms of:
Proliferation
Differentiation
Immortality
Apoptosis
Karyotype and progression
Stimulation of angiogenesis

For discussion of normal cell behaviour please read section 2.1 first.

Tumour cell proliferation

The rate of cell proliferation within any population of cells depends on three things:
The rate of tumour cell division: tumour cells can be pushed into the cell cycle more easily because there
is loss of the regulation that controls movement from one phase of the cycle to the next
The fraction of cells within the population undergoing cell division (growth fraction): this is the
proportion of cells within the tumour cell population that are in the replicative pool. Not all cells within a
tumour are actively replicating and many are quiescent. The growth fraction is only 20% even in rapidly
growing tumours
The rate of cell loss from the replicating pool due to differentiation or apoptosis: overall growth
depends on balance between production and loss by apoptosis. In general tumour cells grow faster than
they die off

Entry of G0 cells into the cycle and transition from G1 to S phase are the two crucial regulators of the cell
cycle. They largely regulate the growth fraction of a cell population. As discussed previously, these
points are regulated by CDK, which is regulated:
Positively by platelet-derived growth factor (PDGF), epidermal growth factor (EGF) and insulin growth
factor (IGF)-1
Negatively by transforming growth factor (TGF)-β

Neoplastic cells may:
Upregulate their receptors
Mutate intracellular pathways (eg retinoblastoma gene and TP53) to evade the requirement for these
signals

Neoplasms initially grow exponentially and then slow down as they increase in size. This is called
gompertzian growth (Figure 5.4). Several mechanisms have been invoked to explain this change in
growth rate with larger tumours:
Decrease in the growth fraction
Increase in cell loss (eg exfoliation, necrosis)
Nutritional depletion of tumour cells resulting from outgrowth of available blood supply (under adverse
conditions tumours may enter G0 until conditions improve)



Figure 5.4 Gompe rtzian growth curve . Initially growth of a s mall tumour is e xpone ntial but as the tumour e nlarge s this patte rn of
growth is uns us tainable . Tumour-ce ll doubling time the re fore re duce s and ove rall growth s lows

Latent period: accumulation of cells is slow, so it can take several years for a single cell to proliferate
into a clinically detectable mass.

Chemotherapy: chemotherapy drugs are most effective on cycling cells; tumours with a high growth
fraction are more susceptible to antinuclear agents. Debulking tumours or treating with radiation pushes
more cells into the cell cycle and therefore increases the number of susceptible cells.

Tumour cell differentiation

Tumour cells may:
Arise at any stage during the process of differentiation and their progeny can replicate while still retaining
the characteristics of that stage of differentiation
Lose the inverse relationship between proliferation and differentiation • De-differentiate
Change lineage
Hypomethylate or hypermethylate genes that would control their replication (eg TP53 is often silenced in
this way)

Tumour cell apoptosis

The role of apoptosis

Apoptosis is the process of programmed cell death. It is a controlled sequence of steps that is activated
by a number of signals and results in ‘suicide’ of the cell. Most importantly it acts to balance mitotic
processes within the body. Apoptosis may be physiological or pathological.

Physiological apoptosis
Development: to create organs of normal size and function (eg creation of web spaces between digits) •

Homeostasis: eg loss of the uterine lining during menstruation or of the tips of the intestinal villi • Immune
function: to recognise antigens that are foreign and not ‘self’

Pathological apoptosis
Cell damage (eg peeling skin caused by sunburn)
Cell infection

The process of apoptosis

Apoptosis occurs as a result of activation of one of two pathways.

Intrinsic pathway
Activated from within the cell as a result of DNA damage or other stress • Regulated by the bcl-2 family of
proteins (pro-apoptotic and anti-apoptotic members) that stabilise the mitochondrial membrane •
Mitochondria release cytochromes which bind to apoptotic factors and activate cell death via the
caspases

Extrinsic pathway
Activated by apoptotic messages via receptors
Via tumour necrosis factor (TNF) superfamily of proteins and CD95

Common final apoptotic pathway

Activation of a cascade of proteolytic caspase enzymes is the final common pathway to cellular
destruction. This manifests as:
Chromatin condensation
DNA fragmentation
Protein cleavage
Reduction in cellular size and membrane blebbing
Fragmentation of the cell into membrane-enclosed apoptotic bodies (without release of the cell contents
into the surrounding environment) • Phagocytes engulf and destroy the apoptotic bodies without causing an
inflammatory reaction

Loss of the apoptotic pathway is responsible for increased levels of genetic instability and accumulation
of genetic mutations. This leads to tumour progression by the expansion of clones with more aggressive
phenotypes. It also confers resistance to chemotherapy, radiation, and immune-mediated cell destruction.

The Bcl-2 gene is particularly important in tumours. The products of this gene represent a superfamily
that associate with each other by homo- and heterodimerisation. Some dimers are pro-apoptotic and
others anti-apoptotic. The ratio of anti-apoptotic:pro-apoptotic dimers is important for determining
resistance of a cell to apoptosis. Mutations causing upregulation of anti-apoptotic dimers (or loss of pro-
apoptotic dimers) result in an overall resistance to apoptosis. Tumours may evade apoptosis by disruption
of the control mechanisms for apoptosis, such as mutation of genes such as Bcl-2 and BAX.

Tumour cell karyotype

The term ‘karyotype’ refers to the chromosomal arrangement of the genetic material in the cell. Virtually
all solid tumours, including non-Hodgkin’s lymphomas, have an abnormal karyotype or chromosomal
abnormality. Some of these abnormalities are limited to a given tumour type, almost like a ‘genetic
fingerprint’. A good example of this is the Philadelphia chromosome, which is characteristic of chronic
myelocytic leukaemia (CML).

Types of chromosome abnormality
Gain/loss of whole chromosome (aneuploidy)
Partial deletion
Translocation from one chromosome to another
Inversion of a segment of chromosome

Rearranging genetic material in this fashion has implications for the control of expression of the genes in
the abnormal segment. It may place oncogenes in a highly transcriptionally active region of the genome or
lead to deletion of tumour suppressor genes.

Tumour angiogenesis

Nutrients can diffuse to tumour cells only over a limited distance, so an adequate blood supply is critical
for a tumour to grow >1–2 mm in diameter. The process by which a tumour recruits and sustains its own
blood supply is called angiogenesis.

The majority of endothelial cells in the body are quiescent. Physiological angiogenesis in the adult occurs
only as a response to trauma and tissue repair or at certain times (eg the menstrual cycle). Pathological
angiogenesis occurs when there is persistent proliferation of endothelial cells in response to a stimulus
(eg from a tumour).

The angiogenic switch

Tumours recruit endothelial cells from surrounding vessels and progenitor cells in the circulation. These
cells are stimulated to grow into the tumour from the outside. When this occurs this stage is called ‘the
angiogenic switch’. The genetic determinant of the angiogenic switch remains unknown. The angiogenic
phenotype of a tumour depends on the net balance between pro-angiogenic and anti-angiogenic growth
factors in the region of the tumour. These growth factors may be produced by the tumour itself or by
stromal or immune cells in the tumour vicinity.

Promoters of angiogenesis

Angiogenic factors are secreted by tumour cells and tumour-associated macrophages. The most important
naturally occurring angiogenesis promoters include:
Fibroblast growth factors (FGFs)
Vascular endothelial growth factor (VEGF)
Angiopoietins (Ang-1 and Ang-2; the ratio between them is likely to be important)

Inhibitors of angiogenesis

Naturally occurring proteins:
Angiostatin
Endostatin
Thrombostatin

For discussion of angiogenesis as a target for cancer therapy see Section 5.5.

2.5 Neoplastic progression – invasion and metastasis



In a nutshell ...

Neoplastic progression is a term that refers to the generation of subclones within the tumour. These
subclones occur by accumulation of further genetic mutations and have an increasingly aggressive
phenotype, allowing invasion and metastasis to distant sites.

Neoplastic invasion



In a nutshell ...

The ability to invade and spread determines the difference between a benign and a malignant
phenotype. Invasion is due to:
Changes in adhesion molecules
• Cell-to-cell interactions
• Cell-to-matrix interactions
Proteolysis
Migration and chemotaxis

Changes in adhesion

Loss of cell-to-cell adhesion
E-cadherin is the major cell adhesion molecule in epithelia; these cell adhesion molecules are
downregulated in several carcinomas.

Loss of cell-to-matrix interactions
Integrins and cadherins bind epithelial cells to the basement membrane; loss of integrins is associated
with increased invasive potential. In particular the integrin v3 mediates adhesion to laminin, fibronectin
and fibrinogen. It is over-expressed on the basement membrane of new blood vessels and its activation
results in increased cell motility and proteolysis.

Cell adhesion to basement membrane
In normal epithelial cells laminin receptors are expressed on one side of the cell and bind to laminin on
the basement membrane; tumour cells have increased numbers of laminin receptors on all sides.

Proteolysis

Degradation of collagen by proteolytic enzymes is a vital step. Upregulation of proteolytic enzymes
groups; the matrix metalloproteases (MMPs) and tissue plasminogen activators (tPAs) correlate with
increased invasiveness.

Tumour cell migration

Tumour cells coordinate proteolysis with migration. Migration consists of intermittent and limited
attachment and detachment. The direction of migration is stimulated by chemotaxis driven by:
Host growth factors, eg IGF, human growth factor (hGF), fibroblast growth factor (FGF) and TGF-β
Tumour-secreted factors (called autocrine motility factors) • Gradient of degraded extracellular matrix
components

Neoplastic metastasis



In a nutshell ...

Natural history of a typical malignant tumour
Neoplastic transformation of a cell
Clonal expansion
Local invasion
Distant spread

Tumour spread may be:
Direct extension (eg direct invasion of bladder from adenocarcinoma of the sigmoid colon) •

Transcoelomic (eg ovary)
Lymphatic (eg axillary nodes from carcinoma of the breast)
Haematogenous (eg bone metastases from follicular carcinoma of the thyroid) • Spillage of tumour cells

during surgery
Haematogenous metastasis comprises:
Entry to the circulation
Dissemination
Extravasation
Establishment of a distant site
Angiogenesis

Lymphatic metastasis

Basement membranes of the lymphatics do not contain collagen or laminin and so are easier for the
tumour cell to invade. This is a common method of metastasis for carcinomas. Cells may become trapped

in the filtering lymph nodes draining the site of the primary tumour, where they are either destroyed or
form deposits and start to grow.

Many primary tumours have well-defined regional lymph nodes that are examined for signs of metastasis
during resection of the primary. See Section 5.1 for discussion of management of these nodes.

Haematogenous metastasis

Entry to the circulation
Tumour cells squeeze through gaps between endothelial cells to enter the circulation in a manner similar
to that employed by cells of the immune system in inflammation (remind yourself from Chapter 4). Many
of the same molecules have been implicated in this process (eg CD44).

Dissemination in the circulation
Malignant cells avoid detection by decreased expression of MHC I. They also shed intercellular adhesion
molecule (ICAM)-1 which interacts with cytotoxic T-cell receptors, stopping their destruction.

Extravasation
Cells attach to the vessel wall and migrate through it (eg increased expression of integrin VLA-4 in
melanoma); reduced expression of the nm23 gene is associated with increased metastases of breast
cancer, but its mechanism of action is unknown.

Establishment of metastasis

This is poorly understood. Traditionally it has been described in terms of the ‘seed and soil hypothesis’.
This may also go some way to explain common sites for development of metastasis from specific tumour
types. Other common sites for metastasis reflect the vascular drainage of the primary tumour (eg cells
shed from a colonic tumour travel via the portal circulation to the liver, where they have an impact in the
capillaries). Millions of cells may be shed into the circulation daily, but only a small fraction is
successful at initiating colonies. Development of a distant metastasis also requires initiation of an
angiogenic process at the chosen site.

Metastasis may be established as an early or late event in the development of the tumour (eg distant
spread with no identifiable primary). This may reflect different molecular processes going on in
subclones within the tumour.



Common patterns of metastasis
Site of metastasis Possible primary source

Liver GI

Pancreas
Lung

Skeletal Breast
Genitourinary
Brain Malignant melanoma
Adrenal
Transcoelomic Lung
Lung Breast
Prostate (osteosclerotic)
Kidney
Thyroid

Lung
Malignant melanoma
Breast

Lung
Breast

Stomach
Colon
Ovary

Kidney
Breast
Colorectal
Ovary

2.6 The immune system and neoplasia



In a nutshell ...

The immune system and neoplasia
Malignant transformation is associated with the expression of tumour antigens • These antigens may be

recognised as foreign by the immune system, resulting in destruction of the tumour cell (theory of
immune surveillance)
Tumour cells may practise immune evasion

The theory of immune surveillance

The process of malignant transformation may be associated with the expression of molecules on the cell
membrane that can be distinguished as foreign by the immune system. These are called tumour antigens
and they include:
Products of point mutations in normal genes
Over-expression of self-antigens (previously expressed at a low enough level not to induce tolerance) •
Viral antigens
Products of silent genes not usually expressed as protein (eg MAGE, BAGE and GAGE) • Products of fetal
proteins (oncofetal antigens)

Tumour antigens may thus be recognised by either arm of the immune system; the cellular and humoral

components and the abnormal cells are destroyed before tumours develop. The success of this strategy
depends on the immunogenicity of the tumour cells.

This is the immune surveillance theory. In particular, tumours are targeted by the complement system,
IgG and components of the cellular system: cytotoxic T lymphocytes, natural killer (NK) cells and
macrophages. Cytotoxic T cells recognise antigens displayed in complexes with MHC class I molecules.
Macrophages and dendritic cells engulf tumour cells, presenting their antigens to T cells in complex with
MHC molecules. The T-helper cells respond by secreting cytokines and recruiting other immunological
cells. Tumours producing interferon (IFN) specifically stimulate NK cells which lyse their targets. IFN-α
concentration also affects the way that antigens are processed within the cell and this alters their
immunogenicity.

Evading the immune system

Tumours may evade the immune system by means of:
Secretion of anti-inflammatory and immunosuppressive factors such as interleukins IL-4, IL-6 and IL-10,
prostaglandin PGE2, TGF-β1 and macrophage colony-stimulating factor (M-CSF)
Induction of apoptosis in immunological effector cells: tumour cells display Fas ligand which induces
apoptosis in the T cell when it binds to its own surface Fas molecule (this exploits the body’s system of
inducing tolerance)
Utilisation of immunological ignorance mechanisms:
• Displaying peptides that are not immunogenic
• Downregulating MHC class I molecules
• Shedding large volumes of antigen into the circulation to swamp the T-cell receptors

SECTION 3

Screening programmes

3.1 Cancer screening



In a nutshell ...

There are criteria for screening programmes and for the screening test used. Current NHS screening
programmes are nationally coordinated and include:
Breast screening
Cervical screening
Colorectal cancer screening
Go to www.cancerscreening.nhs.uk for further information.

Screening programmes

Criteria for screening programmes

A screening programme needs to fulfil certain criteria (defined by the WHO in 1966). These criteria are:
The condition is an important health problem • Its natural history is well understood • It is recognisable at
an early stage • Treatment is better at an early stage • A suitable test exists
An acceptable test exists
Adequate facilities exist to cope with the abnormalities detected • Screening is done at repeated intervals
when the onset is insidious • The chance of harm is less than the chance of benefit • The cost is balanced
against benefit

Criteria for screening tests

The screening test must detect the condition at an earlier stage than it would clinically present. This means
that there should be a detectable latent or preclinical phase during which interventional treatment is
possible.

The screening test should:

Be simple and cheap/cost-effective • Be continuous
Be highly sensitive (few false negatives) • Be highly specific (few false positives) • Have a high positive
predictive value • Be safe
Be non-invasive
Be acceptable to patients
Be offered to a group agreed to be at high risk • Be easy to perform and analyse

There should also be adequate resources to deal with the workload for both screening and treatment of
specific programmes.

3.2 UK screening programmes

Breast screening

The WHO’s International Agency for Research on Cancer (IARC) concluded that mammography
screening for breast cancer reduces mortality. The IARC working group determined that there is a 35%
reduction in mortality from breast cancer among screened women aged 50–69 (ie the number needed to
screen to save one life is 500). See www.cancerscreening.nhs.uk for more information.

Women aged 50–70 are routinely invited for breast screening every 3 years. After the upper age limit
women are invited to make their own appointments. A randomised controlled trial of age extension to
women aged 47–49 and 70–73 is under way.

There are over 90 breast screening units across the UK, each responsible for an average population of
around 45 000 women. These can be mobile, hospital based or permanently based in another convenient
location (eg a shopping centre).

The total budget in England is £96 million (£45.50 per woman screened).

Cervical screening

This is essentially a smear test, sent for cytology looking for early precursor abnormalities that may be
treated to prevent the development of cervical cancer.

All women between the ages of 25 and 64 are invited for a cervical smear test every 3–5 years. Women
aged 25–49 are screened every 3 years and women aged 50–64 are screened every 5 years.

The total budget (including the cost of treating cervical abnormalities) is around £150 million a year
(£37.50 per woman screened).

Colorectal cancer (CRC) screening

The English CRC screening pilot was recently completed. It assessed the feasibility of CRC screening
using the faecal occult blood (FOB) test for patients aged 50–69. This was positive in about 2% and these
people were offered colonoscopy. Based on the success of this programme, an FOB screening programme
has been rolled out in England, aimed at men and women aged 60–69 (screened ages are 50–74 in
Scotland and 60–74 in Wales).

Prostate cancer screening

There is no UK screening programme for prostate cancer; prostate-specific antigen (PSA) screening does
not fulfil the WHO screening criteria and European studies have suggested that it results in high levels of
over-treatment of the disease.

SECTION 4

Clinical and pathological grading and staging of cancers

4.1 Tumour grade

This is an assessment of the degree of differentiation of a tumour and corresponds to the aggressive
behaviour of the tumour. Tumours are graded as:
Well differentiated
Moderately differentiated
Poorly/undifferentiated/anaplastic

Many different grading systems exist for different tumours that take into consideration growth patterns as
well as differentiation status, eg Gleason grade for prostate cancer.

Differentiation refers to the degree to which neoplastic cells resemble their tissue of origin. Features of
poor differentiation are:
Increased nuclear pleomorphism
Atypical mitoses
Hyperchromatic nuclei
Increased nuclear:cytoplasmic size ratio
Possible presence of giant cells

Tumour grading is important for prediction of tumour behaviour and prognosis. In general, the less
differentiated the tumour, the more aggressive its biological behaviour.

4.2 Tumour staging

This refers to the size and spread of the neoplasm as assessed by clinician, pathologist or radiologist. It is
used to determine prognosis and is pivotally important for deciding on appropriate management, including
the need for adjuvant therapy after surgery.

Examples:
Dukes’ classification for colorectal carcinoma • Clarke’s classification for malignant melanoma • TNM
(tumour, node, metastasis) system

Staging often requires extensive investigations of the sites most likely to be involved in disease and is

aimed at assessing degree of tumour spread to regional nodes and distant sites:
Blood tests (eg liver function tests [LFTs], tumour markers) • Cytology or biopsy for histology
Chest radiograph or computed tomography (CT) • Abdominal ultrasonography or CT
Magnetic resonance imaging (MRI)
Isotope bone scanning
Positron emission tomography (PET) • Diagnostic or staging laparoscopy
Full staging may not be possible until after surgery to resect the tumour, when regional lymph nodes can be
inspected histologically for tumour deposits.
Failure to identify distant metastasis at the time of staging does not necessarily mean that the patient is free
from all tumour cells after resection of the primary. Tumour cells continue to be present in the circulation
until the primary is removed and there may be tiny, as yet undetectable, metastatic deposits in other organs
or lymph nodes.

TMN staging system

The TNM classification was first developed by the American Joint Committee on Cancer Staging and End
Result Reporting and has now been modified for systems for most solid tumours, eg breast, colon, thyroid.



The TNM staging system
T = primary tumour
T0 = no primary tumour
Tis = in situ primary tumour
Tx = unknown primary
T1–4 sizes of primary tumour
N = nodal metastasis
N0 = no nodes
N1 = few node(s)
N2–3 relates to number, fixity or distant lymph node group involvement
M = distant metastasis
M0 = no metastasis
M1 = distant metastasis present
Mx = unknown if metastasis present

Solid organ tumours have their own individual numbering for T and N stage, which can be determined
non-surgically, eg by CT or MRI, or by a pathologist on a resected specimen. For example, a pathologist
studying a colonic resection specimen may report the primary lesion as a T2 N2 tumour – the tumour has
invaded the muscularis propria (T2) and cancer is found in four or more lymph nodes (N2). Other
prefixes used in the TNM classification are a ‘p’ before the T stage (as in ‘pT4 tumour’), which indicates
that the T stage had been determined pathologically rather than by any other modality, and ‘y’ before the
staging, which indicates that neoadjuvant therapy had been given before the surgery.

Dukes’ staging (A–D) is still in common usage as an adjunct to TNM staging in determining the
management of colorectal cancer. The Roman numeral cancer staging system has not been completely
superseded by the TNM classification, and is still in common usage; this stratifies tumour stage from 0
(carcinoma in situ) to IV (distant metastasis present). In breast cancer the Nottingham Prognostic Index is
calculated for each tumour, taking into account various tumour characteristics, and is pivotally important

in guiding treatment.

4.3 Tumour markers



In a nutshell ...

Tumour markers are substances in the blood that may be useful in monitoring of specific cancers.
Markers include:
Epithelial proteins, eg prostate-specific antigen (PSA) • Hormones, eg β-human chorionic
gonadotrophin (β-hCG) • Oncofetal antigens, eg carcinoembryonic antigen (CEA)
Tumour markers are useful in diagnosis, staging, treatment, detection of recurrence.

PSA

A prostatic epithelial protein
Elevated if >4 ng/dl (in general)
Used together with digital rectal examination, transrectal sonography and needle biopsy for ‘screening’,
diagnosis and monitoring of treatment for prostatic cancer
It is also elevated in benign prostatic hyperplasia, prostatitis, prostatic infarction, urinary retention,
instrumentation and even ejaculation
Thought not to rise significantly after rectal examination • PSA velocity measures rate of change of PSA
with time (>0.75 ng/dl per year suggests malignancy) • PSA density compares PSA value with volume of
prostate (>0.15 suggests malignancy) • Age-related PSA (older patients have a higher ‘normal’ cut-off) •
Free total PSA ratio (<25% suggests malignancy)

CEA

An oncofetal antigen, normally expressed in embryonic gut, liver, pancreas • Elevated in colorectal
carcinoma in 60–90% of cases • May also be elevated in ovarian and breast carcinoma • Also
occasionally elevated in cirrhosis, alcoholic hepatitis, inflammatory bowel disease, pancreatitis • Not
specific or sensitive enough to be used as a screening tool • Used to monitor efficacy of therapy and
detection of recurrence

Alpha-fetoprotein (α-FP)

An embryonic antigen
Elevated in carcinoma of liver (also in cirrhosis, chronic hepatitis, normal pregnancy, fetal neural tube
defects) • Also elevated in non-seminomatous germ-cell tumour of the testes (NSGCT)

Beta-human chorionic gonadotrophin (b-hCG)

A hormone that is elevated in pregnancy
Elevated in choriocarcinoma, non-small-cell germ-cell tumour (NSGCT) and in 7% of seminomas where
syncytiotrophoblastic elements are present

CA antigens

CA-125: for non-mucinous ovarian cancers. A high concentration is more likely to be associated with
malignancy. Can be used to monitor therapy. Can be raised in other conditions (eg pancreatitis,
endometriosis, breast and pancreatic carcinomas) • CA-15-3: a glycoprotein, occasionally elevated in
breast carcinoma • CA-19-9: a glycoprotein sometimes elevated in pancreatic and advanced colorectal
carcinoma

Thyroglobulin

Elevated in some thyroid carcinomas

Calcitonin

Elevated in medullary thyroid carcinoma

Adrenocorticotropic hormone/antidiuretic hormone

Elevated in some small-cell lung carcinomas

SECTION 5

Principles of cancer treatment

In a nutshell ...

The management of cancer patients is usually decided in the context of a multidisciplinary team. Many
therapies are combined on the basis of tumour type, grade and stage.
Therapies include:
Surgery
Radiotherapy
Chemotherapy
Hormonal therapy
Additional and experimental therapies • Immunomodulation
Monoclonal antibodies
Cryotherapy and radioablation
Gene therapy
Anti-angiogenic treatment

5.1 The role of surgery in neoplasia

Surgery has a diagnostic, staging and therapeutic role in neoplasia. It may be curative or palliative.

It forms a primary treatment for many solid tumours.


In a nutshell ...

Surgery is used in diagnosis, staging, treatment and palliation of cancer • Surgical design is driven by
local invasion and tumour spread (resection en bloc)

Surgical design is influenced by the degree of invasion and spread of the tumour. The two most important
principles of curative oncological surgery are resection en bloc (ie without surgical disruption of the
plane between the tumour and potentially locally infiltrated tissue and without disruption of the
lymphatics draining the region of the tumour) and resection margins that are free from tumour cells.