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SECTION THREE PATHOLOGY
CHAPTER 14
Cellular injury
Causes of cellular injury include: CELL DEATH
l trauma
l thermal injury—heat and cold Cell death is the irreversible loss of the cell’s ability
l chemical agents—drugs, poisons, hypoxia to maintain independence from the environment.
l infectious organisms Two major forms of cell death are recognised:
l immunological mechanisms l necrosis
l nutritional deficiencies l apoptosis.
l ionising radiation.
Necrosis
MECHANISMS OF CELLULAR
INJURY Necrosis is cellular or tissue death in a living organism,
irrespective of the cause. Several types of necrosis are
Cells may be damaged either reversibly or irreversibly described:
in a variety of ways: l coagulative
l Mechanical disruption: l colliquative
l caseous
n trauma by direct mechanical force l gangrenous
n extremes of heat and cold l fibrinoid
n osmotic pressure changes. l fat.
l Failure of cell membrane integrity:
n damage to ion pumps. Coagulative necrosis
l Membrane damage:
n free radicals. l Denaturation of intracytoplasmic proteins.
l Interference with metabolic pathways: l Dead tissue will initially become firm and swollen,
n respiratory poisons and mitochondria
n disruption of protein synthesis. but later becomes soft (ventricle may rupture after
l Deficiency of metabolites: myocardial infarction).
n hypoxia/anoxia l Typically occurs in ischaemic injury (except brain).
n glucose (hypo- or hyperglycaemia)
n hormones. Colliquative necrosis
l DNA loss or damage:
n ionising radiation l Seen in brain, probably due to lack of supporting
n chemotherapy stroma.
n free radicals.
The effect of cell injury on a tissue will depend on: l Necrotic brain tissue liquefies.
l the nature of the injurious agent l Glial reaction at periphery with cyst formation
l the duration of the injury
l the proportion of the type of cell affected occurs eventually.
l the ability of the tissues to regenerate.
Caseous necrosis
l Characteristic of TB.
l Macroscopically cheese-like (caseous).
l Microscopically structureless.
293
294 SECTION THREE PATHOLOGY
Gangrenous necrosis Function of apoptosis
l Necrosis with putrefaction of tissues due to certain l Morphogenesis (elimination of cells in embryonal
bacteria, e.g. clostridia, streptococci. development).
l Tissue black due to iron sulphide from degraded l Removal of cells which have undergone DNA
haemoglobin. damage.
l Ischaemic gangrene may be either ‘dry’ or ‘wet’ l Removal of virally infected cells.
gangrene. l Induction of tolerance to self-antigens by removal of
l Gas gangrene is the result of infection with Clostrid- autoreactive T-lymphocytes.
ium perfringens.
Mediators of apoptosis
l Synergistic gangrene follows infection by a specific
combination of organisms (see Chapter 21). p53
l A tumour suppressor gene which checks the
Fibrinoid necrosis
integrity of the genome prior to mitosis.
l Associated with malignant hypertension. l Switches cells with damaged DNA into apoptosis.
l Necrosis of arteriole smooth muscle wall with seep- l Loss of p53 expression is associated with poor
age of plasma into tunica media and deposition of prognosis in tumours.
fibrin.
l Smudgy eosinophilic appearance in H and E bcl–2
sections. l Inhibits apoptosis.
l Excess bcl–2 expression results in failure of initia-
Fat necrosis
tion of apoptosis with cell accumulation.
l Direct trauma to adipose tissue and extracellular lib- l Overexpression in neoplasia.
eration of fat (e.g. fat necrosis causing breast lump).
fas (CD 95)
l Enzymatic lysis of fat by lipases, e.g. pancreatic l Plasma membrane receptor which, when activated,
lipase in acute pancreatitis. Fats split into fatty
acids which combine with calcium to precipitate is directly coupled to the activation of intracellular
as soaps (seen as white spots on the peritoneum proteases, which lead to apoptosis.
and omentum).
Caspases
Apoptosis l Present in all cells and unless inhibited lead to
Apoptosis is an energy-dependent process for the morphological changes of apoptosis.
deletion of unwanted individual cells. It is to be distin-
guished from necrosis (Table 14.1). It is a biochemically Morphological features of apoptosis
specific mode of cell death characterised by activation
of endogenous endonuclease, which digests nuclear l Cell shrinkage with intact plasma membrane.
DNA into smaller DNA fragments. l Nuclear shrinking (pyknosis).
l Nuclear fragmentation (karyorrhexis).
Table 14.1 Comparison of apoptosis and necrosis
Feature Apoptosis Necrosis
Induction Physiological or pathological stimuli Invariably pathological injury
Extent Groups of cells
Biochemical Single cells Impairment or cessation of ion
Cell membrane integrity Energy-dependent fragmentation of homeostasis
Morphology DNA by endogenous endonucleases Lysosomes leak lytic enzymes
Lost
Inflammatory response Lysosomes intact Cell swelling and lysis
Fate of dead cells
Preserved Usual
Phagocytosed by neutrophils
Cell shrinkage and fragmentation to form
apoptotic bodies with dense chromatin and macrophages
None
Phagocytosed by neighbouring cells
Cellular injury 14 295
l Margination of chromatin. l replacement of exudate by vascularised fibrous
l Surface blebbing of cell. tissue
l Formation of apoptotic bodies (cells break up into
l eventually a collagen-rich scar develops.
membrane-bound fragments).
l Fragments are either shed (if epithelial cells are Granulation tissue
l A combination of capillary loops and myofibroblasts.
involved) or phagocytosed (by neighbouring cells). l Capillary endothelial cells grow into the area to be
Diseases of increased apoptosis repaired.
l Fibroblasts are stimulated to divide.
l HIV (CD4þ cells die through programmed cell death). l Fibroblasts secrete collagen and matrix
l Neurodegenerative diseases.
components.
Diseases of decreased apoptosis l Fibroblasts acquire muscle filaments and attach to
l Neoplasia adjacent cells and become myofibroblasts.
l Autoimmune disease. l Myofibroblasts cause wound contraction.
l Granulation tissue appears red and granular, hence
THE PROCESS OF HEALING
the name.
Regeneration and repair l Excessive granulation tissue protruding above the
l Regeneration refers to total healing of a wound with wound surface is called ‘proud flesh’.
restitution of the original tissues in their usual
amounts, arrangements and with normal function. Clinical problems with organisation
and wound contraction
l Repair refers to the process where the original
tissue is not totally regenerated and the defect is Organisation
made good to a variable extent by scar tissue. l Fibrous adhesions in the peritoneum may cause
Cell renewal intestinal obstruction.
l Obliteration of the pericardial space with scarring
The regenerative capacity of cells varies. Cells can be
classified according to their potential for renewal: may cause constrictive pericarditis.
l Labile cells:
Wound contraction
n good capacity for regeneration l Stenosis (narrowing at an orifice), e.g. anal stenosis
n e.g. surface epithelial cells constantly being
after haemorrhoidectomy, pyloric stenosis after
replaced from deeper layers, e.g. skin, oesoph- peptic ulceration.
agus, vagina. l Stricture (a narrowing in a tube), e.g. narrowing in
l Stable cells: the colon after ischaemic colitis.
n divide at slow rate under physiological condi- l Scarring in a muscle causing a contracture.
tions l Contractures following burns, especially around
n replaced by mitotic division of mature cells and joints.
lost cells are rapidly replaced
n e.g. liver, renal tubular epithelium. INJURIES TO SPECIFIC TISSUES
l Permanent cells:
n never divide in post-natal life Skin
n cannot be replaced if lost
n e.g. nerve cells, striated muscle cells, myocar- Healing depends upon the size of the defect. It
dial cells. depends whether it is an incised wound (surgical
incision) or whether there is tissue loss.
Repair
Skin anatomy (Fig. 14.1)
Organisation is the process whereby specialised tis-
sues are repaired by the formation of mature connec- l Skin is composed of epidermis and dermis.
tive tissue, i.e. fibrous scar. Organisation occurs by: l Beneath the dermis lie subcutaneous fat, fascia and
l fibrinous exudate
l removal of fibrin and dead tissue and phagocytes muscle.
l migration of fibroblasts and capillaries forming l The blood supply to the skin arises from blood ves-
granulation tissue sels which perforate the muscle (perforator vessels)
and travel through the subcutaneous tissue to form
the subdermal and dermal vascular plexus.
296 SECTION THREE PATHOLOGY
Dermal vascular plexus Epidermis
Subdermal vascular plexus Dermis
Segmental artery and perforating
Subcutaneous tissue
branch through muscle Muscle
Fig 14.1 Anterior fascia
The structure of skin with vascular plexus, fat, fascia and muscle. Posterior fascia
Incised wound (surgical incision)— Abnormalities of skin healing
healing by first intention
Keloid
l Edges of incision apposed. l Excessive fibroblast proliferation and collagen
l Fibrin ‘sticks’ edges together.
l Capillaries bridge tiny gap. production.
l Fibroblasts invade fibrin network. l Particularly common in black Africans.
l After 10 days wound is strong and sutures can be l Collagen deposition occurs beyond and above the
removed. wound itself.
l Remodelling occurs from then on. l Occurs after surgery and injury, particularly burns.
l Covered by normal epithelium.
Tissue loss—healing by second l Does not settle.
intention
Hypertrophied scar
l Tissue loss, e.g. trauma, or wound left open, e.g. l Wound broad and raised.
grossly infected wound. l Does not extend beyond the wound itself.
l Usually settles spontaneously in up to 18 months.
l Phagocytes remove any debris.
l Formation of granulation tissue in base of wound. Anatomy of repair of defects
l Myofibroblasts cause wound contraction
l Centripetal growth of epithelium from wound edges l Wherever possible, scars from any wound should be
placed in the lines of relaxed skin tension (Fig. 14.2),
(re-epithelialisation) to cover defect. which are seen in the older patient as wrinkle lines.
l Eventually tissue deficit made good by scar tissue.
l Final cosmetic result depends on degree of tissue l These lines lie perpendicular to the underlying mus-
cle contraction.
loss and amount of scarring.
Cellular injury 14 297
Free flap
Regional/pedicled flap
Local/random pattern flap
Full-thickness skin graft
Split-thickness skin graft
Fig 14.2 Delayed primary closure
Lines of relaxed skin tension.
Primary closure
l These are different to Langer’s lines, which were
anatomically derived using cadaver experiments Fig 14.3
and differ slightly due to lack of mechanical forces. The reconstructive ladder.
Reconstructive ladder (Fig. 14.3) n allograft, e.g. cadaver bone
n xenograft, e.g. animal tendon; rare.
l When assessing any wound or defect the principles
of the reconstructive ladder can be utilised. Skin grafts
l A full-thickness skin graft consists of epidermis and
l Employing the simplest options first, the ladder
outlines different steps for closure of a wound or the whole of the dermis.
defect. l A split-thickness skin graft consists of epidermis
l The ladder can be ‘climbed’ as the complexity of the and a variable thickness of dermis.
reconstructive situation increases.
Mechanism of skin graft take
Grafts Skin grafts take in a series of steps which can be
broken into:
l Common option for closure of defects that cannot l Adherence:
be primarily closed.
n fibrin bonds the graft to the recipient site
l Commonly composed of skin, but may contain a n occurs in < 12 h.
variety of tissue including: l Plasmic imbibition:
n skin n graft absorbs essential nutrients from recipient
n cartilage
n tendon bed
n bone n occurs at 24–48 h.
n or can be composite, using a combination of l Inosculation:
the above. n revascularisation of the graft via growth of
l Are not transferred with their own blood supply. vascular buds
l Rely on the formation of a new vascular system at a n occurs at 48–72 h.
new site.
l Different types of graft include:
n autograft: own tissue; most common
298 SECTION THREE PATHOLOGY l Result in more contraction at the recipient site.
l Can be meshed for large areas needing grafts.
Upper arm l Result in pale, square scar at healed donor site
Buttock (takes 10–14 days).
l Usually ‘take’ well as are thinner, helping them
Thigh
survive the imbibition phase.
Fig 14.4
Split-thickness skin graft donor sites. Full-thickness skin grafts (Fig. 14.5)
Split-thickness skin grafts (Fig. 14.4) l Common donor sites include:
l Common donor sites include:
n groin
n thigh n pre-/post-auricular areas
n buttocks n supraclavicular region.
n upper arm. l Result in less contraction at recipient site.
l Limited to relatively smaller areas due to direct
closure of donor site.
l Result in linear scar at donor site.
l Less reliable ‘take’ due to thicker nature.
Flaps
l Unit of tissue transferred with its own blood supply.
l Used for:
n large defects
n where a graft would produce a poorer cosmetic
result, e.g. face
n where the base of a defect could not support a
graft, i.e. bare bone, exposed tendon or poorly
vascularised bed.
Classification
Can be classified in several ways:
l by composition: cutaneous, fasciocutaneous, myo-
cutaneous, osteofasciocutaneous, etc. (Fig. 14.6)
l by vascular supply: random pattern, axial, island
(Fig. 14.7)
l by location of donor site to defect: local, regional/
pedicled, distant/free (Fig. 14.8)
l by design: transposition, z-plasty, rotation, ad-
vancement (Fig. 14.9).
Local flaps
l Local flaps are composed of tissue raised adjacent
to the defect to be covered.
l Can be a useful method of closing defects without
tension or grafts.
l Can be utilised for scar revision, by changing the
length or direction of a scar.
l This can be useful at cosmetically important sites,
such as the face.
Below are some general examples of random pattern
local flap options.
Transposition flap (Fig. 14.9A)
l A transposition flap can be of varying shape and is
moved laterally into an adjacent defect.
Post-auricular Cellular injury 14 299
Pre-auricular l The angle of movement can be varied, but must
leave significant breadth at the base of the flap to
Supraclavicular ensure vascularity.
Groin l The transposition results in a secondary defect,
which can be primarily closed.
Fig 14.5
Full-thickness skin graft donor sites. Rotation flap (Fig. 14.9B)
l A rotation flap is usually a semi-circular shaped
flap, which is rotated into the defect along the outer
line of the semi-circle.
l This often necessitates a ‘back-cut’ to allow suffi-
cient movement, but as with all flaps there must be
significant width of tissue left at the base of the flap
to ensure its survival.
l The rotation results in a secondary defect, which
can be primarily closed.
Advancement flap (Fig. 14.9C)
l An advancement flap moves tissue into a defect
without the use of lateral transposition or rotation.
l They can be of varying shapes, some of which
produce:
n a primary defect to be closed
n or excess tissue at the flap base which requires
excision (Burrow’s triangles)
n neither of the above affects the width of the flap
base.
Z-plasty (Fig. 14.9D)
l A z-plasty is composed of two interposing triangular
transposition flaps
l These can be used to alter the direction of a scar or
the length of a scar contracture, depending upon the
angles within the triangles of the z-plasty.
Free flaps (Fig. 14.10)
Free flaps are used in a variety of reconstructive
situations including:
l Traumatic reconstruction:
n open fractures with soft tissue loss
n injuries with severe degloving or tissue loss
n burn scar revision.
l Neoplastic/cosmetic reconstruction:
n post-cancer surgery, e.g. breast reconstruc-
tion, mandibular reconstruction
n tissue coverage post-debridement for necrotis-
ing infections.
l Functional reconstruction:
n facial or limb re-animation surgery using
neurotised flaps.
l Below are some common flaps used in the situa-
tions described above.
Radial forearm flap
l Vascular supply from perforating vessels of the
radial artery.
300 SECTION THREE PATHOLOGY
Epidermis Cutaneous flap
Dermis Epidermis + dermis
Subcutaneous tissue Fasciocutaneous flap
Fascia Epidermis + dermis + subcutaneous tissue
+ fascia
Muscle Myocutaneous flap
Epidermis + dermis + subcutaneous tissue
+ fascia + muscle
Osteofasciocutaneous flap
Epidermis + dermis + subcutaneous tissue
+ fascia + muscle + bone Fig 14.6
Bone Flaps by composition.
l Based on the flexor aspect of the forearm. l Donor site is directly closed.
l Donor site can be directly closed, but for larger skin l Can give a large skin paddle with an acceptable
requirements needs skin grafting. abdominoplasty donor scar.
l Can be taken with a segment of radius for, e.g.
Bone
mandibular reconstructions.
l Haematoma resulting from ruptured bone vessels
Anterolateral thigh flap and periosteal vessels forms between the ends of
l Vascular supply from myocutaneous/septocuta- the fracture.
neous perforating vessels of the descending branch l Macrophages invade the haematoma together with
of the lateral circumflex artery. polymorphs and fibroblasts; new vessels form,
l Based on a line drawn from anterior superior iliac fibrosis occurs and by the end of the first week
spine to lateral patella. the clot is organised.
l Donor site is directly closed.
l Can give large skin paddle. l Osteoblasts grow into the haematoma and form
trabeculae of woven bone.
Deep inferior epigastric perforator (DIEP)/transverse
rectus abdominis myocutaneous (TRAM) flap l The new bone (sometimes with islands of cartilage
l Vascular supply from myocutaneous perforating formed by chondroblasts) is called callus.
vessels of the deep inferior epigastric artery. l Internal callus lies within the medullary cavity.
l DIEP flap dissects out perforating vessels to pre- l External callus is related to the periosteum and
serve rectus muscle and function, in effort to reduce envelops the fracture site, acting as a ‘splint’.
donor site morbidity, i.e. hernias. l By 2–3 weeks the repair tissue reaches its
l TRAM flaps take varying amount of muscle with
the flap. maximum girth in long bone, but is still too weak
to support weight.
Cellular injury 14 301
Random pattern flap: relies on dermal/subdermal plexus,
therefore has maximum length:width ratio of 2:1 for safety
Non-random axial pattern flap: based on specific artery
Non-random island flap: isolated on a vascular pedicle and
can be moved to another site
Fig 14.7
Flaps by vascular supply.
l Woven bone is subsequently replaced by lamellar occurs, cirrhosis develops and the architecture
bone. is lost.
l Damage that destroys hepatocytes only may be
l Remodelling takes place according to the direction followed by complete restitution.
of mechanical stress. l Damage that destroys hepatocytes and the
architecture may not be followed by complete
l Restoration to normal may take up to a year. restitution.
Factors affecting bone healing Kidney
l Movement. l Epithelium can regenerate.
l Misalignment. l Architecture cannot regenerate.
l Interposition of soft tissues. l Loss of tubular epithelium, e.g. ischaemia, toxins,
l Infection.
l Pre-existing bone disease. will recover provided enough normal epithelial cells
are left to regenerate.
Liver l Loss of glomeruli (glomerulonephritis) is likely to be
permanent.
l Hepatocytes have excellent regenerative capacity.
l Following surgical resection of areas of the liver for Cardiac muscle
trauma, regeneration is rapid and full recovery of l Permanent cells and therefore no regeneration.
the organ’s mass occurs and the architecture is l Damaged muscle replaced by scar tissue.
maintained.
l When the injurious agent persists—e.g. viral dam-
age, alcohol abuse, autoimmune disease—fibrosis
302 SECTION THREE PATHOLOGY
Local: l Important in MI.
mobilise adjacent l May result in ventricular aneurysm due to weaken-
tissue, e.g. rotation
flap ing of wall.
Distant (pedicled/ Neural tissue
tubed):
mobilise near/distant l Permanent cells; regeneration does not occur in the
tissue on its blood central nervous system
supply, e.g.
gastrocnemius l Peripheral nerves undergo wallerian degeneration
muscle flap distal to the site of trauma. Recovery is variable
depending upon alignment and continuity.
Free:
free tissue transfer Peritoneum
using microvascular
surgery, e.g. ALT flap l Sutured peritoneum may result in local ischaemia
which acts as a stimulus to adhesion formation,
Fig 14.8 especially if contaminated with foreign material.
Flaps by location.
l A clean unsutured defect, no matter how large, will
usually heal without adhesions.
l Perivascular connective tissue cells in the base of
the defect grow towards the surface and differenti-
ate into new mesothelial cells.
l Centripetal growth from the wound margins contrib-
utes little to mesothelial healing.
l Healing of the unsutured peritoneum is rapid and
complete irrespective of the size of the defect,
and occurs with little risk of adhesion formation.
Gastrointestinal tract
Mucosal erosions
An erosion is loss of part of the thickness of the mucosa.
l Erosions regenerate rapidly from adjacent viable
epithelial cells.
l Erosions can repair in a matter of a few hours if the
cause is removed.
l Erosions can cause significant gastrointestinal
bleeds but escape detection by endoscopy a few
hours later as rapid healing has occurred.
Mucosal ulcers
l Loss of full thickness of the mucosa.
l Repaired by granulation tissue in base and
centripetal growth of surface epithelium.
l If cause persists, ulcer may become chronic with
considerable fibrous scarring, e.g. pyloric stenosis
with chronic duodenal ulceration.
Gastrointestinal anastomoses
l Healing better in upper GI tract; stomach and small
bowel heal better than colon.
l Very dependent upon blood supply.
l Interrupted sutures with suturing of only the sero-
muscular layers prevent ischaemia of the mucosa
and allow good mucosal healing.
Cellular injury 14 303
Pivot flaps (A and B)
A Transposition flap B Rotation flap
C Advancement flap D Z-plasty
A B
B A
Broken lines show ‘Burrows triangles’ Fig 14.9
which may need to be excised to
allow advancement Local flaps by design. Pivot flaps.
A Transposition flap. B Rotation flap
(These flaps are termed pivot flaps as
they move around a pivot point).
C Advancement flap. D Z-plasty.
Factors affecting wound healing INJURY DUE TO IONISING
RADIATION
Local
Biological response to irradiation depends on:
l Inadequate blood supply. l physical factors, i.e. dose, character, time of
l Haematoma.
l Infection. exposure
l Early movement (especially delayed fracture l chemical factors, e.g. substrates for generation of
healing). free radicals
l Foreign material, e.g. sutures, extraneous foreign l biological factors, i.e. phase of cell cycle at time of
bodies. exposure.
l Irradiation. Individuals may be exposed to irradiation in several
l Denervation, e.g. peripheral neuropathy (diabetes, ways:
l Background:
neuropathic ulcers).
l Leprosy. n natural sources:
l Charcot’s joints (joint does not repair). l cosmic
l terrestrial
Systemic l airborne
l food sources
l Nutritional problems, e.g. malnutrition, vitamin C
deficiency (required for collagen synthesis), zinc n artificial sources
deficiency. l diagnostic X-rays
l nuclear power industry.
l Drugs, e.g. steroids, immunosuppressive drugs, cy-
totoxic agents. l Accidental:
n Chernobyl disaster.
l Neoplasia.
l Diabetes mellitus: affects polymorph function, mi- l Occupational:
n radiologists
crovascular disease, neuropathy. n mining of uranium.
l Age: younger patients heal better than older patients.
l Jaundice. l Medical:
l Uraemia. n diagnostic tests.
304 SECTION THREE PATHOLOGY radicals (e.g. H and OH ) are formed. In well-
oxygenated cells, oxygen free radicals (e.g. HO2 and
Free radial forearm O2 À) are also formed. These radicals interact with
flap—branches of macromolecules (e.g. membrane lipids and DNA) and
radial artery and cause damage.
skin paddle
The types of radiation-induced DNA damage
include:
l strand breaks
l base alterations
l cross-linking.
The resulting DNA damage may have three possible
consequences:
l cell death either immediately or at the next
attempted mitosis
l repair and no further damage
l a permanent change in genotype.
The outcome will depend upon the dose given and the
radiosensitivity of the cell. Rapidly dividing cell popu-
lations are the most sensitive.
Anterolateral thigh Effects on tissues
flap—branches of
lateral femoral These may be acute or chronic.
circumflex artery and l Acute:
skin paddle
n result in cell death
DIEP/TRAM flap— n most marked in cells that are dividing
branches of the deep
inferior epigastric rapidly, e.g. gut epithelium, bone marrow, skin,
artery and skin gonads
paddle n vascular endothelial damage results in fluid
and protein leakage into the tissue, causing
Fig 14.10 inflammation.
Free flaps. l Chronic:
n damage to endothelium results in exposure of
Mode of action underlying collagen with platelet adherence
and thrombosis
Following the passage of ionising radiation through n results in intimal proliferation and development
tissues, several types of free radicals are formed from of endarteritis obliterans
water in the cells. Short-lived and highly reactive free n this results in long-term vascular insufficiency
and consequent atrophy and fibrosis
n radiation-induced mutation of the genome
increases risks of neoplasia.
Effect on individual tissues
Bone marrow
l Suspends renewal of all cell lines.
l Granulocytes are reduced before erythrocytes,
which survive longer.
l Outcome depends on dose used.
l Varies from complete recovery to aplastic anaemia.
l Increased incidence of leukaemia in long-term
survivors.
Cellular injury 14 305
Skin Ultraviolet light
l Cessation of mitosis in epidermis with desquama- l Non-ionising radiation does not penetrate deeply.
tion and hair loss. l Has a range of wavelengths.
l May act by inducing thymine dimers in DNA; non-
l Regrowth will occur if enough basal stem cells
survive. dimer damage; or inhibiting DNA repair processes.
l Tumours produced are basal cell carcinomas, squa-
l Damage to melanocytes results in melanin release
into tissues, where it is ingested by phagocytes mous cell carcinomas and malignant melanomas.
which remain in the tissue resulting in
hyperpigmentation. THERAPEUTIC IRRADIATION
l Destruction of dermal fibroblasts results in inability Radiotherapy can be used therapeutically in three
to produce collagen, and therefore thinning of the ways:
dermis. l With a view to a cure (radical radiotherapy).
l Adjuvant.
l Damage to small vessels results in thinning of the l Palliative.
wall, dilatation and tortuosity, and the formation
of telangiectasia. Radical applications
Intestines l Basal cell and squamous cell carcinoma of the skin.
l Some head and neck tumours and laryngeal
l Loss of surface epithelium results in diarrhoea.
l Damage of full thickness with fibrosis will result in tumours.
l Hodgkin’s disease.
stricture formation. l Lymph node metastases of a testicular seminoma
Gonads following orchidectomy.
l Extremely radiosensitive. Adjuvant radiotherapy
l Sterility may result with low doses.
l Mutations may occur in germ cells, with resultant This is aimed at clinically undetectable metastases
due to spread locally or into the regional lymph nodes,
teratogenic effect. e.g. carcinoma of the breast giving radiotherapy to
the scar, axillary nodes, supraclavicular nodes and
Lung internal mammary nodes.
l Progressive pulmonary fibrosis may occur. Palliative radiotherapy
l Inhaled radioactive materials may induce pulmo-
l Bony metastases: pain relief is often dramatic.
nary tumours. l Cerebral metastases.
l Ulcerating or fungating breast cancer: controls
Kidney
oozing and bleeding and allows skin healing.
l Gradual loss of parenchyma results in impaired l Lung cancer to prevent cough and haemoptysis.
renal function.
Fractionation of dose
l Endarteritis obliterans of small vessels will cause
intrarenal renal artery stenosis and hypertension. l A higher dose of radiation may be given without
increasing side-effects if it is divided into a number
Whole body irradiation of fractions and given on different days with a break
in between.
l As the dose increases, so does the severity and
rapidity of the onset of the effects. l Normal cells are better able to repair than neoplas-
tic cells.
l Total body irradiation may be used therapeutically
to ablate the bone marrow prior to marrow trans- l Results in differential cell killing of more tumour
plantation with either autologous stored marrow cells than normal cells.
or from another donor.
l A very high dose results in CNS damage with coma
and convulsions occurring within hours. As the dose
reduces, gut damage occurs within a few days;
with further reduction, marrow failure can occur
in weeks; and at low doses there are no immediate
effects, although there is a long-term risk of
neoplasia.
306 SECTION THREE PATHOLOGY
Response modifiers Chemical
l Low oxygen tension in tissues reduces sensitivity l Caused by acids or alkalis in domestic or industrial
of tumours, probably due to fewer oxygen free settings.
radicals.
l Can be very deep and can continue to burn unless
l Compounding this is the fact that tumours may the source is removed.
be relatively avascular and the patient may be
anaemic, therefore transfusion may help. l Particular agents require specific treatments, e.g.
hydrofluoric acid requires calcium gluconate, as it
l Radiosensitisers that enter neoplastic tissue may can cause lethal hypocalcaemia.
enhance response to radiotherapy. Experimental
work with these is in progress, but none is in current Causes of burns
clinical use.
l Accidents:
INJURY DUE TO BURNS n domestic (most common)
n road traffic accidents
l Common form of trauma in the UK: n industrial/workplace.
n approximately 250,000 burns per year of which
70% are seen in A&E l Intoxication (alcohol/drugs).
n approximately 300 deaths per year. l Suicide/self-harm.
l Assault/abuse.
l Incidence differs between age groups:
n 0–14 years ¼ 30% of burns Predisposing medical conditions
n 15–64 years ¼ 60% of burns
n 65þ years ¼ 10% of burns. l Epilepsy.
l Dementia.
l Aetiology differs between age groups: l Motor/sensory dysfunction, e.g. paralysis.
n children suffer more scalds l Learning disability.
n adults suffer more flame burns l Mental health issues.
n elderly suffer more scald and contact burns.
Burn injury response
l Repatriated military burns are an increasing group
to consider. Burn injuries result in both local and systemic
responses.
Types of burn
Local response (Fig. 14.11)
Thermal
Burn injury results in varying degrees of three-
l Flame—can be associated with inhalation injury. dimensional tissue damage, illustrated by Jackson’s
l Scalds—usually hot drinks or bath water. burn wound model:
l Contact—often associated with loss of conscious- l Zone of necrosis:
ness, medical conditions or intoxication. n area of maximum damage
n suffers rapid and irreversible cell death due to
Electrical
coagulation of cellular proteins.
l Caused by an electrical current passing through the l Zone of stasis:
body; will have an ‘entry’ and ‘exit’ point.
n adjacent to the zone of necrosis
l If the path of the electricity crosses the chest it can n compromised tissue perfusion due to damaged
affect the myocardium and produce arrythmias.
microcirculation
l Low-voltage injuries are < 1000 volts; usually n can progress to necrotic tissue if left untreated
domestic; burn the entry and exit points.
or inadequately resuscitated.
l High-voltage injuries are > 1000 volts; usually l Zone of hyperaemia:
industrial; can burn internal tissue, causing
rhabdomyolysis. n outermost burn zone, adjacent to zone of
stasis
l ‘Flash’ injuries occur when an arc of high-voltage
electrical current occurs near to the patient causing n tissue perfusion is increased due to local
thermal burns, but no electrical current passes inflammatory mediator release
through them.
n will usually completely recover.
l When referring to the dynamic nature of burns, it is
the changeability of the zone of stasis to which we
refer, i.e. the ability of a burn to progress to a deeper
burn or appear more superficial.
Cellular injury 14 307
Epidermis Zone of necrosis n circumferential burns to the chest can restrict
Dermis Zone of stasis expansion, furthering respiratory compromise
Zone of hyperaemia n inflammatory mediators create bronchocon-
striction and oedema, and can lead to adult
If adequately resuscitated the burn may progress to: respiratory distress syndrome (ARDS).
Zone of necrosis
Zone of stasis l Metabolic:
n basal metabolic rate can triple, causing mas-
Zone of hyperaemia sive catabolic changes and inducing muscle
wasting
If inadequately resuscitated the burn may progress to: n electrolyte disturbances including hypo- or
Zone of necrosis hypernatraemia, hyperkalaemia and hypocal-
caemia.
Zone of hyperaemia
l Musculoskeletal:
Fig 14.11 n circumferential limb burns can compromise
Jackson’s burn wound model and dynamic changes. limb perfusion due to swelling limb contents
not accommodated by inelastic eschar of
l Factors which can influence this progression include: burnt skin
n hypoperfusion n compartment syndrome can follow prolonged
n infection periods of immobility due to unconscious-
n oedema. ness or electrical injury through a limb/
compartment.
Systemic response
l Renal:
Usually seen in burns of over 20%, where massive n hypoperfusion of kidneys due to hypovolaemia
inflammatory mediator release causes changes in can result in acute renal failure
the following systems: n tissue injury releases myoglobin, which pro-
l Cardiovascular: duces rhabdomyolysis and results in acute
tubular necrosis and renal failure.
n vasodilatation and increased capillary perme-
ability cause intravascular protein loss and l Immunological:
oedema n depression of cellular and humoral immune
responses, increasing risk of sepsis
n peripheral and splanchnic vasoconstriction n systemic inflammatory response syndrome and
n combined result of hypovolaemia, tachycardia, resulting multi-organ failure.
hypotension and increased systemic vascular l Gastrointestinal:
resistance. n gut function impairment, leading to barrier
l Respiratory: breakdown and bacterial translocation
n inhalation of hot gases causing thermal injury n gastric ulceration due to stress response
to the upper airways, resulting in inflammation (Curling’s ulcer).
and life-threatening airway oedema
n inhalation of toxic combustion products (carbon l Skin:
monoxide, cyanide, nitrogen and sulphur oxides, n barrier function of skin lost, increasing infection
etc.), causing severe respiratory compromise or risk and fluid loss.
acute lung injury
Carbon monoxide effects
l Colourless, odourless gas caused by incomplete
oxidation of carbon.
l Detectable in blood of smokers in low levels.
l Produces different symptoms at different levels
(Table 14.2).
l Has an affinity for haemoglobin 250 times that of
oxygen and binds strongly to form carboxyhaemo-
globin.
l Reduces the ability of the blood to transport oxygen,
resulting in respiratory compromise.
308 SECTION THREE PATHOLOGY
Table 14.2 COHb and systemic effects 9%
COHb % in blood Systemic effects
0–15 Nil Front 18% 9%
15–20 Confusion, headache Back 18%
20–40 Disorientation, nausea, lethargy
40–60 Ataxia, hallucinations, collapse, 9%
60þ seizures
Death
l Reduces oxygen available for cytochromes, result- 1% 18%
ing in abnormal cellular functioning and occasion- 18% 18%
ally encephalopathy. Front 18%
Back 18%
l Victims seem confused, disorientated and nau- 9% 9%
seous, and can be dismissed as intoxicated.
14% 14%
l Treatment is by displacing COHb with oxygen—
COHb has a half-life of 250 min in room oxygen Fig 14.12
levels and 40 min with 100% oxygen. Adult and paediatric rule of 9s.
Assessing a burn n paediatric ‘rule of nines’ slightly altered due to
different anatomical proportions; charts used
Assessment of a burn takes into account:
l the extent of body surface area burnt n useful for larger burns where estimation is
l the depth of the burn. essential for fluid resuscitation.
The extent of body surface area burnt The depth of the burn (Fig. 14.13)
(Fig. 14.12) l Estimation of burn depth can be difficult, though
To estimate the percentage of the total body surface area the clinical features of the burn can help the
of the burn (% TBSA) there are two general methods: decision.
l The palmar surface method:
l Diagnostic tools can be useful, such as laser Dopp-
n useful for smaller or patchy burns ler imaging to assess areas of skin perfusion.
n utilises the principle that the patient’s palmar
surface is roughly equal to 1% of their body
surface area.
l The ‘rule of nines’ method:
n divides the adult body into areas based on
single or multiple 9% anatomical blocks
Superficial Burn depth Full thickness
Superficial dermal Deep dermal
Epidermis
Dermis
Subcutaneous tissue
Fig 14.13
Cross-section of skin showing depth of burn.
Cellular injury 14 309
l In practice the majority of burns are of mixed depth n commonly caused by significant flame or
and careful, repeated assessment is needed to chemical burns
ensure correct depth diagnosis.
n have absent capillary refill on examination and
l Remember that burn depth can be dynamic, and absent sensation
insufficient resuscitation, infection or oedema can
increase the percentage of a deep burn. n are painless as all nerve endings are gone
In general burns can be classified from superficial to Chest
deep, depending upon the amount of epidermis, der-
mis and underlying tissue that has been damaged. Radial border of arm
l Superficial epidermal burns: (beware cephalic
vein and radial nerve)
n involve the epidermis alone and are often called
erythema Ulnar border of arm
(beware ulnar nerve)
n appear red but with no blistering of the skin
n commonly caused by sunburn, superficial Inner side of leg
(beware great saphenous
scalds or ‘flash’ burns vein and posterior tibial
n have good capillary refill on examination and artery/vein)
intact sensation Outer side of leg (beware common fibular (peroneal) nerve, sural
n can be very painful nerve and small saphenous vein)
n will heal within seven days from the basal
Fig 14.14
epidermis with no scarring
n are NOT counted as part of the total body Lines of escharotomy placement.
surface area burn estimation.
l Superficial dermal burns:
n involve the epidermis and the papillary dermis
n appear pink, oedematous and blistered
n commonly caused by minor flame and scald
burns
n have good capillary refill on examination and
intact sensation
n can be extremely painful
n will heal within 10–14 days from the adnexal
structures with little or no scarring
n are counted as part of the total body surface
area burn estimation.
l Deep dermal burns:
n involve the epidermis, the papillary dermis and
the reticular dermis
n appear red and often have fixed staining or
petechial points
n commonly caused by flame, chemical, contact
and scald burns
n have reduced or absent capillary refill on exam-
ination and reduced or absent sensation
n often not as painful as the more superficial burns
n will not heal within 14 days and will leave
significant scarring
n are counted as part of the total body surface
area burn estimation.
l Full-thickness burns:
n involve the epidermis, the entire dermis and
possibly fat, muscle and even bone
n appear thick and can be either white or black
and charred (eschar)
310 SECTION THREE PATHOLOGY n on the limbs, may compromise limb
vascularity
n will not heal within 14 days and will leave
significant scarring n escharotomy may be required; escharotomy
placement sites and their relevant anatomy
n are counted as part of the total body surface are shown in Fig. 14.14.
area burn estimation.
OSCE scenario 14.2
l Circumferential burns:
n on the thorax, may restrict chest wall movement You are the A&E doctor in a district general hospital
at 3 am. A 33-year-old male has been trapped in a
OSCE SCENARIOS fire in his home, and had to be rescued from the
house by the fire brigade, who think the fire started
OSCE scenario 14.1 at around 1 am. He has superficial non-blistering
burns to his face with soot around his nose, and
A 77-year-old female presents to your clinic with a blistering burns to the whole of his left leg and
suspicious-looking lesion on her temple. arm, including his hand. He appears confused
1. Outline your history, examination, investigations and the ambulance crew think he may be
intoxicated.
and management plan. 1. Approximately what percentage is this man’s
2. Draw around the lesion on the diagram
burn? What features would you use to assess
(Fig. 14.1Q) to indicate your surgical margins the depth of the blistered burn?
and direction of incision. 2. Assuming that his facial burns are epidermal
The pathology report of the lesion indicates an and his arm/leg burns are full-thickness, cal-
incompletely excised poorly differentiated culate this man’s fluid resuscitation require-
squamous cell carcinoma with ulceration. A ments and detail how this should be
multi-disciplinary skin cancer meeting suggests administered.
re-excision of the scar with a 1 cm margin. 3. What acute injuries and pathology specific to
3. Outline your options for closing this defect. burns would this man be at risk of from the
4. Explain the pathological findings and above description?
management plan to the patient including her 4. Which allied medical staff would you like to
follow-up. involve?
Answers in Appendix page 463
Lesion left temple
Fig 14.1Q
Indicate surgical margins and direction of incision.
SECTION THREE PATHOLOGY
CHAPTER 15
Disorders of growth,
morphogenesis and
differentiation
GROWTH Other factors involved in the cell cycle
l G0 phase: cells can leave the cell cycle temporarily
Growth is the process of increase in size resulting from
the synthesis of specific tissue components. and re-enter later; said to be in the G0 phase.
l Cells can leave the G1 phase permanently, lose the
Physiological growth takes place by several
mechanisms: ability to undergo mitosis, and become terminally
l multiplicative: increase in number of cells, e.g. in all differentiated cells.
l Differences in cell cycle times that characterise
tissues during embryogenesis different tissues are related to the G1 duration
l auxetic: increase in size of cells, e.g. in growing which may last days or even years.
l Once a cell has passed out of G1, the cell cycle
skeletal muscle proceeds to completion.
l accretionary: increase in intercellular tissue compo- l S, G2 and M phases of the cycle are remarkably
constant and independent of the rate of cell division.
nent, e.g. growing bone
l combined patterns, e.g. in embryological develop- Control of cell division
ment. l The cell cycle requires activating signals.
l Activating signals are provided by cyclins, which
Cell turnover
activate a number of proteins involved in various
Growth depends on the balance between an increase phases of the cycle, e.g. DNA replication, spindle
in cell numbers due to proliferation and the decrease formation.
in cell numbers due to cell death. Regeneration is l Inhibitory signals come from tumour suppressor
covered in Chapter 14. genes, e.g. p53 and cyclin-dependent kinase
inhibitors.
Cell cycle l Removal of the growth-inhibiting action of the
retinoblastoma gene allows growth to proceed.
l Cells proliferate by undergoing mitosis. l Protein growth factors direct the proliferation of
l Mitosis is only a small part of the cell cycle. different types of cell, regulating cell population
l The length of the cell cycle determines the cell densities, e.g.:
kinetics of a tissue. n epidermal growth factor (EGF)
n platelet-derived growth factor (PDGF)
Phases of the cell cycle (Fig. 15.1) n insulin-like growth factor (IGF-1).
l Growth factors act on cells in G0 phase, leading to
Four main stages to the cell cycle are: DNA synthesis followed by cell division.
l M phase: comprising nuclear division (mitosis) and
311
cytoplasmic division (cytokinesis)
l G1 phase (gap 1): duration varies between cell types
l S phase: DNA synthesis occurs
l G2 phase (gap 2).
312 SECTION THREE PATHOLOGY
New cell
enters cycle
M Terminal
Division differentiation:
G2 no further division
Interphase G1 G0 Fig 15.1
S
Stimulated by growth The cell cycle. The four main stages of
factors: PDGF, EGF, IGF1 & 2 the cell cycle are the M phase (mitosis
Inhibited by pRb, p53 and cytokinesis, i.e. cell division) and the
interface stages G1 (gap 1), S phase (DNA
Inhibition removed synthesis) and G2 (gap 2). Cells may
by cyclin-dependent enter a resting phase, G0, which may be
of variable duration, followed by re-entry
kinases into the G1 phase. Some cells may ter-
minally differentiate from the G1 phase,
with no further cell division and death at
the end of the normal lifetime of the cell.
The sites at which growth factors and
inhibitors act are shown.
Vincristine Cyclophosphamide
M
G2 G1 G0
Vincristine
S
Cyclophosphamide
Cyclophosphamide Corticosteroids
Methotrexate L-asparaginase
Cytosine arabinoside
Fig 15.2
Pharmacological interruption of the cell
cycle: the sites of action in the cell cycle
of drugs that may be used in the
treatment of cancer.
Therapeutic interruptions of cell Factors affecting growth
cycle (Fig. 15.2)
Normal growth requires a number of factors whose
l Various cancer chemotherapeutic agents act at absence may result in limited or abnormal growth.
specific parts of the cell cycle. These include:
l genetic factors
l Attack rapidly dividing cancer cells. l hormones
l May attack rapidly dividing normal cells, e.g. bone l nutrition
marrow, lymphoid tissue, resulting in anaemia,
thrombocytopaenia and immunosuppression.
Disorders of growth, morphogenesis and differentiation 15 313
l blood supply Oxygen supply
l oxygen supply
l nerve supply l Infants born at altitudes of 15 000 feet have a 16%
l growth factors. lower birth weight due to reduced intrauterine
oxygen availability.
Genetic factors
Nerve supply
l Achondroplasia (dwarfism): a primary disturbance
of endochondral ossification occurring in early fetal l Loss of muscle innervation causes muscle atrophy,
life. An autosomal dominant condition. e.g. poliomyelitis, nerve injury.
l Beckwith–Wiedemann syndrome: increased growth l Loss of whole limb innervation causes disuse
due to duplication of short arm of chromosome 11 atrophy of bone.
where the genes for insulin and somatomedin IGF-2
reside, resulting in excessive growth. Growth factors
Hormones l PDGF, EGF and IGFs act locally in healing skin by
stimulation of basal cell division.
l General body size is controlled by growth hormone
(GH) from the anterior pituitary gland. Increased growth
l GH release is stimulated by hypothalamic growth Growth may occur in relation to physiological or path-
hormone releasing factor (GHRF) and inhibited by ological stimuli by the following mechanisms:
somatostatin. l Hypertrophy: increase in cell size without cell
l GH stimulates release of somatomedin IGF-1 and replication.
IGF-2 from the liver; these act on target tissue such l Hyperplasia: increase in cell number due to cell
as muscle and bone.
division.
l Reduced growth may be due to: l A combination of the two.
n reduced GH production resulting in proportion- l The stimuli for hypertrophy and hyperplasia are
ate dwarfism, which is corrected by GH injec-
tions prior to puberty (when skeletal growth similar.
arrests due to epiphyseal fusion) l In permanent cells, hypertrophy is the only adaptive
n reduced GH receptors (Laron dwarfism): circulat-
ing GH is high but the liver is insensitive to GH; option as the cells cannot divide.
treatment with GH does not increase growth rate l A decreased cell loss by apoptosis is an important
n reduced thyroid hormone secretion causes re-
duced hepatic IGF-1 secretion. Dwarfism results component of hyperplasia.
with stunted limbs because bone ossification is l Hyperplasia and hypertrophy are reversible when
reduced. GH injections do not help, but thyroxin
given before puberty is corrective. the stimulus is removed.
l Hyperplasia and hypertrophy may be physiological
l Increased growth may be due to:
n increased pituitary GH. Before puberty this or pathological.
results in gigantism; after puberty (after
epiphyseal fusion), acromegaly results. Physiological hypertrophy
and hyperplasia
Nutrition
Examples include:
l General catabolic states may cause poor growth. l muscle hypertrophy in athletes
l Starvation in the form of kwashiorkor (protein l hyperplasia of bone marrow at high altitude
l hyperplasia of breast tissue, e.g. puberty, preg-
deprivation) or marasmus (protein and total calorie
deprivation) disturb growth. nancy, lactation
l hypertrophy and hyperplasia of uterus in pregnancy
Blood supply l thyroid hyperplasia as result of increased metabolic
l Maldevelopment of a vessel can lead to non- demands at puberty and pregnancy.
development of the organ it should supply.
Pathological hypertrophy
l Epidermal atrophy occurs in the skin of the lower
limbs with chronic ischaemia due to arterial disease. l Myocardial hypertrophy and hypertension.
l Increased blood flow, e.g. arteriovenous fistula, Pathological hyperplasia
may cause increase in size of a limb.
l Graves’ disease.
l Endometrium exposed to excess oestrogen.
314 SECTION THREE PATHOLOGY
Atrophy l Lack of nutrition, e.g. cachexia in severe starvation,
gut atrophy in starvation.
Atrophy is a decrease in size due to loss of cells or re-
duction in size of individual cells. It may be reversible l Loss of endocrine stimulation, e.g. hypophysectomy
when stimulus returns, with certain exceptions, e.g. results in adrenal atrophy due to lack of stimulation
heart muscle, neurons. Organ atrophy may be due to: from ACTH.
l reduction in cell size
l reduction in cell numbers l Hormone-induced atrophy, e.g. oestrogens and
l both of these. testicular atrophy, corticosteroids and adrenal
For atrophy to occur there must be: atrophy (via ‘negative feedback’ reduction of
l cessation of growth ACTH).
l reduction in cell size and/or cell numbers mediated
Decreased growth (hypoplasia)
by apoptosis.
Atrophy may be physiological or pathological. Hypoplasia is the failure of an organ to attain its nor-
mal size. It is a failure of morphogenesis, although
Physiological (Box 15.1) closely related to atrophy and pathogenesis. Examples
include:
l Occurs any time from early embryological life to old l congenital adrenal hypoplasia associated with
age
anencephaly or pituitary hypoplasia (no ACTH)
Pathological l failure of lower limb development in spina bifida.
l Decreased function, e.g. muscle atrophy of limb DIFFERENTIATION
after immobilisation for fracture treatment.
This is the process whereby a cell develops a specia-
l Loss of innervation, leading to muscle and bone lised function that was not present in the parent cell.
atrophy (osteoporosis), e.g. poliomyelitis, spinal Differentiation is an important part of morphogenesis;
cord injuries. growth also plays an important part in morphogenesis.
l Loss of blood supply, e.g. following tissue hypoxia, Control of differentiation
epidermal atrophy is seen in the skin of lower limbs
in chronic ischaemia. In the fetus, differentiation is controlled by:
l genes
l Pressure atrophy, e.g. destruction of skin and sub- l systemic hormones
cutaneous tissue as in bed sores. l local growth factors
l position within the fetus
Box 15.1 Tissues involved in physiological atrophy l matrix proteins.
and involution Differentiation and morphogenesis may be disturbed
by environmental factors, e.g. teratogens, such as:
Embryo and fetus l irradiation
Branchial clefts l drugs
Notochord l infections.
Thyroglossal duct During embryonic development, cell determination
Mu¨ llerian duct (males) and differentiation occur by transcriptional modifica-
Wolffian duct (females) tions to genomic expression. There is no increase or
decrease in the number of genes present.
Neonate
Umbilical vessels MORPHOGENESIS
Ductus arteriosus
Fetal layer adrenal cortex Morphogenesis is a highly complex process of devel-
opment of structural form and shape of organs, limbs,
Early adult etc. from primitive cell masses during embryogenesis.
Thymus It involves cell growth and differentiation and relative
movement of cell groups. Unwanted features are
Late adult and old age removed by apoptosis.
Uterus, endometrium (females)
Testes (males)
Bones (particularly females)
Gums
Mandible (particularly edentulous)
Cerebrum
Lymphoid tissue
Disorders of growth, morphogenesis and differentiation 15 315
Congenital disorders of Box 15.2 Teratogens and their effects
differentiation and morphogenesis
Teratogen Teratogenic effect
Chromosomal abnormalities affecting
whole chromosomes Irradiation Microcephaly
l Autosomal chromosomes, e.g. trisomy 21 (Down’s Drugs
syndrome).
Thalidomide Amelia/phocomelia (absent/
l Sex chromosomes, e.g. Klinefelter’s syndrome rudimentary limbs; heart,
(47 XXY), Turner’s syndrome (45 X). kidney, gastrointestinal
and facial abnormalities)
Chromosomal abnormalities affecting
parts of chromosomes Folic acid antago- Anencephaly, hydrocephalus,
nists, e.g. cleft lip/palate, skull defects
l Cri-du-chat syndrome (46 XX 5p–, or 46 XY 5p–, i.e. 4 amino PGA
deletion of short arm of chromosome 5).
Anticonvulsants Cleft lip/palate, heart defects,
Single gene alterations minor skeletal defects
l Enzyme defects: Warfarin Nasal/facial abnormalities
l decreased enzyme synthesis
l defective enzyme synthesis, e.g. Testosterone and Virilisation of female fetus,
synthetic atypical genitalia
n accumulation of phenylalanine, causing mental progestogens
retardation due to phenylalanine hydroxylase
deficiency (phenylketonuria) Alcohol Microcephaly, abnormal facies,
oblique palpebral fissures,
n albinism caused by absent melanin production growth disturbance
due to tyrosinase deficiency.
Infections
l Defects in receptors or cellular transport, e.g.
n insensitivity of tissues to androgens due to Rubella Cataracts, microphthalmia,
loss of androgen receptors can lead to microcephaly, heart defects
pseudohermaphroditism
n cystic fibrosis in which there is a defective cell Cytomegalovirus Microcephaly
membrane transport system across exocrine
secretory cells. Herpes simplex Microcephaly, microphthalmia
l Non-enzyme protein defects, e.g. Toxoplasmosis Microcephaly
n abnormal haemoglobin in sickle cell disease
n defective collagen in Marfan’s syndrome and n Hirschsprung’s disease: absence of ganglion
Ehlers–Danlos syndrome. cells in Meissner’s and Auerbach’s plexuses
due to defective migration of cells from neural
l Adverse reaction to drugs, e.g. crest
n G6PD deficiency and haemolysis after adminis-
tration of the antimalarial drug primaquine. n undescended testis (cryptorchidism): often
isolated anomaly, but may be associated with
Functional aspects of developmental Klinefelter’s syndrome.
disorders
Anomalies of organogenesis
l Embryo division abnormalities, e.g. Siamese twins,
fetus in fetu. These include:
l agenesis: failure of development of an organ or
l Exposure to teratogens: organ development occurs
in first 4–8 weeks of intrauterine life and teratogens structure
have major effects at this time (Box 15.2). l atresia: failure of development of a lumen in a
l Failure of cell and organ maturation, e.g. normally tubular structure
n Kartagener’s syndrome: defect in ciliary motil- l hypoplasia: failure of an organ to attain its normal size
ity affects cell mobility during organogenesis, l dysgenesis: failure of normal organ differentiation
resulting in situs inversus; in later life results
in bronchiectasis and infertility (due to sperm or persistence of primitive embryological structures
immobility)
316 SECTION THREE PATHOLOGY
l ectopia: development of mature tissue at an l often represents an adaptive response of tissues to
inappropriate site. environmental stress
Agenesis (aplasia) l is due to activation and/or repression of genes
involved in maintenance of cellular differentiation
l Renal agenesis:
n may be unilateral or bilateral l metaplastic tissue is better able to withstand
n failure of mesonephric duct to give rise to adverse environmental changes
ureteric bud, with failure of induction of
metanephric blastema. l itself does not progress to malignancy, but may un-
dergo further indirect transformation to neoplasia
l Thymic agenesis (di George syndrome): via dysplasia.
n resulting in absent T-cells and deficiency of
cell-mediated immunity. Examples of metaplasia in epithelial tissue include:
l squamous metaplasia in ciliary epithelium of bron-
l Anencephaly:
n absence of cerebrum due to neural tube defect; chus in smokers
fatal. l squamous metaplasia in transitional epithelium in
Atresia the bladder in schistosomiasis
l replacement of squamous epithelium in the oesoph-
l Oesophageal atresia:
n failure of separation of trachea and oesophagus agus with columnar glandular epithelium in patients
from primitive foregut with reflux (Barrett’s oesophagus)
n may be associated with tracheo–oesophageal l transformation of the columnar lining of the gall
fistula. bladder to squamous epithelium in the presence
of gallstones and chronic inflammation
l Biliary atresia: l squamous metaplasia in the nose, bronchi and
n absence of bile ducts; obstructive jaundice in urinary tract associated with vitamin A deficiency.
infancy. Examples of metaplasia in mesenchymal tissues include:
l bone formation (osseous metaplasia):
Hypoplasia
n calcium deposition in atheromatous arterial
l Developmental dysplasia of the hip. walls
n failure of development of bone of acetabulum,
causing dislocation of hip due to flattened n in bronchial cartilage.
acetabular roof.
Dysplasia
Dysgenesis (dysplasia)
Dysplasia is a premalignant condition characterised by
l Renal dysgenesis due to anomalous metanephric increased cell growth, cellular atypia and decreased
differentiation. differentiation.
Ectopia (heterotopia) Dysplasia:
l may be caused by long-standing irritation of tissues
l Gastric mucosa in a Meckel’s diverticulum.
by chronic inflammation or exposure to carcinogens
Acquired disorders of differentiation l in the early phases may be reversible if the initial
and growth
stimulus is removed
These include: l if severe, will progress to malignancy unless
l metaplasia
l dysplasia adequately treated.
l polyps Dysplasia may be recognised by:
l neoplasia. l Evidence of increased growth:
Metaplasia n increased tissue bulk
n increased mitotic activity.
Metaplasia is the reversible transformation of one type l Cellular atypia:
of terminally differentiated cell into another fully n pleomorphism
differentiated cell type. n high nuclear–cytoplasmic ratio
n hyperchromatic nuclei (denser staining due to
Metaplasia:
l may affect epithelial or mesenchymal cells increased nuclear DNA).
l Decreased cellular differentiation:
n cells more primitive than normal.
Other features of dysplasia:
l May be present for many years before malignancy
develops.
Disorders of growth, morphogenesis and differentiation 15 317
l May occur in tissue which has coincidental meta- l anaemia:
plasia, e.g. n ulceration
n dysplasia in metaplastic squamous epithelium
in the bronchus of smokers l mechanical effects:
n dysplasia in metaplastic glandular epithelium in n obstruction
Barrett’s oesophagus. n intussusception.
l May develop without coexisting metaplasia, e.g. Examples of polyps
n squamous epithelium of uterine cervix
n glandular epithelium of the stomach. Polyps occur in many organ systems. Accurate diag-
nosis is essential and histopathological examination is
Polyps required to determine a precise pathological diagno-
sis. Examples of polyps include:
A polyp is a sessile or pedunculated protrusion from a l Nasal:
body surface.
n very common
Polyposis is a term used to describe a condition or n due to chronic infective or allergic inflammation
syndrome where there are multiple polyps in an organ n consist of oedematous masses of connective
or organ system, e.g.
l organ: polyposis coli of large bowel tissue with inflammatory cells and glands.
l organ system: Peutz–Jeghers syndrome: hamarto- l Uterine (endometrial):
matous polyps throughout the gastrointestinal tract. n hyperplastic/metaplastic polyps
The term polyp: n found in perimenopausal women
l is purely descriptive of the shape of a lesion n caused by inappropriate response of endome-
l does not imply any specific underlying pathological
trium to oestrogenic stimuli
process, e.g. hyperplasia, neoplasia n malignant change is rare.
l is a result of focal tissue expansion at a site, at or l Uterine (cervical):
n epithelial non-neoplastic polyps
near a body surface, which, when enlarging, takes n common
the line of least resistance, i.e. outwards to a n consist of columnar mucus-secreting epithe-
surface or lumen rather than inwards.
lium with oedematous stroma
Pathological processes causing polyps n no malignant potential.
l Colonic:
These may be either non-neoplastic or neoplastic. n the large bowel is by far the most common site for
l Non-neoplastic:
gastrointestinal polyps. Types of polyps occurring
n inflammation in the large intestine are shown in Table 15.1.
n hyperplasia
n metaplasia Table 15.1 Polyps of the large intestine
n dysplasia.
l Neoplastic: Type Benign Malignant
n epithelial
n mesenchymal Epithelial Neoplastic Adenocarcinoma
n lymphoid.
Non-neoplastic and most neoplastic polyps are com- l adenoma Carcinoid
mon and benign, but a small proportion of malignant
neoplasms have a polypoid appearance, e.g. polypoid l tubular adenoma
adenocarcinoma of the colon, lymphomatous polyps
of GI tract. l tubulo-villous
Symptoms of polyps adenoma
Polyps may be asymptomatic or may produce l villous adenoma
symptoms:
l haemorrhage Inflammatory
l local trauma
l torsion l pseudopolyp, e.g.
l inflammation
l ulceration ulcerative colitis
Hamartomas
l juvenile polyp
l Peutz–Jeghers
syndrome
Metaplastic
l adenoma
Mesenchymal Lipoma Sarcomas
Leiomyoma Lymphomatous
Fibromas polyps
Haemangiomas
318 SECTION THREE PATHOLOGY
NEOPLASIA l associated with genetic alteration
l influences behaviour of normal cells by production
Neoplasia has the following characteristics:
l abnormal and excessive cell growth unco-ordinated of hormones (a paraneoplastic effect) and growth
factors.
with that of normal tissues Neoplasia is covered in detail in Chapter 18.
l persists after the initiating stimulus has been
withdrawn
OSCE SCENARIOS OSCE scenario 15.2
OSCE scenario 15.1 A 40-year-old-male presents to your orthopaedic
outpatient clinic having been referred by his GP
A 66-year-old male is admitted through A&E with for ‘tingling’ sensations in his hands. He complains
painless red bleeding per rectum. He has no past of the symptoms progressing over the last
medical history and a subsequent colonoscopy 9 months. He is a carpenter by trade and is starting
shows multiple benign-looking polyps only, which to drop things due to weakness in his grip. He has
have been biopsied. He is anxious and worried no past medical history and takes no medications.
about his condition and has asked to speak to a He is concerned about his hands, as being self-
doctor. employed his inability to work is impacting upon
1. Answer the patient’s questions about polyps him financially.
1. Take a brief history regarding this patient’s
and rectal bleeding. Explain the different types
of polyps and the need for the biopsy, avoiding symptoms and examine his hands.
medical jargon. 2. What is the diagnosis?
The patient then explains that several members
of his family have had ‘camera tests’ in their The patient then explains that he has seen his
bowel, and you notice some small dark dots GP for headaches recently, which he feels are
on his lower lip. stress-related due to his worry about his job.
2. Name the most likely condition causing this 3. In view of this new information and your
patient’s polyps. previous diagnosis, what condition are you now
3. Explain to the examiners the type of polyps concerned about?
caused by this condition, any risks from the 4. Explain to the examiners the other symptoms
polyps and any screening procedures that need and signs you would now check for in this
to be in place. patient, and briefly outline the investigations
and management.
Answers in Appendix page 465
SECTION THREE PATHOLOGY
CHAPTER 16
Inflammation
Inflammation is the local physiological response to l Physical agents:
injury. n trauma
n ionising radiation
CLASSIFICATION n heat
n cold.
l Acute inflammation: the initial and often transient
reaction to injury. l Tissue necrosis:
n ischaemia
l Chronic inflammation: the subsequent and often n infarction.
prolonged tissue reaction to injury.
Macroscopic signs and symptoms
Acute inflammation of acute inflammation
l Vascular phase: l Redness (rubor):
n change in vessel calibre n small vessel dilatation.
n increased vascular permeability
n formation of fluid exudates. l Heat (calor):
n increased blood flow in skin.
l Exudative cellular phase:
n adhesion of neutrophils l Swelling (tumour):
n neutrophil migration n oedema.
n diapedesis
n neutrophil chemotaxis. l Pain (dolor):
n stretching and tissue distortion
l Outcome: n pus under pressure in abscess
n resolution n chemical mediators, e.g. prostaglandins,
n suppuration bradykinins.
n organisation
n chronic inflammation. l Loss of function (functio laesa):
n conscious and reflex inhibition of movement by
Causes of acute inflammation pain
n swelling may physically immobilise tissues.
l Microbial infections:
n pyogenic bacteria Stages of acute inflammation
n viruses.
l Change in vessel calibre.
l Hypersensitivity reactions: l Increased vascular permeability.
n parasites l Formation of cellular exudates.
n tubercle bacilli.
Changes in vessel calibre
l Chemical agents:
n corrosives l Changes described by Lewis in 1927 as ‘triple
n acids response to injury’: flush, flare, weal.
n alkalis
n toxins. l If a blunt instrument is drawn across the skin the
following changes take place:
n transient white line due to arteriolar
vasoconstriction
319
320 SECTION THREE PATHOLOGY
n flush: dull red line due to capillary dilatation l Lysosomal compounds:
n flare: red irregular zone due to arteriolar dilatation n source: neutrophils.
n weal: zone of oedema due to fluid exudate in to n release stimulated by bacteria, damaged
tissue
the extravascular space. n action: increased vascular permeability
n activate complement.
Increased vascular permeability
l Prostaglandins:
l Capillary hydrostatic pressure increased in acute n source: platelets, endothelium, monocyte/
inflammation. macrophage, other cells
n action: different actions:
l More fluid leaves vessels than returns to them. l potentiate increase in vascular permeability
l Formation of an exudate: a protein-rich fluid. l platelet aggregation (pA2)
l Fluid exudates: l platelet disaggregation (pI2).
n protein content up to 50 g/L l Leukotrienes:
n contains immunoglobulins: destruction of n synthesised from arachidonic acid
n synthesis occurs in neutrophils, mast cells,
invading micro-organisms basophils, some macrophages
n coagulation factors: fibrinogen converted to n SRS-A (slow reacting substance of anaphylaxis)
is a mixture of leukotrienes involved in type I
fibrin in fibrinous exudates. hypersensitivity.
l Removal of exudate by lymphatic channels and
l Cytokines:
replacement with new exudate if stimulus to n source: many cells
inflammation persists. n action: attract various types of leucocyte to site
of inflammation, e.g. IL-8 mainly specific for
Formation of cellular exudate neutrophils.
l Margination of neutrophils. l Nitric oxide:
l Neutrophil adhesion: n source: endothelium, macrophage, short-lived
free radicals
n interaction between paired adhesion molecules n action: toxic to bacteria; major factor in endo-
on leucocyte and endothelial surfaces toxic shock.
n leucocyte surface adhesion molecule expres- Plasma factors
sion increased by:
l complement C5a l Complement.
l leukotriene B4 l Kinins.
l tumour necrosis factor (TNF). l Coagulation system.
l Fibrinolytic system.
n endothelial expression of adhesion molecules
increased by: Complement system
l interleukin-1 (IL-1)
l endotoxins l Cascade of enzymatic proteins.
l TNF. l Series of 20 proteins synthesised in liver and
l Neutrophil migration. macrophages.
l Amoeboid movement through venules (C5a and l Activated during acute inflammatory response:
leukotriene B4). n enzymes released from dying cells during
l Diapedesis: tissue necrosis
n escape of red cells from capillaries n infection
n passive; depends on hydrostatic pressure. n products of kinins, coagulation and fibrinolytic
l Neutrophil chemotaxis:
n leukotriene B4 system.
n IL-8. l Products of complement activation important in
Chemical mediators of acute inflammation are:
inflammation n C5a: chemotactic for neutrophils; increase
vascular permeability, release of histamine
l Histamine: from mast cells
n source: mast cell, basophil, eosinophil, platelets n C3a: similar action to C5a but less active
n release stimulated by C3a, C5a, neutrophil
lysosomal protein
n action: vasodilatation transiently increases
vascular permeability.
Inflammation 16 321
n C5, 6, 7: chemotactic for neutrophils Role of neutrophil polymorphs
n C5, 6, 7, 8, 9: cytolytic activity
n C4b, 2a, 3b: opsonisation of bacteria and l Characteristic cell of acute inflammatory exudates.
l Movement: amoeboid movement in a directional
facilitate phagocytosis by macrophages.
response (chemotaxis) to chemicals of acute
Kinin system inflammation.
l Bind to micro-organisms which have been
l Activated by coagulation factor XII. opsonised by immunoglobulins or complement
l Converts prekallikrein to kallikrein. components.
l Kallikrein cleaves kininogen to release bradykinin. l Phagocytosis: facilitated by opsonisation. Cells
l Bradykinin controls vascular permeability and is a ingest particle into vacuole, which fuses with
lysosome, resulting in killing of micro-organism.
chemical mediator of pain. l Release of lysosomal products: damage local tis-
sues by proteolysis, e.g. elastase and collagenase.
Coagulation system Some compounds released increase vascular
permeability, while others are pyrogens causing
l Protein synthesised in liver in inactive form. systemic fever.
l System responsible for conversion of fibrinogen
SPECIAL TYPES OF
to fibrin, a major component of the inflammatory INFLAMMATION
response.
l Coagulation factor XII is activated by exposed base- 1. Serous
ment membranes and various proteolytic enzymes
of bacterial origin. In turn it activates coagulation, l Abundant protein-rich fluid with low cellular
kinin and fibrinolytic systems. content.
Fibrinolytic system l Inflammation of serous cavities, e.g. peritonitis
(peritoneal cavity), synovitis (synovial joint).
l Protein synthesised in liver.
l Negative feedback arm that limits coagulation. l Vascular dilatation apparent to naked eye, e.g.
l Plasmin (released by action of activated factor XII), conjunctivitis.
lyses fibrin to fibrin degradation products (FDP). 2. Catarrhal
Role of macrophages l Hypersecretion of mucus in acute inflammation of a
mucous membrane, e.g. coryza (common cold).
l Stimulated by local infection or injury.
l Produce IL-1 and TNF-a which stimulate endothe- 3. Fibrinous inflammation
lial cells to produce adhesion molecules which bind l Exudate contains much fibrinogen.
and activate neutrophils. l Fibrin forms a thick coating, e.g. acute pericarditis,
Role of lymphatics fibrinous peritonitis.
Terminal lymphatics are blind-ended endothelium- 4. Haemorrhagic inflammation
lined tubes present in most tissues in similar numbers
to capillaries. l Accompanied by vascular injury or coagulopathy.
l Lymphatics drain into collecting lymphatics, which l Examples include acute haemorrhagic pancreatitis
have valves and propel lymph passively to lymph due to proteolytic digestion of vessel walls; and
nodes. meningococcal septicaemia, resulting from associ-
l Gaps open passively between lymphatic endo- ated disseminated intravascular coagulation (DIC).
thelial cells, allowing large protein molecules to
enter. 5. Suppurative inflammation
l In acute inflammation lymphatic channels become
dilated as they drain away oedema fluid of inflam- l Production of pus, i.e. dying and degenerate neutro-
matory exudates. phils, organisms and liquefied tissues.
l This tends to limit the extent of tissue oedema.
l Important in the immune response to infecting l May become walled-off by fibrin or fibrous tissue
agents as antigens are carried to regional lymph to produce an abscess, i.e. a localised collection
nodes for recognition by lymphocytes. of pus.
l May form an empyema (a collection of pus in a
hollow viscus, e.g. gall bladder).
322 SECTION THREE PATHOLOGY
6. Membranous inflammation Sequence of events leading to resolution
l Phagocytosis of bacteria.
l Epithelium coated with a membrane of fibrin, l Fibrinolysis.
desquamated epithelial cells and inflammatory l Phagocytosis of debris by macrophages.
cells. l Resolution of vascular dilatation.
l Example: grey membrane seen in pharyngitis due to Suppuration
diphtheria.
l The formation of pus.
7. Pseudomembranous inflammation l Pus is a mixture of living, dead and dying bacteria and
l Superficial mucosal inflammation and ulceration neutrophils with cellular debris and liquefied tissue.
with sloughing of mucosa, fibrin, mucus and inflam- l The causative organisms are usually pyogenic bac-
matory cells.
teria, e.g. Staphylococcus aureus, Staph. pyogenes,
l Example: pseudomembranous colitis due to Clos- coliforms and Neisseria spp.
tridium difficile. l The causative stimulus is usually persistent.
l An accumulation of pus in the tissues becomes sur-
8. Necrotising inflammation rounded by a ‘pyogenic membrane’, i.e. capillaries,
neutrophils and occasional fibroblasts.
l Tense oedema may cause vascular occlusion and l Bacteria within abscess cavities are relatively
thrombosis, resulting in septic necrosis. inaccessible to antibiotics and antibodies; hence
the need to drain pus.
l Example: gangrenous appendicitis.
Organisation
Effects of acute inflammation
l Organisation is replacement of the tissue by
Beneficial effects (exudate) granulation tissue.
l Dilution of toxins. Circumstances favouring organisation
l Arrival of antibodies. l Excess fibrin formation with swamping of the
l Transport of drugs.
l Fibrin formation. fibrinolytic system.
l Delivery of oxygen and nutrients. l Substantial volume of necrotic tissue.
l Stimulation of immune response. l Exudate and debris cannot be removed or discharged.
Harmful effects (release of lysosomal Sequence of organisation
enzymes) l Capillaries grow into the inflammatory tissue.
l Fibroblasts proliferate under the influence of TGF-b,
l Digestion of normal tissue.
l Swelling. resulting in fibrosis.
l Inappropriate inflammatory response, e.g. type I l Example: after peritonitis a fibrinous exudate
hypersensitivity reactions. covers the bowel and loops stick together in a
fibrinous adhesion. Failure to remove the fibrin
Sequelae of acute inflammation results in its invasion with capillaries accompanied
by fibroblasts, which lay down collagen resulting in
l Resolution. a permanent fibrous adhesion between loops of
l Suppuration. bowel.
l Organisation.
l Chronic inflammation. Progress to chronic inflammation
Resolution l Acute inflammation may progress to chronic if the
causative agent is not removed.
l Resolution is complete restoration of tissues to
normal. l The tissues become organised and the cellular
exudate changes with lymphocytes, plasma cells
Conditions favouring resolution and macrophages, and multinuclear giant cells
Include: replacing polymorphs.
l Minimal tissue damage.
l Occurrence in organ with regenerative capacity, e.g. Systemic effects of inflammation
liver, rather than one that cannot regenerate, e.g. brain. l Pyrexia.
l Rapid destruction of causal agents, e.g. bacterial l Weight loss.
phagocytosis.
l Rapid removal of fluid and debris.
Inflammation 16 323
l Constitutional symptoms, e.g. malaise, nausea, l Autoimmune diseases, e.g. Hashimoto’s thyroiditis,
anorexia. chronic gastritis of pernicious anaemia, rheumatoid
arthritis.
l Haematological changes:
n increased ESR l Specific diseases of unknown aetiology, e.g. chronic
n leucocytosis. inflammatory bowel disease—ulcerative colitis.
l Reactive hyperplasia: l Primary granulomatous disease, e.g. Crohn’s
n lymphadenopathy disease, sarcoidosis.
n splenomegaly.
Progression from acute inflammation
l Anaemia:
n loss of blood into exudates, e.g. acute pancre- l Commonest variety of acute inflammation to pro-
atitis gress to chronic inflammation is the suppurative
n haemolysis, e.g. bacterial toxin type.
n ‘anaemia of chronic disease’—bone marrow
depression. l Inadequate drainage of pus which is deep-seated,
e.g. chronic abscess of osteomyelitis or chronic
l Amyloidosis (secondary or reactive): empyema thoracis.
n long-standing chronic inflammation, e.g. TB,
rheumatoid arthritis, bronchiectasis. l Foreign-body reactions may develop into granulo-
matous reactions, e.g. suture material, wood,
CHRONIC INFLAMMATION metal, glass, implanted prosthesis.
Chronic inflammation implies that the process has ex- Recurrent episodes of acute
tended over a long period of time; however, the term inflammation
‘chronic’ applied to inflammation indicates a cellular
infiltrate that differs from acute inflammation, i.e. lym- l Recurring cycles of acute inflammation and healing
phocytes, plasma cells and macrophages predomi- eventually result in chronic inflammation.
nate in chronic inflammation. Chronic inflammation
is usually primary but occasionally follows acute l Best example of this in clinical practice is chronic
inflammation. cholecystitis due to gallstones. Multiple recurrent
episodes of acute inflammation lead to replacement
Features of chronic inflammation of the gall bladder muscle with fibrous tissue.
l Lymphocytes, plasma cells and macrophages Transplant rejection
predominate.
l Cellular rejection of renal transplants involves
l Usually primary but may follow acute inflammation. chronic inflammatory cell infiltration.
l Granulomatous inflammation is a specific type of
Macroscopic appearances of chronic
chronic inflammation. inflammation
l May be complicated by secondary amyloidosis.
l Chronic ulceration:
Causes of chronic inflammation n venous stasis ulcer
n peptic ulcer.
l Primary chronic inflammation.
l Progress from acute inflammation. l Chronic abscess:
l Recurrent episodes of acute inflammation. n osteomyelitis.
l Transplant rejection.
l Caseating granulomatous inflammation:
Primary chronic inflammation n pulmonary tuberculosis.
l Resistance of infective agents to phagocytosis and l Thickening of a hollow viscus:
intracellular killing, e.g. tuberculosis, leprosy, viral n chronic cholecystitis
infections. n Crohn’s disease.
l Foreign body reactions: l Fibrosis:
n endogenous materials, e.g. necrotic bone, uric n distortion, e.g. pyloric stenosis after peptic
acid crystals ulceration.
n exogenous materials, e.g. asbestos fibres, suture
materials, implanted prostheses. GRANULOMATOUS DISEASE
A granuloma is an aggregate of epithelioid histiocytes.
324 SECTION THREE PATHOLOGY
Epithelioid histiocytes l Touton:
n ring of central nuclei
l Named because of vague histological resemblance n clear peripheral cytoplasm with accumulated
to epithelial cells. lipid, seen at sites of adipose tissue breakdown
and in xanthomas.
l Arranged in clusters.
l Little phagocytic activity. Causes of granulomatous disease
l Produce angiotensin-converting enzyme (raised in
l Specific infections:
sarcoidosis). n mycobacteria, e.g. tuberculosis
l Caseous necrosis may occur in granulomas, e.g. n fungi
n parasites.
tuberculosis.
l Histiocytes may be converted into multinucleate l Foreign bodies:
n endogenous, e.g. keratin, necrotic bone, uric acid
giant cells. crystals
n exogenous, e.g. talc, silica, suture materials,
Types of giant cell silicone.
l Histiocytic: l Specific chemicals:
n form where particulate matter is indigestible by n beryllium.
macrophages, e.g. silica, tubercle bacilli.
l Drugs:
l Langhans: n hepatic granulomatous due to allopurinol,
n horseshoe arrangement of peripheral nuclei at phenylbutazone, sulphonamides.
one pole of cell
n characteristically seen in tuberculosis. l Unknown:
n Crohn’s disease
l Foreign body: n sarcoidosis
n large cells with nuclei randomly scattered n Wegener’s granulomatosis.
throughout cytoplasm
n seen in relation to particulate foreign body OSCE scenario 16.2
material.
A 19-year-old male is admitted with a history of
OSCE SCENARIOS central abdominal pain localising to the right iliac
fossa after 12 h. It is now 5 days since the onset of
OSCE scenario 16.1 symptoms. On admission to A&E he has a temper-
ature of 38.5 C with a tachycardia of 120, and
A 16-year-old male presents to your clinic with a abdominal examination reveals a tender mass in
6-month history of weight loss and vague abdom- the right iliac fossa. A clinical diagnosis of appendix
inal pain with intermittent rectal bleeding. abscess is made and this is confirmed by CT scan.
1. Outline your history, examination and 1. What is suppuration? Why in some cases does
investigations acute appendicitis perforate and cause peritonitis
2. What is your differential diagnosis? while in others abscess formation occurs?
2. Why do abscesses require drainage?
The colonic mucosal biopsy shows chronic 3. What organisms are likely to be cultured from
inflammation with focal colitis and granulomas. the pus?
The patient is currently well but is worried as 4. What sequelae other than suppuration may
he does not know what this means. follow acute inflammation?
3. Explain the findings and diagnosis to the patient. The patient is re-admitted to hospital 1 year later
with vomiting, central abdominal colicky pain, ab-
dominal distension and constipation. Plain abdom-
inal X-ray shows dilated loops of small bowel and a
diagnosis of small bowel obstruction is made.
5. Why is this likely to have occurred? Explain the
pathology of the condition.
Answers in Appendix page 466
SECTION THREE PATHOLOGY
CHAPTER 17
Thrombosis, embolism
and infarction
THROMBOSIS l Factors increasing the risk of atherosclerosis and
thus indirectly of thrombosis:
A thrombus is defined as a solid mass formed in the n family history
living circulation from the components of the stream- n male sex
ing blood. n smoking
n hypertension
This is to be distinguished from clotting, which is n hypercholesterolaemia
solidification of the blood when it is: n diabetes mellitus
l static n homocysteinaemia.
l outside a blood vessel
l outside a body Venous thrombosis
l within a vessel in a dead body. l The commonest cause is stasis.
l Mechanical damage due to pressure on calf veins
Causes of thrombosis
during surgery may be contributory.
Several factors contribute to thrombus formation l The main sites of venous thrombosis are calf veins
and these are usually grouped together as Virchow’s
triad, i.e. and pelvic veins.
l changes in the vessel wall l Emboli occur to the lungs via the right side of the
l changes in blood flow
l changes in the constituents of the blood. heart.
Damage to vessel wall Alterations in blood flow
l Arteries: atherosclerotic plaques or synthetic Normal laminar flow may change to a turbulent
grafts. pattern. This may occur with:
l prolonged inactivity following surgery, trauma or
l Heart: congenital abnormalities or artificial valves.
l Veins: local injury caused by pressure on the calves myocardial infarction
l cardiac failure
from bed or operating table. l proximal occlusion of venous drainage, e.g.
Arterial thrombosis pregnancy, pelvic tumour.
l The commonest cause is atherosclerosis.
l Vessels most commonly affected are the coronary Alterations of the constituents of the
blood
arteries, abdominal aorta, mesenteric arteries,
cerebral arteries, renal arteries and arteries of These include:
the lower limb. l increased number of platelets and increased
l Arterial thrombosis is more associated with damage
to the vessel wall, as compared with venous throm- adhesiveness of platelets following surgery or
bosis, which is most associated with blood flow injury
disturbances. l dehydration, which may increase viscosity
l thrombophilia: abnormal balance of clotting factors
and natural anticoagulants.
325
326 SECTION THREE PATHOLOGY
Stages in the development l tumour
of thrombosis l amniotic fluid
l foreign body, e.g. i.v. cannula, particulate matter
l Thrombus may develop in heart, arteries or veins.
l First stage involves platelets sticking to damaged with i.v. drug abuse
l therapeutic emboli, e.g. gel foam, steel coils.
endothelium.
l A dense layer of fibrin and leucocytes adheres to the Thromboembolism
surface of the platelets. Venous thromboembolism
l Blood clot (fibrin and red cells develop on this layer
l Venous thromboembolism gives rise to pulmonary
of leucocytes and platelets). embolism.
l A secondary layer of platelets collects on the
l The overwhelming majority of emboli arise from
surface of the blood clot. thrombi in the veins of the lower limb.
l Gradual extension of thrombosis leads to a
l They travel through the inferior vena cava to the
propagated or consecutive thrombus. right side of the heart and impact in the pulmonary
l Organisation then begins, with adherence to the artery or one of its major branches, depending upon
the size of the embolus.
vessel wall as mural thrombus.
l A second stage develops, with a further batch of l The effect of the embolism depends on its size:
n small emboli may be thrown off in showers and
platelets laid down over the initial aggregate, and are asymptomatic until their cumulative effect
then a further layer of blood clot. limits respiration
l In this way, alternate layers of platelets and blood n medium emboli may cause dyspnoea, respira-
clots form a lamina arrangement. tory distress and chest pain
l This causes a differential contraction of platelets n large emboli may occlude both pulmonary
and fibrin and gives a rippled appearance, reminis- arteries and cause sudden death.
cent of rippling of sand on a beach.
l Ridges on the surface of the thrombi are known as l If only one major pulmonary vein is blocked, severe
the lines of Zahn. shortness of breath and circulatory collapse may
occur. This may be due to a vagal reflex inducing
Fate of thrombi spasm of the coronary and pulmonary arteries
associated with peripheral vasodilatation.
l Lysis (resolution): the thrombolytic system may
remove thrombi completely, especially if they are Arterial thromboembolism
small.
l Systemic emboli from arteries deposit in arteries
l Recanalisation: following organisation, new vessels more distally along the arterial tree.
may grow through the thrombus, eventually forming
a single or several new channels. l Total occlusion of such arteries may produce rela-
tive ischaemia. A collateral supply may be available.
l Propagation: because the thrombus itself results in
slowing of the blood flow, it may cause further l If there is no collateral supply, infarction will take
thrombosis and the clot may increase in length. place.
l Embolisation: part of the thrombus or the whole l Arterial thromboembolism may come from the
thrombus may become dislodged and move through following:
the circulation until arrested in a vessel which is of n heart, e.g. left auricular thrombus in AF, mural
similar size to itself, causing that vessel to be thrombus following MI
occluded. n valvular disease, including prosthetic valves
n proximal atherosclerotic plaques
EMBOLISM n aneurysms
n paradoxical: from the venous system via a right-
An embolus is an abnormal mass of undissolved to-left shunt, e.g. patent interatrial septum.
material which passes in the blood stream from one
part of the circulation to another, impacting in blood Gas embolism
vessels too small to allow it to pass.
Gas must be free within the blood stream and not in
Emboli may consist of: solution. There are two main causes of gas embolism,
l thrombus i.e. gas entering the blood stream usually as air, and
l gas (air and nitrogen) gas dissolved in the blood coming out of solution.
l fat
Thrombosis, embolism and infarction 17 327
Gas entering the blood stream: l Onset is indicated by severe respiratory difficulty
l injection of air (100 mL or more) with shock and fits.
l trauma to neck veins: low pressure during inspira-
l Death is due to disseminated intravascular coagu-
tion causes air to flow in, especially with patient in lation in many cases.
erect sitting position.
Nitrogen embolism may occur in decompression sick- Foreign body embolism
ness when a diver ascends too rapidly:
l Nitrogen (previously in solution under high pressure) l Pieces of cannulae may break off during i.v.
forms bubbles within the circulation as pressure is instrumentation.
rapidly reduced.
l Bubbles may also be found in ligaments and joints, l Intravenous injection with undissolved drugs may
causing severe pain which causes the patient to lie also be involved in i.v. drug abusers.
and bend double in an attempt to relieve the pain;
hence, ‘the bends’. l Accidental intra-arterial injection may occur with
arterial embolus and thrombosis.
Fat embolism
Therapeutic embolism
l Most commonly associated with long bone
fractures. l Therapeutic emboli such as gel foam or steel coils
may occasionally be used to:
l Initially thought to be due to entry of globules of fat n stop haemorrhage
to the circulation from the bone marrow, but now n thrombose aneurysms
considered more probably to be due to metabolic n reduce vascularity of a tumour prior to surgical
changes. removal
n treat arteriovenous fistulae.
l Can be demonstrated in about 90% of multiple
fracture cases, although significant clinical conse- Non-thromboembolic vascular
quences are rare. insufficiency
l The emboli may pass through the pulmonary ves- Causes include:
sels and into the systemic circulation, where they l atheroma
may become impacted in the capillaries of brain, l torsion
kidneys, skin and other organs. l spontaneous vascular occlusion, e.g. spasm in
l Symptoms consist of fever, respiratory distress and Raynaud’s disease
cerebral symptoms. Occasionally brain damage is l ‘steal’ syndrome, i.e. redirected blood supply
sufficient to cause coma and death. l external pressure occlusion, e.g. tumours, tourni-
l Haemorrhagic skin eruptions may occur as may quets, fractures, tight plasters.
subconjunctival and retinal haemorrhages.
Atheroma
Tumour emboli
l Tends to occlude the lumen of arteries progres-
l All malignant tumours tend to invade blood vessels sively.
at an early stage, and isolated malignant cells are
commonly present in the circulation. l Risk of thrombosis occurring on atheromatous
plaque.
l Various factors are responsible for survival of met-
astatic tumours within the blood stream, and for the l With thrombus formation, total occlusion may occur,
ability to escape to surrounding tissues and to grow with development of gangrene.
following impaction within a vessel bed of small
enough calibre to impede its further progress (see Torsion
Chapter 18).
l May affect testis, ovary, bowel.
Amniotic fluid embolism l As organ rotates on pedicle or mesentery, venous
l Occurs in labour when the placenta is detached return is affected first.
from the uterine wall and amniotic fluid enters l Arterial supply unaffected initially and continues to
the maternal circulation.
pump blood into organ, which becomes engorged
l Rare event 1:50 000 deliveries. and swollen.
l Effects may be produced by thromboplastins in l Eventually with oedema, venous pressure equals
arterial pressure, flow ceases and there is impend-
amniotic fluid. ing infarction.
328 SECTION THREE PATHOLOGY
Spontaneous vascular occlusion l Venous obstruction:
n tissues become engorged with blood such that
l May be due to vascular spasm. eventually arterial pressure and venous pres-
l Spasm may occur in such vessels as coronary sure equate and arterial blood flow ceases
n strangulated hernias
arteries (myocardial infarction), peripheral arteries n mesenteric venous thrombosis
(Raynaud’s disease). n phlegmasia caerulea dolens: a severe form of
l Spasm occurs due to contraction of smooth muscle deep vein thrombosis with venous engorgement
in vascular wall. such that venous gangrene may supervene.
‘Steal’ syndrome l Small vessel obstruction:
n spasm, e.g. Raynaud’s phenomenon
l Occurs when blood is redirected preferentially along n vasculitis
one branch of a vessel to the detriment of the end n frostbite
territory of the branch. n microembolism
n precipitated cryoglobulins
l May be seen with proximal arteriovenous fistula n thrombocythaemia.
(usually created for dialysis) in the proximal part
of a limb, e.g. between brachial artery and cephalic Severity of ischaemia
vein at the elbow. The flow from the brachial artery
goes preferentially through the cephalic vein with This depends upon:
very little blood passing down the ulnar and radial l speed of onset
arteries to the hand. l the extent of obstruction
l the extent and patency of collateral circulation
External pressure occlusion l the metabolic requirements of the tissues.
l May be caused by tumours, tourniquets or tight Infarction
plaster of Paris cast.
Infarction is death of the tissue following acute ischae-
l May also be caused by fractures, e.g. super-condylar mia when irreparable damage has occurred.
fracture of the femur where the distal fragment is
drawn backwards, compressing and damaging the Sequence of events
popliteal artery.
l Dead tissue undergoes progressive autolysis of
ISCHAEMIA, INFARCTION parenchymal cells and haemolysis of red cells.
AND GANGRENE
l Living tissue surrounding the infarct undergoes an
Ischaemia acute inflammatory response.
Ischaemia is the condition of an organ or tissue where l Demolition phase: when there is an increase in the
the supply of oxygenated blood is inadequate for its polymorphs, and after a few days macrophage
metabolic needs. infiltration.
Causes l Repair phase: gradual ingrowth of granulation tissue
and the infarct is eventually organised into a fibrous scar.
General
l Ischaemia may follow a sudden fall in cardiac l Infarcts may either be described as red or white (pale).
l White infarcts are usually due to arterial occlusion
output.
l Myocardial infarction occasionally results in of ‘end’ arteries in solid tissues, e.g. heart, spleen,
kidneys.
symmetrical gangrene of the extremities. l Red infarcts are due to venous infarcts and occur in
l Different tissues are affected with different degrees loose tissues, e.g. the lung, where the bronchial
arteries continue to pump in blood.
of severity, e.g. the brain is the most sensitive to l In the long term, dystrophic calcification may occur
ischaemia. in some infarcts.
Local Systemic effects of infarcts
l Arterial obstruction:
l Fever.
n atherosclerosis l Leucocytosis.
n intra-arterial thrombosis l Raised ESR.
n embolism l Rise in certain specific enzymes according to the tis-
n external pressure.
sue affected, e.g. CK raised in myocardial infarction.
Thrombosis, embolism and infarction 17 329
Low-flow infarction Gangrene
In some tissues, infarction may be due to impaired
blood flow (or oxygenation), rather than complete This is the death of tissue.
cessation of flow. Areas involved include: Two types of gangrene are recognised:
l ‘watershed’ areas
l splenic flexure of the colon, which is situated l Dry gangrene:
n tissue dies
between the territories of the superior and inferior n becomes mummified
mesenteric arteries (ischaemic colitis) n healing occurs above it
l the deep myocardium between the subendocardial n eventually the dead area drops off below a line
myocardium, oxygenated directly from the blood of of demarcation (auto-amputation), e.g. gangre-
the ventricles and the remainder which is perfused nous toes in diabetes.
by the coronary arteries
l tissues perfused by a portal vasculature, e.g. the l Wet gangrene:
anterior pituitary, which is perfused by blood that n bacterial infection and putrefaction occur
has already perfused the hypothalamus n gangrene spreads proximally
l tissues distal to pathological arterial stenoses, e.g. n there is no line of demarcation
arteriosclerotic narrowing of arteries may be suffi- n proximal amputation is required where the
cient to allow distal perfusion in normotensive indi- blood supply is better
viduals, but in hypotension, the blood flow falls and n death may occur from overwhelming sepsis.
the distal tissue may become infarcted
l metabolically active tissues, e.g. cerebral neurons, Specific forms of gangrene
in which irreversible damage can occur within
a few minutes of cessation of blood flow and l Gas gangrene.
oxygenation. l Meleney’s gangrene.
l Fournier’s gangrene.
l Necrotising fasciitis.
These conditions are dealt with in Chapter 21.
OSCE SCENARIOS OSCE scenario 17.2
OSCE scenario 17.1 A 69-year-old male presents to A&E an hour after
developing acute pain in his left buttock, thigh and
A 42-year-old female on your ward develops a calf. He has a history of angina and hypertension,
painful calf 5 days after having a mastectomy and and admits to episodes over several months of
free flap reconstruction for breast cancer. She has cramp-like pain in the left buttock, thigh and calf
a BMI of 25, is otherwise fit and well and takes when walking uphill. On examination his left leg is
no medications. paler, cooler and the patient complains of a ‘pins
1. Take a brief history from this patient. and needles’ sensation in it.
2. What is your diagnosis? 1. What is the likely diagnosis?
3. What specific risk factors does this patient have 2. An arteriogram is carried out (Fig. 17.2Q). What
for a DVT? abnormalities are shown? Is there evidence that
4. What venous thromboembolism prophylaxis this is acute-on-chronic rather than simply
acute?
measures would you check that she had 3. Outline your immediate management plan to the
received? examiners.
5. Outline your assessment and any investigations Answers in Appendix page 468
you would perform.
The vital signs and blood tests were all unre-
markable; however, the duplex Doppler reveals
a DVT in the popliteal vein of the affected calf.
6. Outline your management plan.
330 SECTION THREE PATHOLOGY
Fig 17.2Q
The patient’s arteriogram.
SECTION THREE PATHOLOGY
CHAPTER 18
Neoplasia
A neoplasm is a lesion resulting from abnormal growth Box 18.1 Behavioural classification
of a tissue, which is partly or completely autonomous
of normal growth controls, and persists after the Benign Malignant
initiating stimulus has been removed.
Slow growing Rapidly growing
CLASSIFICATION OF TUMOURS
Low mitotic rate High mitotic rate
l Behavioural classification: benign or malignant.
l Histogenetic classification: cell of origin. Resembles parent tissue Differs from parent site
Behavioural classification Non-infiltrating Infiltrating
The behavioural classification divides tumours into: Cells normal Cells abnormal
l benign
l malignant. Never metastasises Frequently metastasises
The pathological criteria for classifying a tumour as
benign or malignant are shown in Box 18.1. Often circumscribed or Often poorly defined or
encapsulated irregular
Histogenetic classification
Rarely ulcerates Frequent ulceration on
l Classification by cell of origin. skin/mucosal
l Histologically determined. surfaces
l Degree of histological resemblance allows tumour
Rarely undergoes necrosis Necrosis common
to be graded.
l Grading correlates with clinical behaviour. Only fatal if damaging vital Always fatal if untreated
function, e.g. cerebral
Major categories of tumour origin tumour
l From epithelial cells. l Moderately differentiated: intermediate between
l From connective tissue cells (mesenchymal). well- and poorly differentiated tumours.
l From lymphoid and haemopoietic tissue.
l Tumours defying histogenetic classification are
Differentiation called anaplastic.
The degree to which the tumour histologically resem- NOMENCLATURE OF TUMOURS
bles its cell or tissue of origin. Degree of differentiation
determines the tumour grade. l All have the suffix ‘-oma’.
l Well-differentiated: resembles parent tissue more l Benign epithelial tumours are either papillomas or
than poorly differentiated tumours. adenomas.
l Poorly differentiated: may be so poorly differenti- l Benign connective tissue tumours have a prefix
ated that they lack easily recognisable histogenetic denoting the cell of origin, e.g. lipoma (fat), osteoma
features. They are more aggressive than well- (bone).
differentiated tumours. l A carcinoma is a malignant epithelial neoplasm.
331
332 SECTION THREE PATHOLOGY
Table 18.1 Examples of tumour nomenclature
Tissue of origin Benign Malignant
Epithelium Adenoma Adenocarcinoma
Glandular Squamous cell papilloma Squamous cell carcinoma
Squamous Transitional cell papilloma Transitional cell carcinoma
Transitional
Lipoma Liposarcoma
Mesenchyme Rhabdomyoma Rhabdomyosarcoma
Fat Leiomyoma Leiomyosarcoma
Striated muscle Osteoma Osteosarcoma (osteogenic sarcoma)
Smooth muscle Chondroma Chondrosarcoma
Bone Angioma Angiosarcoma
Cartilage Fibroma Fibrosarcoma
Blood vessel
Fibrous tissue
l A sarcoma is a malignant connective tissue Embryonal tumours (blastomas)
neoplasm.
These bear a histological resemblance to the embry-
Examples of tumour nomenclature are shown in onic form of the organ from which they arise.
Table 18.1. l Nephroblastoma: Wilms’ tumour; kidney.
l Neuroblastoma: adrenal medulla, autonomic
Epithelial tumours
ganglia.
Benign tumours l Retinoblastoma: eye (inherited predisposition).
l Hepatoblastoma: liver.
l Papilloma: benign tumour of non-glandular or non-
secretory epithelium, e.g. transitional or stratified Apudomas and carcinoid tumours
squamous epithelium.
l APUD (amine content and/or precursor uptake and
l Adenoma: benign tumour of glandular or secretory decarboxylation).
epithelium, e.g. colonic adenoma.
l Describes cells of diffuse (neuro-) endocrine system.
Malignant tumours l Examples of apudomas and their clinical manifesta-
l Carcinoma: malignant tumour of epithelium, e.g. tions are:
squamous cell carcinoma. n insulinoma: episodes of hypoglycaemia
n gastrinoma: extensive peptic ulceration
l Adenocarcinoma: malignant tumour of glandular (Zollinger–Ellison syndrome)
epithelium, e.g. adenocarcinoma of the stomach. n phaeochromocytoma: paroxysmal hypertension
n carcinoid: if metastases are present, flushing,
Carcinoma in situ palpitations and pulmonary valve stenosis.
A lesion with all the cytological features of cancer but Mixed neoplasm
no evidence of invasion through the epithelial base-
ment membrane, e.g. ductal carcinoma in situ (DCIS) A neoplasm showing more than one neoplastic com-
of the breast. ponent; usually both epithelial and mesenchymal, e.g.
pleomorphic adenoma of the parotid (glandular tissue
Connective tissue tumours in a cartilaginous or mucinous matrix), fibroadenoma
of the breast. Carcinosarcomas are most common in
Tumours of connective tissue are named according the female genital tract.
to the cell of origin and behavioural classification.
Hamartomas
Teratomas
A hamartoma is a tumour-like lesion which lacks au-
A teratoma is a germ cell neoplasm representing all three tonomy but in which the elements are fully differenti-
germ cell layers, i.e. ectoderm, mesoderm and endo- ated and are normally found in the tissue of origin.
derm. Ovarian teratomas tend to be benign and cystic. They usually contain two or more mature cell types
Testicular teratomas tend to be malignant and solid.
Neoplasia 18 333
native to the organ of origin but the constituent parts n hormones
are abnormally organised, e.g. pigmented naevi, n bacteria, fungi, parasites
pulmonary hamartomas, which consist of a mixture n other agents.
of cartilage and bronchial epithelium.
Chemicals
Poorly named tumours (misnomas!)
l Polycyclic aromatic hydrocarbons:
l Lymphoma: malignant, therefore lymphosarcoma. n scrotal cancer in chimney sweeps due to
l Hepatoma: malignant, therefore hepatocellular exposure to polycyclic aromatic hydrocarbons
in soot (of historical interest)
carcinoma. n 3,4-benzpyrene in tobacco smoke. Carcino-
l Melanoma: malignant, therefore melanocarcinoma. genic on direct contact, e.g. smoking, but
absorbed into blood stream, which may explain
TUMOUR GROWTH PATTERNS why smokers have higher incidence of cancer
at other sites, e.g. kidney, bladder
l Sessile, polypoid and papillary tumours are likely to n carcinogenic components of tar, which can
be benign (but not always). cause skin cancers by direct contact.
l Fungating, ulcerating, annular and infiltrating tumours l Aromatic amines:
are likely to be malignant. n b-naphthylamine: high incidence of bladder
cancer in dye and rubber industry.
l Ulcerated tumours can often be distinguished from
benign ulcers. The latter have sloping edges while l Nitrosamines:
the former have rolled, everted edges, e.g. squa- n gut cancers in animals.
mous cell carcinoma.
l Azo dyes:
l Encapsulated tumours tend to be benign. Beware n bladder and liver cancers in animals.
the false capsule of compressed connective tissue,
e.g. pleomorphic adenoma of the parotid. ‘Shelling l Alkylating agents, e.g. cyclophosphamide:
out’ this tumour would leave residual tumour. n small risk of leukaemia in humans.
Histological pattern Radiation
Malignant features include: l UV light is a major cause of skin cancer.
l loss of differentiation l Exposure to ionising radiation is associated with
l disordered growth pattern
l variability in cell size increased risk of cancer at many sites, e.g.
l variability in nuclear size n carcinoma of the thyroid after childhood irradi-
l high nuclear:cytoplasmic ratio ation of the neck
l increased mitotic activity n increased incidence of leukaemia and carci-
l abnormal nucleoli may be multiple noma of breast, lung and thyroid after nuclear
l abnormal chromatin pattern. explosions at Hiroshima and Nagasaki during
the Second World War
CARCINOGENESIS n cancer of thyroid after Chernobyl disaster,
which released radioactive iodine
l This is the process by which normal cells are con- n leukaemia and liver neoplasms developing
verted into cells capable of forming neoplasms. years after exposure to thorium-containing
contrast medium (thorotrast).
l A carcinogen is an agent known or suspected to
participate in the causation of tumours. Such agents Viruses
are said to be carcinogenic (cancer-causing) or
oncogenic (tumour-causing). Strictly speaking, l HPV:
carcinogenesis applies to the causation of n common wart
malignant tumours, whereas oncogenesis includes n cervical carcinoma, strong association with
all tumours, benign and malignant. HPV type 16 and 18.
l The main classes of carcinogen are: l EBV:
n chemicals n Burkitt’s lymphoma
n radiation n nasopharyngeal carcinoma
n viruses n B-cell lymphoma in immunosuppressed patients.
334 SECTION THREE PATHOLOGY
l Hepatitis B virus: HOST FACTORS AND
n hepatocellular carcinoma. CARCINOGENESIS
l HIV: l Race.
n Kaposi’s sarcoma. l Diet.
l Inherited predisposition.
l HTLV-1: l Age.
n T-cell lymphoma/leukaemia. l Gender.
Hormones Race
l Experimentally, oestrogens can be shown to promote l Precise role unknown due to coincidence with diet,
formation of breast and endometrial carcinoma. habit and location.
l Increased incidence of endometrial carcinoma in l Incidence of oral cancer high in India and South East
post-menopausal women treated with oestrogen- Asia, but probably related to chewing betel nut.
containing compounds.
l High incidence of hepatocellular carcinoma in
l Androgenic and anabolic steroids are known to Africa and South East Asia, but is probably related
induce hepatocellular tumours in humans. to exposure to dietary carcinogens and viral
hepatitis.
Bacteria, fungi, parasites
l Immigrant groups tend eventually to assume the
l Helicobacter pylori implicated in the pathogenesis disease profile of their adopted country.
of gastric lymphoma.
Diet
l Aflatoxins (B1) produced by Aspergillus flavus have
been linked to high incidence of hepatocellular l Aflatoxins and hepatocellular carcinoma.
carcinoma in certain areas of Africa. l Diet low in fibre in colorectal cancer.
l High dietary fat in breast cancer.
l Schistosoma is strongly implicated in the high inci-
dence of bladder cancer where infection (schistoso- Inherited predisposition
miasis) is rife, e.g. Egypt.
l Some diseases appear to run in families (‘cancer
l Clonorchis sinensis (liver fluke): dwells in bile ducts families’).
where it may cause cholangiocarcinoma.
l A woman whose mother and one sister have breast
Other agents cancer stands a 50% probability of developing the
disease.
l Asbestos:
n mesothelioma (strong association) l Examples of familial cancer are shown in Table 18.2.
n carcinoma of the bronchus.
Age
l Metals:
n nickel exposure is associated with nasal and l The incidence of cancer increases with age.
bronchial carcinoma. l This reflects the cumulative effects of exposure to
l Betel nut: carcinogens with age.
n chewing betel nut is associated with increased l Effects of immune defences may be lost with old age.
risk of neoplasms of oral cavity.
Table 18.2 Examples of familial cancer syndrome
Syndrome Gene affected Resultant neoplasms
Li–Fraumeni p53 Breast and ovarian carcinomas, astrocytomas, sarcomas
Retinoblastoma Rb1 Retinoblastoma, osteosarcoma
Familial polyposis coli APC GI tract carcinomas; mainly colon
von Hippel–Lindau VHL Renal carcinoma, phaeochromocytoma, haemangioblastoma
Multiple endocrine neoplasia RET, others Tumours of pituitary parathyroids, thyroid, pancreas, adrenal
syndromes (1–111) BRCA1, BRCA2 glands (combination depends on which syndrome)
Familial breast cancer Breast, ovarian syndrome, prostatic carcinomas
Neoplasia 18 335
l Familial neoplasms occur at a younger age than Box 18.2 Commonest cancers by gender
sporadic neoplasms.
Male Female
l Individual neoplasms have their own specific age
distribution, e.g. fibroadenoma of the breast Carcinoma of the prostate Carcinoma of the
(18–35 years), carcinoma of the breast (more breast
common after the menopause), neuroblastoma
(childhood). Bronchopulmonary Bronchopulmonary
carcinoma carcinoma
Gender
Colorectal adenocarcinoma Colorectal
l Carcinoma of the breast is 200 times more common adenocarcinoma
in women than in men.
Urinary tract carcinoma Uterine carcinoma
l The commonest tumours in men and women differ,
and current statistics can be seen in Box 18.2.
PREMALIGNANT DISEASE Examples include:
l benign neoplasms that can become malignant, e.g.
A premalignant lesion is a discrete identifiable lesion
associated with an increased risk of progression to a colorectal adenoma–carcinoma sequence (Fig. 18.1)
malignant neoplasm. l dysplasia/in situ malignancy
l metaplasia–dysplasia sequence (Table 18.3).
Small adenoma
Normal epithelium
5q deletion
APC mutation
MCC mutation
c-myc activation
bcl-2 mutation
Large adenoma
Invasive adenocarcinoma
K-ras mutation 18q deletion
DCC mutation
17p deletion
p53 mutation
APC = adenomatous polyposis coli gene (Chromosomal location 5q 21) Fig 18.1
MCC = mutated in colon cancer gene (Chromosomal location 5q 21)
DCC = deleted in colon cancer gene (Chromosomal location 18q 21.3) Molecular genetics of the
adenoma–carcinoma sequence.
336 SECTION THREE PATHOLOGY
Table 18.3 Examples of metaplasia–dysplasia sequence
Organ Metaplasia undergoing dysplasia Resulting malignancy
Oesophagus Barrett’s oesophagus (intestinal metaplasia) Oesophageal adenocarcinoma
Stomach Intestinal metaplasia (associated with achlorhydria) Gastric adenocarcinoma
Bronchus Squamous metaplasia (smokers) Bronchogenic squamous cell carcinoma
Cervix Squamous metaplasia Squamous cell carcinoma
Kidney (renal pelvis) Squamous metaplasia (stone or chronic infection) Squamous cell carcinoma of renal pelvis
Box 18.3 Examples of premalignant conditions l Promotion: the event stimulating clonal proliferation
of the initiated transformed cell. A promoter is a
Premalignant lesion/ Cancer risk substance that will cause cancer in an initiated cell
condition but not a normal cell, e.g. croton oil in experimental
skin cancers initiated by methylcholanthrene.
Colorectal adenomatous Colorectal
polyp adenocarcinoma l Persistence: initiators and promoters no longer re-
quired. The tumour becomes autonomous with vas-
Epithelial hyperplasia of Carcinoma of the cular ingrowth, increased growth rate, invasiveness
the breast breast and metastasis.
Cervical epithelial dysplasia Carcinoma of the GENETICS OF CANCER
cervix
An increased predisposition to development of malig-
Ulcerative colitis Colorectal nant neoplasm may be inherited as:
adenocarcinoma l part of a clinical syndrome with other diagnostic
Bile duct carcinoma features in addition to the increased risk of malig-
nancy, e.g. acute leukaemia in Down’s syndrome
Xeroderma pigmentation Skin cancer l an increased likelihood of neoplasia developing as
the only manifestation, e.g. familial retinoblastoma
Cirrhosis of the liver Hepatocellular syndrome.
carcinoma Inherited syndromes associated with an increased risk
of malignancy are:
Paget’s disease of bone Osteogenic sarcoma l syndromes with a major chromosomal abnormality,
e.g. Down’s syndrome and acute leukaemia
A premalignant condition is a non-neoplastic condition l syndromes determined by single gene defects, e.g.
which is associated with an increased risk of develop- familial polyposis coli and colorectal cancer.
ing malignant tumours. Examples of premalignant
lesions and conditions are shown in Box 18.3. Evidence for genetic alterations
causing cancer
CARCINOGENIC PROCESS
l Translocations: part of one chromosome becomes at-
Multistep theory tached to another, e.g. Philadelphia chromosome and
chronic myeloid leukaemia (CML), Burkitt’s lymphoma.
l Latency: the causal event is usually followed by a
variable but usually lengthy delayed period. This l Extra chromosomes: usually trisomies (i.e. three
is because: copies of a chromosome rather than two), e.g. tri-
n more than one effect is required for cancer to somy 21 (Down’s syndrome), acute leukaemia.
develop (multistep)
n it takes time for the mutated cell to produce a l Familial aggregations, e.g. retinoblastoma.
clone of a significant number of cells to produce l Increased risk of malignancy associated with inca-
signs and symptoms.
pacity to repair damaged DNA, e.g. xeroderma
l Initiation: exposure of cell/tissue to carcinogen and pigmentosum and skin cancers.
induction of lesion in cell’s genome bestowing l Association between chemical mutagens and their
neoplastic potential; irreversible. carcinogenic effects (see above).
l Evidence that mutation or unregulated expression of
certain genes converts normal cells to malignant cells.
Neoplasia 18 337
Genetic mechanisms in l Growth factors, receptors, signalling enzymes and
carcinogenesis transcription factors are encoded by proto-oncogenes.
Two important genetic mechanisms leading to neopla- l Oncogenes arise from mutations of proto-oncogenes.
sia are: l Oncogenes code for altered versions or excessive
l abnormal or excessive expression of dominant
quantities of growth-controlled proteins disrupting
stimulatory genes—oncogenes the growth-signalling pathway of the cell.
l loss or inactivation of recessive inhibitory genes— l The growth-signalling pathway becomes hyperac-
tive and cells grow and divide more rapidly.
tumour suppressor genes. l A cancer cell may contain one or more oncogenes,
Abnormal expression of oncogenes drives normal cells such that one or more components of the pathway
towards a neoplastic state. Loss of tumour suppressor may be abnormal.
gene function allows neoplastic transformation as a Examples of oncogenes and their products are shown
result of oncogene expression. in Table 18.4.
Oncogenes Tumour suppressor genes
l Genes whose presence in certain forms and/or l Normal genes whose absence can lead to the devel-
activity can stimulate the development of cancer. opment of cancer.
l Oncogenes contribute to the development of cancer l Tumour suppressor genes are categorised accord-
by instructing cells to make proteins that stimulate ing to their mechanism of action (Table 18.5):
excessive growth and cell division. n caretaker genes maintain the integrity of the
genome by repairing DNA damage
l Oncogenes are related to normal genes called n gatekeeper genes inhibit proliferation, or pro-
proto-oncogenes. mote the death of cells with damaged DNA.
l Proto-oncogenes are a family of normal genes that l If a pair of tumour suppressor genes are lost from a
code for proteins involved in the normal growth- cell, or inactivated by mutation, cancer can result.
control pathway of a cell.
Table 18.4 Examples of oncogenes
Oncogene Protein produced Abbreviated from
Growth factors and their Platelet-derived growth factor Simian sarcoma virus
receptors Epidermal growth factor receptor Erythroblastosis virus
Macrophage colony-stimulating factor Feline McDonagh Sarcoma virus
sis
erb-B receptor Rat Sarcoma virus
fms Abelson mouse leukaemia virus
G-protein
Signal transduction molecules tyrosine kinase Myelocytomatosis virus
ras
abl DNA binding proteins
Transcription factors
myc
Table 18.5 Tumour suppressor genes and associated tumours
Category Gene Tumour susceptibility if mutation Other associations
Gatekeepers p53 Li–Fraumeni syndrome (predisposed to wide Mutated in 50% of human
range of tumours, e.g. breast, ovary, sarcoma) epithelial cancers
Rb1
APC Familial retinoblastoma Often mutated in sporadic
Familial adenomatous polyposis colorectal cancers
Caretakers BRCA1 Familial breast and ovarian cancer Rarely mutated in sporadic breast
BRCA2 Familial breast cancer cancers
338 SECTION THREE PATHOLOGY
l Individuals who inherit an increased risk of develop- l Decreased cellular adhesion:
ing cancer are often born with a defective copy on n loss of surface adhesion molecules, e.g. cad-
one tumour suppressor gene. haerins enable migration of individual cells.
l Because genes come in pairs an inherited defect in Clinical consequences of local invasion
one copy will not cause cancer if the other normal
copy is functional. Clinical consequences of local invasion depend upon
the site of the tumour. Box 18.4 indicates some of
l If the second copy undergoes mutation then cancer the clinical consequences of local invasion of bron-
may occur because there is no longer a functional chial carcinoma.
copy of the gene.
Metastasis
Examples of tumour suppressor genes
Metastasis is the process whereby malignant tumours
Rb gene and retinoblastoma spread from their site of origin (primary) to form other
l Individuals with an inherited predisposition to tumours (secondary) at distant sites. Metastasis is tu-
mour spread in discontinuity as distinct from invasion,
develop retinoblastoma are born with absence of which is spread in continuity.
one of normally paired Rb1 suppressor genes. Only
one further mutational loss of remaining Rb1 gene is Steps in the metastatic cascade
required for retinoblastoma to develop. High risk of
bilateral familial retinoblastoma. l Detachment of tumour cells.
l Individuals with paired Rb1 genes have a low inci- l Invasion of surrounding tissues to reach vessels.
dence of retinoblastoma because two mutational l Intravasation into lumen of vessels (blood and
losses in the same cell or daughter cells would
be required; hence, sporadic retinoblastoma is very lymphatics).
rare. Risk of unilateral retinoblastoma. l Evasion of host defence mechanisms.
l Adherence to endothelium at remote location.
p53 tumour suppressor gene l Extravasation from vessel lumen into surrounding
l Situated on short arm of chromosome 17.
l Most frequently mutated of the class of genes. tissue.
l Normal functions are: l Survival and growth within the tissue.
l Establish own blood supply.
n repair of damaged DNA before S phase of cycle by
arresting cell cycle in G until damage is repaired Box 18.4 Clinical consequences of local invasion
of bronchial carcinoma
n apoptotic cell death if DNA damage is extensive.
l Inherited germ line mutations of p53 occur in the Structure invaded Consequence
rare Li–Fraumeni syndrome, giving an inherited Oesophagus Dysphagia
predisposition to a wide range of tumours.
Thoracic major Massive haemoptysis
BEHAVIOUR OF TUMOURS vessels
Invasion Superior vena cava Facial oedema/cyanosis
Invasion is the sole most important criterion for malig- Recurrent laryngeal Hoarseness
nancy. Metastases are a consequence of invasion. In- nerve
vasion demands that tumours should be removed in
continuity with a wide margin of apparently normal Sympathetic chain Horner’s syndrome
tissue.
Brachial plexus Pancoast syndrome (also
Factors influencing tumour invasion include: Horner’s syndrome and
l Abnormal or increased motility: unilateral recurrent
laryngeal nerve palsy)
n malignant cells are more mobile than their
normal counterparts. Phrenic nerve Paralysis of hemidiaphragm
l Secretion of proteolytic enzymes: Pericardium Pericardial effusion
n matrix metalloproteinases are secreted by
malignant cells
n they digest surrounding connective tissue, e.g.
interstitial collagenases degrade collagens
Type I, II and III.
Neoplasia 18 339
Routes of metastasis l Pressure on adjacent structures, e.g. nerves, blood
vessels, bile ducts (cancer of head of pancreas and
l Lymphatic: regional lymph nodes. obstructive jaundice).
l Haematogenous: via the bloodstream.
l Transcoelomic: across peritoneal, pleural and peri- Systemic
cardial cavities. Effects of metastases
l Seeding or implantation during surgery.
l Enlarged lymph nodes: may be discrete or hard,
Lymphatic irregular and matted.
l Most carcinomas spread via lymphatics. l Hepatomegaly: primary tumour in stomach, colon,
l May remain discrete in lymph nodes or invade out- bronchus or breast.
side nodes, involving adjacent nodes and connec- l Jaundice: nodes in porta hepatis with primary
tive tissue when they become matted together. tumour in stomach, pancreas or colon.
l Melanomas may permeate lymphatics and appear
as black streaks in subcutaneous tissue. l Ascites: ovarian or any GI malignancy.
l Lymphatic blockage causes lymphoedema of tis- l Abdominal mass due to omental secondaries often
sues; in the breast is associated with peau d’orange.
in association with ascites.
Haematogenous l Pathological fractures due to bony metastases:
l Bone is a favoured site for haematogenous spread breast, bronchus, thyroid, prostate or kidney.
from five carcinomas: lung, breast, thyroid, kidney, l Pleural effusion: bronchial carcinoma and breast
prostate.
cancer.
l Other favoured sites are lung, liver and brain. l Fits, confusion, personality change from cerebral
l Sarcomas spread by the bloodstream and NOT
metastases, e.g. breast, bronchus or malignant
lymphatics. melanoma.
l Anaemia—pancytopaenia: bone marrow deposits.
Transcoelomic
Paraneoplastic effects
l Spread of carcinoma of stomach to ovaries (Kruken-
berg tumours). These are effects that occur in the presence of a
neoplasm which are not directly caused by the
l Spread of ovarian cancer to omentum and perito- tumour itself or metastases. They can be divided
neum (ascites). as follows:
l humoral (mediated by a tumour-secreted product)
l Spread of bronchial carcinoma to pleura (pleural l immunological (usually autoimmune).
effusion).
Seeding or implantation at surgery
l Tumour grows in sites of surgical incision or inves-
tigation, e.g. FNA.
CLINICAL EFFECTS OF TUMOURS Humoral
These may be: l Bronchial carcinoma and Cushing’s syndrome due
l local to inappropriate secretion of ACTH.
l systemic
l paraneoplastic l Bronchial carcinoma and inappropriate secretion of
l metabolic ADH.
l others.
l Hypercalcaemia of malignancy caused by secretion
Local of parathyroid hormone related peptide.
l Mass. l Carcinoid syndrome with liver metastases from a
l Bleeding due to ulceration: haematemesis, carcinoid tumour due to 5HT.
haematuria. Immunological
l Pain.
l Obstruction: hollow tube, e.g. large bowel obstruc- l Autoimmune disease may be triggered by
malignancy.
tion with carcinoma.
l Irritation at tissue of origin, e.g. cough due to l Dermatomyositis developing in later life may be due
to an underlying malignancy.
bronchial tumour.
l Membranous glomerulonephritis can be initiated by
an underlying malignancy.
340 SECTION THREE PATHOLOGY
Metabolic effects l Some markers may be detected in histological
sections using immunohistochemistry.
These are usually hormonal and reflect appropriate
secretion of hormones: l Tumour markers are rarely sufficiently specific to be
l thyrotoxicosis from thyroid adenoma of absolute diagnostic value.
l Cushing’s syndrome from adrenal cortical adenoma
l hyperparathyroidism from parathyroid adenoma l The main value of tumour markers is in follow-
l insulin from an insulinoma. ing the course of a malignant disease and
monitoring the response to treatment and hence
Others prognosis.
l Cachexia: all tumours; probably multifactorial. l Tumour markers can also be used for tumour
l Pyrexia of unknown origin (PUO): lymphoma, localisation and antibody-directed therapy.
hypernephroma. TUMOUR DEPENDENCY
l Hypertrophic pulmonary osteoarthropathy associ-
Although the growth of tumours is autonomous, some
ated with bronchial carcinoma. retain a requirement for growth factors/endocrine
l Thrombophlebitis migrans associated with visceral support. Good examples of those requiring endocrine
support are carcinomas of the breast, prostate and
cancer, usually carcinoma of the head of the pancreas. thyroid.
l Acanthosis nigricans associated with carcinoma of
Breast
the pancreas.
l A large proportion of breast carcinomas express
TUMOUR MARKERS oestrogen receptors.
Neoplastic cells often have quantitative and qualitative l The degree of oestrogen-receptor expression corre-
abnormalities of protein synthesis. They may either lates well with the response of the tumour to
overproduce a normal product or they may produce oestrogen blockade, e.g. with selective oestrogen
a substance which is abnormal for their tissue of receptor-modulating drug tamoxifen.
origin. Protein production by some tumours has
been utilised clinically as tumour markers. Examples l Oestrogen-receptor-positive tumours tend to be of
of tumour markers are shown in Box 18.5. a lower grade and have a better prognosis than
oestrogen-receptor-negative tumours.
A tumour marker:
l May be a substance which is secreted into the blood Prostate
or other body fluid or expressed on the cell surface l Prostatic epithelium is dependent on androgenic
of malignant cells in larger quantities than in normal stimulation.
counterparts.
l Detection is by measuring the concentration of the l Castration results in apoptosis of prostate epithelial
marker in the body fluids, usually by immunoassay. cells and partial involution of the gland.
Box 18.5 Examples of tumour markers l Many prostatic carcinomas retain the above charac-
teristics, allowing their growth to be inhibited by
Tumour Marker androgen blockade.
Prostatic adenocarcinoma Prostate-specific l Androgen blockade can be achieved by:
antigen (PSA) n orchidectomy
n oestrogens (side-effects unacceptable)
Hepatocellular carcinoma a-fetoprotein n luteinising hormone (LH) released from pituitary
stimulates androgen production by Leydig
Testicular cancer b-HCG, a-fetoprotein, cells. LH production can be inhibited by lutei-
placental alkaline nising hormone releasing hormone (LHRH),
phosphatase which after transient stimulation causes long-
term depression of LH release.
Choriocarcinoma b-HCG
l After a period of time, androgen sensitivity is lost
Ovarian carcinoma CA 125 and therefore the above treatments are not
curative.
Colorectal cancer Carcinoembryonic
antigen (CEA)
Neoplasia 18 341
Thyroid n T1: tumour < 2 cm
n T2: tumour 2–5 cm
l Papillary and follicular carcinoma respond in the n T3: tumour > 5 cm
same way as normal thyroid epithelium to TSH. n T4: extension to chest wall
n N0: no nodal involvement
l TSH suppression with thyroxin in conjunction with n N1: mobile ipsilateral axillary nodes
surgery and radioiodine therapy is used to treat n N2: fixed ipsilateral axillary nodes
these neoplasms. n N3: ipsilateral supraclavicular nodes
n M0: no metastases
PROGNOSIS OF TUMOURS n M1: distant metastases
n MX: metastases suspected but not confirmed.
This depends on:
l type of tumour Other staging
l stage (extent of spread)
l grade (degree of differentiation) l Malignant melanoma:
l surface receptors, e.g. oestrogen receptors in n Breslow’s classification (depth of invasion in
mm from the basal layer of the epidermis):
breast cancer l < 0.76 mm: good prognosis
l gene expression l > 1.5 mm: poor prognosis and high risk of
l sensitivity to treatment modalities metastases
l age n Clark’s classification (defined according to an-
l nutritional status atomical boundaries) relates to anatomical area
l immune status and human leucocyte antigen (HLA) of penetration, e.g. level 1: confined to epider-
mis, to level 5: tumour cells present in the sub-
type. cutaneous tissue.
Tumour staging Breslow’s classification tends to be more widely used
and has an influence upon the surgical margins taken.
This represents the extent of spread. Staging can be At present, if the lesion is < 1 mm thick then a 1 cm
assessed as follows: margin is taken, whereas if the lesion is over 1 mm
l clinical assessment thick a 2 cm margin is taken.
l imaging techniques
l histopathological examination of resected SCREENING
specimen. Population screening programmes are aimed at reduc-
Some types of staging rely on one of the above alone ing morbidity and mortality from a particular disease
(e.g. Dukes’ classification) and some rely on a combi- within an entire population. Screening should be di-
nation (TNM). Staging is designed to define prognosis. rected at an asymptomatic population at risk. The prin-
ciples underlying screening depend on the following:
Dukes’ classification l for screening to be cost-effective, the cancer must
A pathological classification drawn up by Cuthbert constitute a major health risk, i.e. high incidence
Dukes (pathologist) originally to stage rectal cancer and high mortality rate
but now extrapolated to colorectal cancer. l it must be a relatively common disease, e.g. breast
l Dukes A: invasion into, but not through, the bowel wall. cancer in the UK; gastric cancer in Japan
l Dukes B: invasion through the bowel wall. l there must be an established and effective treat-
l Dukes C: involvement of regional lymph nodes. ment for the disease
l Dukes D was not in the original classification but l it must be demonstrated that early diagnosis and
treatment do increase the cure rate
was added later: indicates distant metastases. l there must be a diagnostic test available that can be
applied to a large number of people
TNM classification l the test must have a high level of sensitivity and
specificity
l T: primary tumour. Number suffix indicates tumour l the test should not cause harm to the individual
extent or size. being tested
l the cost of screening large populations must be
l N: lymph nodes. Number suffix indicates number of justified by the yields.
lymph nodes or groups of lymph nodes involved.
l M: metastases. Number suffix indicates presence or
absence.
l Example: TNM classification for carcinoma of the
breast:
n T1S: carcinoma in situ
n T0: no primary located
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