Oxford Textbook of Fundamentals of Surgery

William E. G. Thomas (ed.) et al.

https://doi.org/10.1093/med/9780199665549.001.0001
Published: 2016 Online ISBN: 9780191810817 Print ISBN: 9780199665549

CHAPTER

1.4.1 Surgical pathology 

Downloaded from https://academic.oup.com/book/31816/chapter/266636047 by University of Sydney user on 25 September 2022

David Lowe

https://doi.org/10.1093/med/9780199665549.003.0019 Pages 125–166

Published: July 2016

Abstract
Pathology is the study of disease; its causes and mechanisms. This chapter rst covers chromosomal
abnormalities, tissue response to injury, and cellular growth and repair. It then considers metabolic
and endocrine disorders, vascular disorders and the body’s response to injury.

Keywords: chromosomes, cellular growth and repair, inflammation, immune response, blood disorders,
benign and malignant neoplasia, metabolic disorders, endocrine disorders, vascular disorders, injury
Subject: Surgery, Urology, Paediatric Surgery, Cardiothoracic Surgery, Peri-operative Care, Trauma and
Orthopaedic Surgery, Upper Gastrointestinal Surgery, Colorectal Surgery, Surgical Oncology, Neurosurgery,
Breast Surgery, Transplant Surgery, Vascular Surgery, Surgical Skills
Series: Oxford Textbooks in Surgery

Introduction

Surgery and pathology are indivisible. The study of the causes and e ects of a disease a ects the
management and prognosis of it. Many of the processes in pathology are generic and apply in many
circumstances, and the common ones of these are included here.

Cell processes

There are two principal ontological imperatives that de ne living organisms: the imperative for survival
and the imperative for procreation. The simplest living organisms such as viruses have defence mechanisms
and a genetic impetus to multiply; complicated biochemical structures, such as prions, freely multiply by a
cascade e ect but have no imperative to do so, and no de ned defensive or aggressive capacity to ensure
their continued existence.

The cell processes of life as we now recognize it began as:

◆ vegetative growth of single-celled organisms, permitted by the availability of an energy source such
 as sunlight or thermal energy from crustal fractures, and from simple endocytosis and breakdown of
particles that provided energy

◆ di erentiation permitting alimentation of inanimate material and of competitors and predators

◆ diversi cation through chromosomal modi cations and sexual division.

Growth mechanisms and the cell cycle

Downloaded from https://academic.oup.com/book/31816/chapter/266636047 by University of Sydney user on 25 September 2022

The parts of the cell cycle
Figure 1.4.1.1 shows a cell cycle with checkpoints. G1 and G2 are the gap phases. About 98% of the variation
in the duration of the cell cycle is accounted for the time spent in G1, the other 2% variation occurring in G2
phase. The length of both gap phases varies in di erent cell types and among species. Growth promoter and
growth inhibitor products act principally in G1, in which synthesis of RNA leads to translation of cell wall
and cytoplasmic proteins. If the cell cycle is permitted to advance beyond the restriction point in G1, the cell
will probably complete the other phases of the cycle and undergo mitosis.

Fig. 1.4.1.1

Cell cycle with checkpoints.

G0 The ʻresting phaseʼ in which the cell is active in synthesis, secretion, and other functions but is not undergoing the process of
division. G1 Gap phase 1, in which there is synthesis of cell components necessary for division into daughter cells, except for
synthesis of DNA. The checkpoint in G1, at which progress further through the cycle is controlled, is called the restriction point,
RP. It is the point at which growth inhibitor factors such as retinoblastoma gene product and p21 gene product act. S Synthesis
phase, in which DNA is synthesized. The checkpoint (CP) in this phase is towards its end, and also responds to growth inhibitor
gene products. G2 Gap phase 2, in which there is protein synthesis and condensation of chromosomes begins. There is a
checkpoint towards the end, at which DNA integrity is examined before the cell is permitted to undergo mitosis. M Mitosis phase,
in which the cell passes through prophase, metaphase, anaphase, and telophase to form two separate daughter cells. The
checkpoint is in metaphase, at which the spindle assemblies are examined for competence. Adapted from David Lowe, Surgical
Pathology Revision, Second Edition, Cambridge University Press, Cambridge, UK, Copyright © 2006. Reprinted with permission.
S is the synthesis phase in which DNA and other nuclear components are formed. In G2 phase there is more
protein synthesis. M is the phase of mitosis. The duration of these phases is relatively constant for a cell
type. G0 phase is the so-called resting phase before the cell re-enters the cycle. This phase is variable and
1
also depends on growth-modifying gene products.

Factors that control progression around the cycle

Cyclins are a series of enzymes that act during the di erent phases of the cycle to ensure their smooth
progression. They are controlled by cyclin-dependent kinases (CDKs), another series of enzymes which in

Downloaded from https://academic.oup.com/book/31816/chapter/266636047 by University of Sydney user on 25 September 2022

turn are a ected by growth modi ers.

Growth inhibitor gene products that suppress the actions of CDKs include p53, p27, and p21 proteins.
Retinoblastoma gene product and related genes hold the cell in G1 by acting at the restriction point. Once the
cell has passed the restriction point it is very likely to undergo mitosis.

Growth-promoting agents include those that are:

◆ circulating:

• hormones: human growth hormone (hGH), triiodothyronine and tetraiodothyronine (T3 and T4),
cortisol, testosterone, and oestrogen

• growth factors: platelet-derived growth factor from α granules, broblast-derived growth factor,
macrophage-derived growth factors, and insulin-like growth factor 1

◆ cell membrane bound:

• protein receptors such as epidermal growth factor receptor (EGFR), homologous with c-erbB-2
gene product

• intracytoplasmic: steroid receptors

• intranuclear: c-myc, c-ras.

Growth-suppressing agents include:

◆ circulating hormones such as progesterone

◆ intracellular agents: p53 protein, retinoblastoma gene product, APC gene product in familial
adenomatous polyposis, BRCA1 and BRCA2 gene products in breast and ovarian cancer, and Wilms’
tumour gene product. It is abnormalities of these genes and their protein products that permit the
development of neoplasia in some cases, not the presence of the genes themselves in the genome.

DNA damage in a cell results in activation of the p53 gene to make p53 protein. This arrests the cell cycle by
increasing the concentration of the CDK inhibitor p21 protein and so prevents the damaged DNA being
replicated. The cell will be forced into apoptosis by p53 protein if the DNA defect is not remedied within a
2
time-span that varies among cells.

Abnormalities of the p53 gene prevent this protective mechanism—p53 is the commonest growth inhibitor
gene found to be abnormal in human neoplasms. Decreased p53 activity may be by:

◆ deletion of the p53 gene or mutation of it into an inactive form

◆ overactivity of the mdm-2 gene, the regulator of p53, which results in excess protein product which
binds with and inactivates p53 protein
 ◆ abnormal handling of p53 protein

◆ metabolism of p53 protein by viruses which stimulate cell division.

Chromosomes and chromosomal abnormalities

Chromosomes in normal cells

Downloaded from https://academic.oup.com/book/31816/chapter/266636047 by University of Sydney user on 25 September 2022

Most human cells have 46 chromosomes, 22 pairs of autosomes and one set of sex chromosomes. These can
be a pair of X chromosomes or an unmatched set of an X and a Y. When chromosomes developed over 30
million years ago, the X and Y chromosomes were identical in size and composition and would have been at
the position of chromosome pair 7 in the modern terminology, in which position 1 represents the largest
chromosome and position 21 the smallest (chromosome 22 is in fact larger than 21—this was a labelling
mistake). Primates other than human beings have 48 chromosomes; two small non-human primate
autosomes fused together resulting in human chromosome 2.

About 10% of tissue cells are in process of mitosis and have built up 96 chromosomes. These coalesce in
prophase, line up in a bar in metaphase, are separated in prophase by spindle contraction, and as new sets of
46 chromosomes, are ready to repeat the cell cycle when the daughter cells pull apart in telophase.

Cells with 23 chromosomes are haploid. They are found in the testes as late spermatocytes, spermatids, and
spermatozoa, and in the ovary as oocytes. When a spermatozoon fertilizes an oocyte they become an ovum,
which has 46 chromosomes. Other possible numbers of chromosomes in normal cells include zero, in
erythrocytes and reticulocytes which are anucleate, and multiples of 46, such as 92 in cells about to divide,
and higher multiples of 46 in multinucleate cells such as osteoclasts and myocytes.

Chromosome abnormalities are classi ed as those of autosome quality and number, and of sex chromosome
quality and number. The two principal types of abnormality of chromosome quality or structure are:

◆ translocations, in which parts of chromosomes are transposed onto others. Translocations may be
balanced, when material is reciprocally transferred and so the total chromosomal material is
una ected, or unbalanced when material is gained or lost

◆ deletions, in which there is loss of chromosomal material of an amount or type that is compatible with
development of a living embryo. Deletion of material from both ends of a chromosome with fusion of
the ends results in ring chromosome formation.

DNA ploidy and chromosome numbers

Ploidy is the amount of DNA in a cell, which in a normal cell correlates directly with the number of
chromosomes present. A normal cell which has one or more nuclei is haploid, diploid, tetraploid, or
polyploid. An abnormal cell may be triploid or aneuploid, either by gaining or losing chromosomal material
in odd amounts or by gaining or losing entire chromosomes. A triploid gestation, in which the cells of the
embryo have 69 chromosomes, is compatible with a life of only a few weeks. Ploidy is measured by a variety
of methods, most commonly ow cytometry; DNA densitometry is less widely used.

Monosomy refers to cells which have one of a pair of autosomes or sex chromosomes missing. The cells
have 45 chromosomes, such as in Turner’s syndrome, X0 (X zero). Absence of one of a pair of autosomes is
almost always lethal, but absence of a Y or one X chromosome is compatible with life. In each cell of a
normal woman one of the X chromosomes is inactivated at random, though only partially (the Lyon
hypothesis).

Trisomy refers to cells with one extra chromosome in a set, and so 47 chromosomes in a typical cell. In
Down’s syndrome, there is either an extra chromosome 21 or an extra amount of chromosome 21 genetic
material translocated onto another chromosome. Another example is XYY males—as the Y chromosome
carries so little genetic material, these men are normal.

In very rare cases, multiple X chromosomes may be present in a viable cell, such as XXX and XXXX, which
are examples of trisomy and tetrasomy. As there is at least partial inactivation of the redundant copies this

Downloaded from https://academic.oup.com/book/31816/chapter/266636047 by University of Sydney user on 25 September 2022

is compatible with life, but the patients are usually infertile and have other developmental abnormalities.

Abnormalities of chromosome quality

Autosomal dominant conditions

If a single copy of an abnormal autosome confers a phenotypic abnormality it is called an autosomal
dominant disease. The prevalence is the same in both sexes. At least one parent must be a ected, assuming
that the patient does not have a spontaneous mutation: if only one, the patient will be heterozygous; if both,
the patient may be heterozygous or homozygous. If the patient is heterozygous and has a normal partner,
3
half of their children would be expected to have the condition.

Examples of surgical importance include:

◆ familial adenomatous polyposis: several chromosomal abnormalities a ect mucosal cells in the large
bowel and elsewhere in sequence to result in adenomatous polyps and, in almost all cases,
adenocarcinoma

◆ some forms of polycystic disease, which may present in a young adult with the complications of a
berry aneurysm such as subarachnoid haemorrhage, and in older adults with hepatic, splenic,
pancreatic, and bilateral renal cysts and chronic renal failure. Less commonly, polycystic disease is
associated with aneurysm of the aorta, diverticula of the intestines, and ovarian cysts

◆ Marfan’s syndrome, a connective tissue defect in which there are heart valve abnormalities leading to
cardiac failure, and an increased risk of aortic dissection and of subluxation of the lens

◆ spherocytosis, in which there is haemolytic anaemia which may be episodic and an increased risk of
gallstones as a consequence.

Autosomal co-dominant conditions

There is random inactivation of one copy of most paired genes (as with the paired X chromosomes in female
cells). The other copy contributes all of the body’s requirement for the gene product. A small number of
genes are unusual in that they provide only about half of the requirement for the gene product and so both
copies must be active for normal production; these are called co-dominant genes. Examples include genes
for some blood groups, enzymes, red cell constituents, and some antigens such as human leucocyte antigen.
The principal condition of surgical interest in which a co-dominant gene is defective is sickle cell disease.
Autosomal recessive conditions
An autosomal recessive disease is one in which both copies of the causative abnormal gene must be present.
Both parents must have at least one copy of the abnormal gene. They could be:

◆ both heterozygous carriers and so asymptomatic

◆ one a carrier and one homozygous showing symptoms and signs of disease

◆ very rarely, both homozygous especially if the disease causes little risk of infertility or death before
puberty.

Downloaded from https://academic.oup.com/book/31816/chapter/266636047 by University of Sydney user on 25 September 2022

When a heterozygous carrier has a normal partner, half of the children would be expected to be carriers.
When two carriers have children, one in four would be expected to have the disease, half of them expected to
be carriers, and one in four normal.

Autosomal recessive conditions of surgical importance include:

◆ cystic brosis, in which patients have susceptibility to infections and risk of developing intestinal
obstruction from meconium ileus, bronchiectasis, pancreatitis, and cirrhosis

◆ alpha-1 antitrypsin de ciency (better called protease inhibitor de ciency, as the inhibitor is non-
speci c), in which patients develop hepatitis and cirrhosis, and early-onset emphysema without the
usual risk factors.

X-linked (or sex-linked) conditions

These are disorders caused by an abnormality on the X chromosome. The Y chromosome carries little
genetic message: the SRY gene, genes for immunological functions, and genes which lay down calcium in
male animals’ teeth. Sex-linked diseases a ect males almost exclusively as they have no extra X to
compensate; heterozygous females are normal, while homozygous females are a ected.

If a woman who is a carrier has children with a normal man actuarially half of all sons would be a ected and
half of the daughters would be carriers. All of the daughters of a father who is a ected must be carriers. Sons
who do not have the disease cannot be carriers.

Examples of X-linked diseases include:

◆ haemophilia and Christmas disease as the result of de ciency or abnormality of factor VIII and factor
IX respectively. A ected men su er from intramuscular bleeding, haemarthrosis, and intracranial
bleeding. Undiagnosed, there is a risk of severe intraoperative haemorrhage. Until relatively recently a
common cause of death was hepatitis C and human immunode ciency virus (HIV) infections from
contaminated blood transfusions

◆ glucose-6-phosphate dehydrogenase de ciency, in which there is haemolysis caused by drugs such

as antimalarials, sulphonamides, aspirin, and dapsone

◆ fragile X syndrome, a rare condition but the commonest reason for inherited severe learning
disability. Of surgical importance is that these patients have very large testes that could present a
diagnostic problem unless the condition is recognized.

◆ red-green colour blindness, which can be of surgical importance when a surgeon is colour blind and is
unaware of the fact (red-green colour blindness is statistically commoner in consultant
histopathologists than would be expected by chance. This is unexplained).
Abnormalities of chromosome number

Trisomy 21, Downʼs syndrome

People with Down’s syndrome have three copies of chromosome 21 material, rather than the normal two, in
all or some cells. This may be as three distinct chromosomes identi able as 21, or by translocation of the 21
genetic material onto another chromosome. Chromosome banding and other techniques can be used to
clarify this. They can develop many diseases of surgical importance. The commonest include:

◆ increased susceptibility to infections

Downloaded from https://academic.oup.com/book/31816/chapter/266636047 by University of Sydney user on 25 September 2022

◆ increased risk of glue ear

◆ congenital heart defects: patent ductus arteriosus, ventricular septal defect, and atrial septal defect

◆ increased risk of neoplasia.

The three main mechanisms in the development of Down’s syndrome are non-disjunction, translocation,
and mosaicism. Almost all people with Down’s syndrome have the syndrome because of non-disjunction.
Their cells all have trisomy 21 with three identi able chromosomes. The extra copy is the result of non-
disjunction (failure of separation) of a pair of chromosomes during anaphase. This occurs during a meiotic
division in the formation of oocytes or spermatozoa. One daughter cell receives both copies of chromosome
21 and the other none. The gamete with the extra copy therefore has 24 chromosomes rather than the
normal 23 and is viable because 21 is very small. The gamete without a copy of chromosome 21 is non-viable.
When the gamete with the extra chromosome 21 is fertilized by a normal gamete from the other parent,
three copies are present in the resulting ovum. Non-disjunction is commoner in women but may occur in
both sexes: the prevalence of children with Down’s syndrome is higher when the father as well as the
mother is older.

Translocation of chromosome 21 material onto another autosome, such as chromosome 14, accounts for a
small proportion of cases (Figure 1.4.1.2). A normal parent can have absence of one chromosome 21 but one
elongated chromosome 14 carrying the missing translocated genes. This is called a balanced translocation.
The gametes of this parent will be of four types:

◆ one normal chromosome 14 and one normal chromosome 21—23 chromosomes altogether and
entirely normal

◆ one normal chromosome 14 and no chromosome 21 material—22 chromosomes altogether and non-
viable

◆ one abnormal chromosome 14 with 21 translocation and one normal chromosome 21—23
chromosomes but carrying twice the normal amount of chromosome 21 material

◆ one abnormal chromosome 14 with 21 translocation and no chromosome 21— 22 chromosomes

altogether but with the normal amount of chromosome 21 material.
Fig. 1.4.1.2

Downloaded from https://academic.oup.com/book/31816/chapter/266636047 by University of Sydney user on 25 September 2022

Translocation of chromosome 21.

Reproduced from David Lowe, Surgical Pathology Revision, Second Edition, Cambridge University Press, Cambridge, UK,
Copyright © 2006. Reprinted with permission.

One-quarter of the a ected parent’s gametes will have two copies of the genetic material of chromosome 21
(the third bullet point in the previous list). When this oocyte or spermatozoon joins with a normal
complementary gamete from the other parent, an ovum with three copies of chromosome 21 will result. One
in three of the surviving gestations will therefore be normal, one will have Down’s syndrome, and one a
balanced translocation that can transmit Down’s syndrome.

About 1 in 100 cases of Down’s syndrome are due to mosaicism. The ovum has a normal complement of
chromosomes but there is non-disjunction of chromosome 21 after the blastocyst starts to develop. Only a
proportion of cells will be a ected by the changes caused by mosaicism.

Abnormalities of sex chromosomes

In Turner’s syndrome, the genotype is X0 (X zero). The phenotypic e ects are numerous but only some are
of surgically importance. Those which are include:

◆ coarctation of the aorta

◆ short stature, important in the di erential diagnosis of dwar sm syndromes

 ◆ germ cell tumours in streak ovaries—the malformed ovaries may contain germ cells.

In Kleinfelter’s syndrome the genotype is XXY. The Y chromosome with its SRY sex determining region
induces testicular development and a male phenotype. Very rarely men with Kleinfelter’s syndrome are
XXXY or XXXXY. Surgically important features include small external genitalia and infertility, and bilateral
gynaecomastia with the risk of breast cancer that is the same as that of a woman.

Hermaphroditism and pseudohermaphroditism

Downloaded from https://academic.oup.com/book/31816/chapter/266636047 by University of Sydney user on 25 September 2022

True hermaphroditism is when a person has both ovarian and testicular tissue. This may be either together
in the same gonad or as a testis and a contralateral ovary. The karyotype is usually XX though a Y
chromosome or translocated Y chromosomal material may be found in some patients. When either of these
is present there is a higher risk of the patient developing teratoma, dysgerminoma, and other neoplasms.

Pseudohermaphroditism is when the gonads re ect the genotype but the phenotype is mismatched. For
example, a boy may have normal chromosomes and testes but ambiguous genitalia because of androgen
insensitivity or de ciency in conversion of testosterone to dihydrotestosterone; a chromosomally normal
girl may develop ambiguous genitalia from congenital adrenal hyperplasia.

Inflammation

The immune functions of in ammatory cells, related cytokines, and in ammatory mediators are given in
the later section on ‘Surgical immunology’. The general pathology aspects of acute and chronic
in ammation are dealt with here with speci c examples.

Acute inflammation
Acute in ammation has the time-honoured Celsian features of pain, heat, redness, and swelling and the
addition by Galen of variable loss of function. Some of these may be honoured in the breach rather than the
observance. An acutely in amed appendix is at core temperature and so cannot become hotter, and loss of
function of the appendix would be very di cult to determine. Indeed, whether Galen really did contribute
4
‘functio laesa’ or variable loss of function has been questioned. Descriptive terms such as brinous,
catarrhal, serous, and ulcerative acute in ammation are seldom used nowadays.

In acute in ammation there is a uid component and a cellular component. The uid component is
characteristically an exudate, but in some speci c acute in ammatory conditions such as lobar pneumonia
there is an outpouring of uid from the plasma through endothelial cells that remain intact, a transudate. A
transudate characteristically has a protein content of less than 30 g/L and a speci c gravity of less than
1.020. This usually forms because of an imbalance between hydrostatic pressures, oncotic pressures, and
surrounding tissue pressures resulting in a uid of low protein content, but can be initiated by
in ammation. An exudate is typically formed by an in ammatory process resulting in a uid of high protein
content traversing a damaged endothelial surface. An exudate characteristically has a protein content of
more than 30 g/L and a speci c gravity of more than 1.020.

Both of these processes but particularly exudation are initiated by macrophages already present at the site
of damage (such as by infection, burn, mechanical trauma, foreign bodies, or ionizing radiation) which
release in ammatory mediators that have chemotactic e ects on granulocytes and other macrophages,
vasodilator e ects, and stimulatory e ects on B lymphocytes to produce immunoglobulins. The cardinal
feature of many agents that cause acute in ammation is abscess formation though some, like streptococci,
cause spreading infection (cellulitis) without pus formation.

An abscess is a localized tissue collection of pus, characteristically bounded by granulation tissue (the term
‘pyogenic membrane’ is obsolete). If pus forms in a potential body cavity or hollow viscus like the pleura,
gall bladder, or subdural space it is an empyema. Pus is the product of both the exudative and cellular
processes of acute in ammation. In in ammation, the exudate consists mostly of water which contains
albumin, immunoglobulins, complement components, clotting cascade components, and other
in ammatory mediators. If the in ammation is caused by an infective organism, the solid phase would be
expected to consist of live and dead bacteria or other microorganisms; human cells which might be alive or

Downloaded from https://academic.oup.com/book/31816/chapter/266636047 by University of Sydney user on 25 September 2022

dead, including in ammatory cells, epithelial cells and connective tissue cells; and brin and neutrophil
extracellular trap material.

The natural history of an abscess is to discharge itself. The osmotic pressure in pus constantly increases
because albumin and other proteins are broken down by enzymes released by granulocytes and
macrophages, and uid is therefore drawn into the abscess. The pressure increase in time results in
discharge of the pus through a line of least resistance—through the skin or mucosa, into a body cavity or
hollow viscus, or along fascial lines.

Chronic inflammation
Chronic in ammation is de ned as in ammation continuing at the same time as attempts at healing. The
tissue changes may be non-speci c with a di use in ltrate of macrophages, lymphocytes, mast cells and
other in ammatory cells, with developing brosis, or it may be granulomatous. A granuloma in histological
terms is a localized, apparently expansile collection of macrophages (in immunological terms, it is a
collection of activated macrophages). Lymphocytes and caseous or other necrosis may be present but are
not part of the de nition, and the macrophages need not be epithelioid or form giant cells. Collections of
macrophages are normal in the sinuses of reactive lymph nodes (‘sinus histiocytosis’) but are not expansile.

Granulomatous diseases are classi ed as caused primarily by in ammation, which may be infective or non-
infective, or by a neoplastic process as part of the neoplasm or as a reaction to it. Organisms causing
infective granulomas include bacteria such as mycobacteria, Actinomyces, and Treponema; fungi such as
Aspergillus and Mucor; protozoa such as amoebae and Leishmania: and metazoa such as schistosomes and
ecchinococci. Non-infective in ammatory granulomas may form around particulate material like beryllium
and silica and other inorganic indigestible and foreign materials; they are also features of sarcoidosis,
rheumatoid arthritis, and Crohn’s disease. A granulomatous response can develop directly around tumour
cells, as in seminoma of testis, and severe reactive granulomatous lymphadenitis can be found in axillary
5
lymph nodes of patients with breast carcinoma in the absence of metastatic involvement.

Giant cells can be found in many in ammatory conditions. They are usually formed by fusion of
macrophages but lymphocytic and epithelial giant cells can occur. Macrophage giant cells include foreign
body multinucleate giant cells in granulomatous reactions around stitch, talc, or other foreign material,
which have haphazardly arranged nuclei, and Langhans giant cells in tuberculous infection, Crohn’s
disease, and sarcoidosis. These have nuclei in a ring or horseshoe and are derived from foreign body giant
cells, which reorganize their nuclei if they persist for over a month. Viruses can induce giant cell formation
by causing lymphocytes to fuse, as in the Warthin–Finkeldey giant cells of measles, or by infecting
epithelial cells and causing nuclear damage with multinucleation as seen in herpes simplex virus and
Cytomegalovirus (CMV) infections.
Destruction and healing

Cell damage by ionizing radiation

Ionizing radiation can be particulate or electromagnetic (which in current subatomic theory are the same).
It supplies enough energy to free an electron from an atom, so making it highly reactive. In some cases a
proton can be expelled, which also causes ionization. High-energy radiation such as γ-rays and X-rays are
ionizing but even lower-energy, lower-frequency radiation such as radio waves, infrared light, and laser
visible light when focused at very high intensity have enough energy to free electrons from tissues. Particles

Downloaded from https://academic.oup.com/book/31816/chapter/266636047 by University of Sydney user on 25 September 2022

such as α-particles (helium nuclei), β-particles (free electrons), and cosmic rays (which are really particles,
mostly free protons) are ionizing—in fact, any charged subatomic particle moving near the speed of light is
ionizing.

A cell or tissue exposed to ionizing radiation can be:

◆ unharmed

◆ impaired

• but able to repair and function normally

• but unable to function and dies, by necrosis or apoptosis.

A total-body instant dose of 100 000 roentgens (R) results in death within minutes; 10 000 R causes death in
hours from central nervous system (CNS) e ects; 1000 R causes death in weeks from pancytopenia and
6
gastrointestinal tract (GIT) bleeding. Less than 100 R is not fatal but can cause nausea and vomiting.

In general terms, rapidly dividing cells such as those of the bone marrow, mucosa of the alimentary system,
testis and skin (the so-called labile cells) are particularly radiosensitive, but other tissues which have few
mitoses normally, such as the lens of the eye, the thyroid, and the pituitary, are also relatively sensitive.
Stable cells divide slowly though the rate increases when there is tissue damage; these include cells in the
renal tubules, liver, and brous connective tissue. They are less sensitive to the direct e ects of ionizing
radiation but can su er from ischaemia or infarction if the radiation damages the tissues’ endothelial cells
and causes thrombosis. Permanent cells have very limited capacity to divide after the very early postnatal
period, and include muscle cells and neurons in the CNS and retina. They are the least radiosensitive but can
also su er because of radiation-induced thrombosis.

Diagnostic and therapeutic radiation in surgical practice

The absorbed dose is a measure of the likelihood that biochemical changes will be induced in di erent tissues
by ionizing radiation. It is expressed in milligrays (mGy), which is the energy absorbed by a given mass of
tissue. One Gy equals 100 rads.

The equivalent dose, expressed in millisieverts (mSv), is a measurement of the extent of tissue and cell
damage predicted from the absorbed dose, and so considers the type of ionizing radiation used—for a given
absorbed dose, di erent types and frequencies of ionizing radiation have di erent e ects and so are given a
di erent weighting factor. For diagnostic procedures the radiation used has only a small chance of harming
the tissues, and the absorbed dose is numerically identical to the equivalent dose. One Sv equals 100 rem.

The e ective dose is a measure of long-term e ects that might arise, and is also expressed in mSv. It is
calculated from data on the tissue type, the absorbed dose, and the sensitivity of each tissue to the e ects of
the radiation.
Free radicals
Free radicals are induced by the energy contributed by ionizing radiation and heat. A free radical is an atom,
ion, or molecule that has unpaired electrons or an open electron shell. They are highly reactive, able to
damage normal cell components, and also react with each other to form polymers or modi ed monomers.
Free radicals mostly comprise the reactive oxygen species, reactive nitrogen species, hydrogen free radicals,
and carbon free radicals which may be alkyl or aryl. They occur normally inside mitochondria and other
7
cellular organelles.

Oxygen free radicals include superoxide O2• (an O2 molecule with a missing electron) and peroxides. They

Downloaded from https://academic.oup.com/book/31816/chapter/266636047 by University of Sydney user on 25 September 2022

are a product of normal cellular metabolism and have an essential function in cell-to-cell signalling,
apoptosis, and in the killing of microorganisms. Macrophages in particular make large amounts of
superoxide with NADPH oxidase, used internally to kill bacteria and fungi in phagosomes. Superoxide reacts
physiologically with nitric oxide in blood vessels and elsewhere to limit its e ects on smooth muscle tone
and blood pressure. In animal species, free radicals are used for defence and procreation. The bombardier
beetle uses the energy from the peroxide reaction to re boiling liquid at its attacker. In the re y, a similar
reaction provides energy for photoluminescence which in re y larvae is a defence mechanism and in
re y adults attracts a mate.

Overproduction of free radicals results in damage to:

◆ DNA and RNA: there is abnormal cross-linking of DNA with formation of thymidine–thymidine (TT)
dimers, there may be base deletions that make nonsense or harmful sequences, and there may be
chain breaks that can be misrepaired to form translocations. If the damage is relatively mild and non-
fatal these errors may be replicated in daughter cells and exacerbated by further radiation exposure.
Damage to RNA is less harmful as messenger RNA is evanescent but there may be su cient damage to
microsomes to cause cell death

◆ proteins

◆ lipids

◆ enzymes.

Because of this damage, aerobic organisms including human beings require scavenging mechanisms to
destroy excess free radicals. These mechanisms may be intrinsic or extrinsic. Intrinsic protection against
free radicals is important in plasma and includes molecules of superoxide dismutase, catalase, glutathione
peroxidase, and uric acid. Extrinsic factors include vitamins C and E.

Embolus
An embolus is an abnormal mass of undissolved material that is carried in the bloodstream from one place
to another. There is no requirement for an embolus to have the capacity to impact: impaction is usual but
not essential to the de nition.8

Most emboli, about 95%, consist of thrombus, clot, or a mixture of both. When a thrombus occludes a vein
such as a deep vein of the leg, the blood ow stops and a clot forms in the column of blood proximal to the
thrombus, as far as the next communicating vein (the propagated clot). Clot retraction (because of platelet
contractile laments) occurs with shrinkage from the endothelium of the vein, so that dislodgement can
result in separation. Some of the thrombus would be attached to the clot and so the resulting embolus would
be of mixed thrombus and clot.8

Others materials that can embolize include:

 ◆ fat usually from fractured long bones in adults; rare causes of fat embolus include severe burns or soft
tissue injuries

◆ bone marrow from fractured long bones in children

◆ malignant tumour cells9

◆ lipid material from aortic atheroma

◆ gas, which might be:

Downloaded from https://academic.oup.com/book/31816/chapter/266636047 by University of Sydney user on 25 September 2022

• air from intravenous cannulae, neck veins disrupted by trauma or operative surgery, or dialysis

• carbon dioxide from fallopian tube or peritoneal insu ation

• nitrogen in caisson disease

◆ amniotic uid usually during parturition, which can cause disseminated intravascular coagulopathy
(DIC)

◆ microorganisms such as thrombus containing bacteria in infective endocarditis, and metazoa such as
schistosomes. In cadavers, diatoms can be found in the bone marrow which have embolized from the
lungs to the marrow, evidence of death by inhalation of water from streams and other natural water
masses

◆ foreign materials such as talc or chalk in intravenous drug abusers and plastics from medical
interventions

◆ normal cells: adrenal cortical cells pass through the wall of the adrenal vein into the circulation, and
trophoblast cells can embolize to the mother’s lungs in a normal pregnancy.

The consequences of embolization are dealt with in Chapter 5.7.

Ischaemia and infarction

Ischaemia (Greek iskaimos, stanching or stopping blood) is an abnormal reduction of the blood supply to or
drainage from an organ or tissue. Infarction (Latin farcire, to stu ) is the result of cessation of the blood
supply to or drainage from an organ or tissue. Both may have local causes, general causes, or both.

Local causes of ischaemia include:

◆ arterial obstruction by atheroma, thrombus, embolus, pressure from outside, and spasm

◆ venous obstruction by thrombus, pressure from mechanical abnormalities (such as strangulation of

hernia, torsion, or intussusception), and e ective obstruction by stasis from varicose veins

◆ capillary obstruction

◆ vasculitis from any cause

◆ small vessel obstruction in caisson disease with nitrogen bubbles, cryoglobulinaemia, sickle cell
disease, and frostbite, and from external pressures such as in decubitus ulcers.

General causes include:

◆ hypoxaemia: decreased cardiac output as a consequence of myocardial ischaemia, infarction, or heart

 block

◆ anaemia.

The extent of ischaemic damage in arterial obstruction depends on the tissues involved and their sensitivity
to hypoxia, and is in proportion to the:

◆ speed of onset

◆ degree of obstruction of the arterial lumen

Downloaded from https://academic.oup.com/book/31816/chapter/266636047 by University of Sydney user on 25 September 2022

◆ presence of collaterals and of disease in them

◆ level of oxygenation of the blood supplying the ischaemic tissue

◆ presence of concomitant heart failure

◆ state of the microcirculation of the tissue, as in diabetes mellitus.

Infarcts are classi ed as pale and dark (or white and red, which equate). In venous infarcts, the out ow of
blood is obstructed and the reason for the tissues becoming hyperaemic is obvious. If the infarcted tissue is
not constrained within a restricted space or by a capsule, the volume can increase to accommodate the
in ow of blood. This occurs in the small and large bowel and produces dark or red infarcts. In arterial
infarcts, the ischaemia caused by cessation of the incoming blood produces severe tissue hypoxia and
vasodilatation of the draining capillaries and veins, permitting back ow of blood into the a ected area. If
the organ has a brous capsule such as the kidney or spleen, the volume cannot change and so the pressure
must increase. This local increase in pressure pushes the capsule outwards slightly and forces blood out of
the area. The infarct is therefore pale or white with a hyperaemic rim of surviving non-infarcted tissue at
the edges; the shape is characteristically triangular on cross-section because of the area of supply of the
obstructed artery.

Necrosis
Necrosis is abnormal tissue death during life. It is energy independent, associated with in ammatory
changes, and usually results from factors outside the a ected cells. The three classical types are coagulative
or structured necrosis, colliquative or liquefactive necrosis, and caseous or unstructured necrosis.

In coagulative necrosis, the tissue architecture is preserved, as seen when a tissue is put into boiling water:
the proteins coagulate rapidly from the heat, the reticulin framework of the tissue is kept intact, and the
architecture is maintained as a consequence. Structured necrosis is seen in kidney, heart, and spleen and
can be easily recognized microscopically—the normal tissue components are present but the nuclei of the
necrotic cells undergo pyknosis (condensation and shrinkage), karyorrhexis (fragmentation), and
karyolysis (dispersal of chromatin) and so disappear.

Colliquative or liquefactive necrosis occurs in the CNS in tissues with cytoplasmic membranes rich in lipid.
Enzymes from macrophages and microglia ingest the lipid along with haemosiderin and lipofuscin, and
remove it. A cystic space containing liquid derived from plasma results. Colliquative necrosis may also be
found in the lung after suppurative in ammation with infection has been overcome by large numbers of
polymorphs.

Caseous necrosis is unstructured. It di ers histologically from coagulative necrosis as it is impossible to

identify the tissue a ected by the necrosis because its architecture is destroyed; it di ers from colliquative
necrosis as necrotic cells and cell debris (from macrophages and mycobacteria, typically) remain. This type
of necrosis is classical for mycobacterial infection but may also be found in orid fungal granulomas.

Speci c tissue types of necrosis include:

◆ fat necrosis, which may result from the chemical changes of high plasma concentrations of lipase and
amylase on adipose tissue, for example, in the skin. There is no signi cant in ammatory reaction but
because of the change in pH of the tissues, dystrophic calci cation can occur. In traumatic fat
necrosis, such as in the breast, there is a chronic in ammatory reaction with foreign-body giant cell
formation and phagocytosis of extracellular lipid

Downloaded from https://academic.oup.com/book/31816/chapter/266636047 by University of Sydney user on 25 September 2022

◆ dry gangrene is desiccation (mummi cation) of a tissue without infection, such as can occur in an
extremity of a diabetic patient

◆ wet gangrene is necrosis in which there is infection and digestion by enzymes from the
microorganisms and from polymorphs.

Autolysis, homolysis, and heterolysis

Autolysis is the degradation of a cell by activation of enzymes present in the a ected cell (self-digestion).
Autolysis occurs in the processes of necrosis and apoptosis, and is found at autopsy. Homolysis is
degradation of a cell by other cells of the same or similar type: for example, digestion of pancreatic exocrine
cells by proteases and lipases from adjacent damaged exocrine cells, or digestion of macrophages by
enzymes from other macrophages. Heterolysis is degradation of a cell by enzymes from a di erent cell line,
such as digestion of epithelial cells by enzymes from neutrophils and macrophages in in ammation.

Malnutrition
Malnutrition is the failure to achieve proper nutrition. This failure may be due to undernutrition or
overnutrition, obesity being the commonest type of malnutrition in the Western world.

Classification of malnutrition
Undernutrition may be classi ed as cases that result from inadequate availability of food or from inability to
digest and absorb food and its components. Too little food results in starvation, called marasmus (Greek
marasmus, to wither or waste away) in some parts of the world. Too little protein in food causes protein-
energy malnutrition, called kwashiorkor (Ghanaian kwasioko, given as ‘the jealous one’) in parts of Africa—
the name derives from malnutrition in a young child who must be weaned from the breast when the next
baby arrives.

Vitamin de ciency in starvation manifests as lack of water-soluble vitamins such as the vitamin B series
(except vitamin B12), folate, and vitamin C as body stores are small. Large quantities of the fat-soluble
vitamins (vitamins A, D, E, and K) and of vitamin B12 are stored in the liver and take years to become
depleted. Iron, iodine, and trace metals eventually become depleted. All of these have severe implications for
wound healing and infection risk.

Food might be available but the patient is unable to utilize it adequately. This might be because of chronic
disease of the alimentary system such as malabsorption, increased intestinal transit time, and infections;
from chronic renal failure, from malignancy, and other diseases that cause anorexia; and from drug
addiction. In a small number of cases food may be plentiful but the lifestyle choice of people not to eat
certain components of food leave them open to undernutrition.
Overnutrition may be classi ed as being from too much food of all kinds, too much speci c ingestion of fats
or vitamins, too little exercise, and peculiar diets. Vitamins that are toxic in high quantities (such as may be
ingested in tablet form by compulsive health-driven people) include vitamin A, niacin (vitamin B3),
2
pyridoxine (vitamin B6), and vitamin D. Obesity is de ned as a body mass index (BMI) of 30 kg/m or above,
2
and morbid obesity as a BMI of 40 kg/m or above.

Risk of malnutrition
People who are at risk of malnutrition can be classi ed by age group, the presence of relevant acquired
diseases, and people living in certain social conditions. In relation to age groups:

Downloaded from https://academic.oup.com/book/31816/chapter/266636047 by University of Sydney user on 25 September 2022

◆ neonates may have vitamin K de ciency, and vitamin B12 de ciency may develop in breastfed babies
of vegans

◆ children on an inadequate diet may develop folate, vitamin A, vitamin C, iron, copper, and zinc
de ciencies

◆ pregnant and lactating women may become folate de cient if not supplemented, and if there is
excessive alcohol intake may develop magnesium, zinc, and thiamine (vitamin B1) de ciencies

◆ the elderly may develop osteoporosis from relative calcium de ciency and lack of exercise;
osteomalacia from lack of sunlight exposure and dietary de ciency of vitamin D; and iron de ciency
from an inadequate intake possibly related to poverty.

Patients of any age with chronic diseases:

◆ patients with potential or chronic diseases from living in areas of famine or extreme poverty

◆ patients who have had gastrectomy or excision of the terminal ileum and related operations

◆ patients with AIDS

◆ patients with drug dependencies including alcohol.

People on unusual diets:

◆ vegetarians may develop iron de ciency

◆ vegans may develop vitamin B12 de ciency and calcium, iron, and zinc intake tend to be low

◆ people on very low-calorie diets

◆ people in societies in which excessive consumption is usual.

Overnutrition is of surgical importance because obese patients may su er dehiscence of abdominal wounds,
ventral herniation, and deep vein thrombosis. They are also at increased risk of impaired respiratory
function because of forced elevation of the diaphragm from the upwards force of the abdominal contents.

Undernutrition can lead to poor wound healing, iron and megaloblastic anaemias and impaired immunity
with a tendency to pulmonary and other infections. The hypoproteinaemia and risk of infection also
10
contribute to ascites.
Healing by resolution and repair
Resolution is the process of healing by replacement of dead or damaged tissue by the functional tissue
normally found at that site. It occurs especially in partial thickness loss of an epithelium (an erosion, see
‘Erosion and ulceration’) and in bone marrow. There is no (or almost no) brosis in resolution. Repair is the
process of healing by replacement of dead or damaged tissue by collagen or glial bres which completely or
partially ll the defect but have no specialized function. Repair occurs where there is full thickness loss of an
epithelial surface (an ulcer, see ‘Erosion and ulceration’), and in solid organs such as the liver when the
capacity for resolution is exceeded.

Downloaded from https://academic.oup.com/book/31816/chapter/266636047 by University of Sydney user on 25 September 2022

Fibrosis is the general repair process in the body, in which tropocollagen is secreted by broblasts and
polymerizes into a linear structure with a repeat o set of three tropocollagen molecules to form collagen.
Collagen then contracts to reduce the damaged area. Contraction usually is biologically bene cial but can
11
result in gross scarring, distortion of skin and joints, arthrodesis, and dis gurement.

Gliosis occurs in the CNS. Astrocytes (Greek astron, a star) are the principal source of glial brillary acidic
protein (Greek glia, glue) that supports the cytoskeleton of astrocytes as they elongate and complicate their
pseudopodia to form a network that lls in the potential space of degenerating neurons. The bene t of
gliosis over brosis is that gliosis does not contract; brosis in the CNS would cause distortion and possibly
epileptogenic foci and blockage of cerebrospinal uid (CSF) ow.

Erosion and ulceration

An erosion is a partial loss of an epithelial surface which heals by resolution. By de nition, an erosion can
occur only in a strati ed epithelium—simple squamous or columnar epithelial can undergo only ulceration.
An ulcer is a full-thickness loss of epithelium which heals by repair; there may be resolution as well, or not.

Causes of both include in ammation from an extrinsic agent such as aspirin and other drugs; physical
damage from oesophagogastroduodenoscopy, colonoscopy, and radiotherapy; and external pressure as in
decubitus ulcers. Intrinsic causes include peptic acid imbalance; infections such as schistosomiasis and
amoebiasis; idiopathic in ammatory conditions such as ulcerative colitis and Crohn’s disease; ischaemia;
and the development of neoplasia.

The rate of healing of an erosion and an ulcer is in uenced by the persistence of the causative agent. There
may be infection of the ulcerated site secondarily, such as with skin ulcers; complications of ulceration,
such as peritonitis and pancreatitis; development of carcinoma in the ulcer, especially in chronic ulcers;
immunosuppression from any cause, such as diabetes mellitus, viral infections, and malignancy; and
malnutrition.

Organization, granulation tissue, and wound healing

Organization is the process by which material such as clot, thrombus, or pus is transformed into organic,
living tissue. Replacement of the inanimate material is characteristically by granulation tissue, which is
unspecialized but responsive to the growth control factors of the body. Granulation tissue has three
components: proliferating capillary buds, broblasts, and macrophages. It is an important part of healing
but has little protection against chemical injury or physical damage by trauma or ionizing radiation; it is,
though, very resistant to infection. There can be deleterious e ects when granulation tissue persists
chronically because of the lytic enzymes secreted by macrophages, which can cause joint damage in patients
such as those with rheumatoid arthritis. Granulation tissue characteristically lines sinuses and stulas.
Sinuses and fistulas
A pathological sinus (Latin sinus, a hole or bay) is a passage from a focus of in ammation (usually caused by
infection, though sometimes by neoplasia or trama) in deep tissues. This is to an epithelial surface.
Examples include a skin sinus in chronic osteomyelitis and a pilonidal sinus. Sinuses are usually lined by
granulation tissue but can become lined by squamous cell carcinoma (SCC), as in a Marjolin’s ulcer in
osteomyelitis.

A stula is an abnormal communication between two epithelial surfaces, also usually lined by granulation
tissue. The de nition of an epithelial surface in this de nition subsumes mesothelial and endothelial

Downloaded from https://academic.oup.com/book/31816/chapter/266636047 by University of Sydney user on 25 September 2022

surfaces. The length of the stula is immaterial: there are very short anal stulas and long gastroenteric
stulas. Examples include anorectal stulas, enteroenteric stulas between two parts of the small bowel,
enterocolic, enterovesical, enterocutaneous, and gastroenteric stulas. Fistulas are caused by:

◆ in ammatory conditions such as Crohn’s disease and diverticulitis

◆ necrosis in a carcinoma that has grown between two epithelial surfaces, such as the vagina and
rectum or trachea and oesophagus, or by a sarcoma that has bridged two epithelial surfaces such the
pleura and lung

◆ iatrogenic interventions, such as operative surgery, radiotherapy, and insertion of venous lines.
Fistulas are abnormal but not necessarily undesirable—arteriovenous stula, colostomy, ileostomy,
and tracheostomy can be therapeutic.

Factors that determine the rate of healing of a sinus or stula can be local and systemic. Local factors
include:

◆ continuation of the causative event, such as osteomyelitis or malignancy

◆ the presence of foreign material

◆ the presence of infection

◆ passage of material through the track such as bowel contents or pus

◆ the width of the track

◆ reduced local blood supply or drainage

◆ epithelialization of the track

◆ malignant change.

Systemic factors that have a bearing on healing include the general state of nutrition of the patient and
whether there is immunosuppression, diabetes mellitus, vitamin de ciency, or radiotherapy damage.
Ascites
Ascites (Greek askos, a bag) is the accumulation of an abnormal amount of free uid in the peritoneal cavity.
This can be an exudate, which is almost always in ammatory to some extent, or a transudate. In ammatory
causes of protein leakage include peritonitis, pancreatitis, widespread carcinoma, and uraemia. A
transudate can be caused by hypoproteinaemia from starvation, nephrotic syndrome, liver failure, and
protein-losing enteropathy. It can also be the result of hydrostatic changes from right heart failure,
cirrhosis, Budd–Chiari syndrome, and thoracic duct obstruction. Metabolic changes such as secondary
hyperaldosteronism in liver failure and hypothyroidism can also contribute.

Downloaded from https://academic.oup.com/book/31816/chapter/266636047 by University of Sydney user on 25 September 2022

Investigations helpful in determining the cause of the ascites include microbiology for microscopy for
bacteria, and culture and sensitivity; cytology examination for red cells, white cells, and malignant cells that
might be carcinoma or lymphoma; and biochemistry for protein content and amylase.

First- and second-intention wound healing

First-intention wound healing refers to the repair process in clean wounds without tissue loss that can be
repaired by suturing and heal well classically with only small amounts of brosis. Healing by second
intention usually involves tissue loss or wounds that have intentionally been left open because of infection.
The granulation tissue that forms to ll the defect will heal by brosis, but this can be considerable and
result in contractures and cosmetic problems.

Taking a skin wound as an example, the stages of healing begin with clot formation. If there is healing by
rst intention, squamous cells from the wound edges migrate by amoeboid movement to cover the clot.
Keratinocytes in damaged skin have surface integrins that are not present in intact skin; these bind to
bronectin, which facilitates migration. In the dermis there is an in ltrate of in ammatory cells, rst
polymorphs and then macrophages, which secrete chemokines and phagocytose debris. Fibroblasts secrete
tropocollagen which polymerizes into collagen and restores tensile strength (in tissues other than skin, this
varies from weak to almost normal tissue strength). At the same time there is vascularization of the scar and
gradual contraction of myo broblasts to reduce its size.

There are several cytokine and growth factor systems involved in wound healing. Cytokines include
modulators of macrophages and lymphocytes, interferons, and interleukins. Growth factors include:

◆ epidermal growth factor (EGF) which accelerates the rate of epidermal and dermal regeneration. This
family of molecules is found in external secretions such as saliva and tears, internal secretions in the
upper GIT, and in platelet granules. Transforming growth factor alpha is part of the EGF family

◆ platelet-derived growth factor (PDGF) which has a signi cant role in angiogenesis; vascular
endothelial growth factor is part of the PDGF family

◆ transforming growth factor beta, which controls proliferation and di erentiation of most cells and
acts as a chemoattractant.
Classification of wounds in relation to surgical site contamination

Clean wounds
Clean surgical wounds have no signi cant signs of in ammation and do not breach the mucosae of the
respiratory, gastrointestinal, or urogenital tracts. Thyroid and breast operations, elective orthopaedic
surgery, and vascular surgery operations would be considered clean. This does not mean that prophylactic
antibiotics are inappropriate—in the last two cases prophylaxis is important as the consequences of
infection would be severe.

Downloaded from https://academic.oup.com/book/31816/chapter/266636047 by University of Sydney user on 25 September 2022

Clean contaminated wounds
These are clean wounds that have a greater risk of infection. Wounds that breach the lumen of the
respiratory, gastrointestinal, or urogenital tracts (including gynaecological operations) are considered to be
clean contaminated. Prophylactic antibiotics are appropriate.

Contaminated wounds
Wounds are considered to be contaminated if there is spillage of GIT contents (especially of the large bowel)
into the site; when there are in amed or infected tissues around the operative site; or when there has been a
penetrating injury to the body. Prophylactic antibiotics are inappropriate as therapeutic antibiotics should
be given.

Dirty wounds
Dirty surgical wounds are those with pus or faecal material, traumatic wounds when treatment is delayed,
and wounds in which a foreign body is present. Therapeutic antibiotics are given.

Scars

A scar results from healing by repair in which there is deposition of brous tissue or in the CNS, glial tissue.
Scars are generally more orid in young adults; the elderly form scars that have less brosis but heal at the
same rate as young people. The person’s skin type is related to the degree of scarring—those with skin types
IV and VI with darker pigmentation tend to have more orid scars. Scarring is often worse over the deltoid
and sternal areas, whereas in the conjunctivae and oral tissues can be minimal.

Classification of scars

Typical scar
A typical scar is the type most often encountered after elective abdominal, orthopaedic, thoracic, and skin
operations. The healing is by rst intention and the scar is clearly visible as a thin red line which fades to
white.
Minimal scar
A minimal scar is the result of meticulous apposition of the wound edges, aimed for by reconstructive and
aesthetic surgeons. The scar is visible as a faint line which may become unapparent with time.

Wide scar
Widening or sideways stretching of a scar can occur over joints such as the knee and shoulder. It begins
about a month after operation, when the scar becomes increasingly pale and thin. Wide scars are usually
asymptomatic but are cosmetically undesirable.

Downloaded from https://academic.oup.com/book/31816/chapter/266636047 by University of Sydney user on 25 September 2022

Atrophic scar
An atrophic scar is usually small, at and depressed. They are commonly seen after chicken pox and
scarring acne.

Hypertrophic scar
A hypertrophic scar is raised but remains within the boundaries of the scar before the growth excess (which
is in fact hyperplasia rather than hypertrophy) occurrs. They can be in amed, itchy, and painful but often
regress spontaneously. Intralesional injection of corticosteroid can speed regression.

Keloid scar
A keloid scar (Greek chele, like a crab’s claw) is raised like a hypertrophic scar but extends beyond the
margins of the original scar before the development of keloid change. Keloid scars can a ect any site but are
found especially on the central sternal area (‘necklace area’), over the deltoids, and on the ear lobes after
piercings. They continue to grow slowly and rarely regress spontaneously. Treatment is di cult;
intralesional cortisone injections are usually ine ective and simple excision is followed by recurrence.

Scar contracture
A distorted or contracted scar classically crosses a skin crease or joint at right angles. They are usually
hypertrophic and disabling or dysfunctional. Burns involving joints commonly heal with some degree of
contracture.

Predictors of abnormally severe scarring

These include aspects relating to severity, site, and predisposition:

◆ severe symptoms

◆ large amount of tissue loss

◆ large size of scar

◆ continuing in ammation

◆ poor response to treatment

◆ scars in speci c anatomical locations, as above

 ◆ positive family history of severe scarring

◆ previous abnormal scarring in the same or other sites.

Complications of skin scars

Scars may be unsightly and be the root of psychosocial problems, and can cause physical symptoms and
signs:

◆ tenderness, pain, and pruritus (with or without formation of a traumatic neuroma)

Downloaded from https://academic.oup.com/book/31816/chapter/266636047 by University of Sydney user on 25 September 2022

◆ physical deformities

◆ compression of nerves and vessels

◆ problems of anxiety and depression with sleep disturbance, loss of self-esteem, and post-traumatic
stress.

Surgical immunology

Immunology is an essential study for surgeons. Changes in our knowledge of immunology happen weekly.
12
The classical division into humoral and cellular events broadly still holds.

The complement system

The complement cascade starts with cleavage of the C3 component by several mechanisms, including C2b4b
complex, antigen/antibody complexes, plasmin, microbial membranes, and polysaccharides. C3 is the most
abundant of the complement components in plasma. C3a is an anaphylatoxin and to some extent a
chemotactic factor (though not as active as C5a). C3a is further split into more fragments which activate B
lymphocytes. C3b is an opsonin and, with C2b4b complex, splits C5 into its components.

Component C5a is an anaphylatoxin, is a strong chemotactic factor, and activates macrophages to secrete
interleukin (IL)-5 which is also chemotactic. C5b joins with and anchors C6, C7, C8, and C9 to make the nal
large component that causes membrane damage; components C7, C8, and C9 have hydrophobic sites that
breach the cell membrane, and C9 polymerizes around the hole to keep it open.

Bacterial cells are prokaryotes without a de ned nucleus, and so they have very little capacity to repair
membrane damage. A single hole results in the death of the bacterium because the osmotic pressure within
draws in extracellular uid which disrupts the bacterial wall. Human cells damaged by complement have
much more likelihood of survival as their nuclei can generate more membrane proteins and so they can
repair holes quickly.
Immunoglobulins
There are ve classes of immunoglobulins: IgG, IgA, IgM, IgD, and IgE in order of abundance in plasma.
Each has a basic unit of two light chains and two heavy chains. The two light chain are identical to each
other, as are the two heavy chains; both chains have variable regions of the same size and constant regions
of di erent sizes. Two or more of these basic units can be linked to form IgA and IgM molecules. The light
chains are lambda and mu chains, shared among all of the ve classes, and so are not de ning. The heavy
chains are speci c for the classes. The binding sites are clonal and highly speci c for one or more sites on
the stimulatory antigen. The heavy chains forming the stem of the Y structure have binding sites for
complement, and on IgG have sites for placental transfer. Both of these function only when the antigen-

Downloaded from https://academic.oup.com/book/31816/chapter/266636047 by University of Sydney user on 25 September 2022

binding sites on the arms of the Y are occupied.

IgG is the most prevalent immunoglobulin, found in the plasma (75–80% of all immunoglobulins) and the
tissues. It is composed of one basic Y unit. Its main functions are opsonization and complement activation—
macrophages, polymorphs, and some lymphocytes can internalize IgG and so it can act as an opsonin.
Cross-linkage of IgG molecules with precipitation is unusual. There is a rise in IgG in all infections in non-
compromised patients, in rheumatoid arthritis, and in IgG myeloma.

IgA accounts for about 10% of plasma immunoglobulin. In the plasma, the molecule is a monomer, and only
after attachment of the J chain does it dimerize. IgA is produced by plasma cells in the lamina propria of
mucosae and elsewhere adjacent to other surfaces. It binds to Ig receptors on the basement membrane
aspect of epithelial cells and is taken inside them by endocytosis. The J chain is also made in plasma cells
and links two monomers of IgA to form the typical dimer. The secretory component is synthetized by
epithelial cells in the mucosa and it is this extra chain which permits transport through the epithelium. It
also confers some resistance to degradation by enzymes in mucus, tears, colostrum, saliva, and other
secretions. IgA does not x complement unless it is aggregated. It can also bind to polymorphs and some
lymphocytes, and there are increased plasma concentrations in chronic infection, cirrhosis, rheumatoid
arthritis, and IgA myeloma.

The pentamer IgM is the largest immunoglobulin. It is the immunoglobulin that rises quickest after an
antigen challenge, and so can be used to monitor the acute phase of a disease. In the fetus, IgM is the rst
immunoglobulin to be made and also the rst synthesized when a B lymphocyte is stimulated by an antigen
to become a plasma cell. The ve-unit structure cross-links between antigens and between other IgM
molecules to form large polymers that do not enter tissues well. The pentamer itself is not a good opsonin,
though it is good at xing complement which acts as an opsonin. IgM increased in infections including
malaria, in rheumatoid arthritis, and in Waldenström’s macroglobulinaemia. IgM myeloma accounts for
only 0.5% of myeloma types.

IgD levels are increased in chronic infections and IgD myeloma, which accounts for 2% of all myeloma
types. The precise function of IgD is unknown.

Mast cells carry monomeric IgE molecules on their surfaces attached by their heavy chains. When two or
more IgE units are cross-linked by a suitable antigen, the mast cell is triggered to degranulate; attachment
to only one IgE does not trigger histamine, bradykinin, and heparin release. Degranulation of mast cells
occurs principally in type I hypersensitivity reactions and results in atopy, asthma, and anaphylactic shock.
IgE is the rarest type of myeloma.
Lymphocytes
Helper T cells are CD4 positive and bind to major histocompatibility complex (MHC) class II sites principally
on macrophages and B cells. They are the most important cells in adaptive immunity. They secrete cytokines
that help to change B cells into memory B cells and mature into plasma cells, and they modulate the activity
of cytotoxic T cells and macrophages. Helper T cells are activated by antigen-presenting cells like
macrophages and dendritic cells.

Cytotoxic T cells are CD8 positive; they bind to MHC class I targets on all nucleated cells, and are able to
destroy virus infected cells and some tumour cells. The cytotoxic T cell binds to an infected cell, bores a

Downloaded from https://academic.oup.com/book/31816/chapter/266636047 by University of Sydney user on 25 September 2022

microscopic hole in the membrane with the enzyme perforin, and injects enzymes from its cytoplasmic
granules, the so-called granzymes. These damage mitochondria and other structures in the infected cell and
activate that cell’s own cytoplasmic enzymes, which then break down DNA and induce apoptosis.

There are three other T cells of particular signi cance. Memory T cells can be CD4 or CD8 positive and
multiply on contact only with recognized antigens. Regulatory T cells, which were called suppressor T cells,
are CD4 positive; they inhibit T-cell function at the end of an immune reaction. Natural killer T cells
recognize abnormal glycolipid moieties on cells which are seen as antigenic without previous sensitization.
They secrete interferon gamma, IL-4, and other interleukins, and tumour necrosis factor alpha (TNF-α), all
of which contribute to tumour cell lysis.

Natural killer cells are also part of the innate system but have no T-cell or B-cell markers. They have
cytoplasmic granules containing enzymes which make holes in the target cell as do the cytotoxic T cells of
the adaptive immune system; natural killer cells can develop adaptive memory in some conditions.

Except for one notable exception, T cells are unable to recognize antigens unless they are presented by
another cell type, such as macrophages, dendritic cells, and B lymphocytes. The exception is the so-called
superantigen family, produced by viruses, bacteria, and other organisms. Superantigens induce polyclonal
T-lymphocyte proliferation and release of large quantities of cytokines which activate macrophages. These
produce their own range of cytokines including TNF-α which, at the very high levels involved, can result in
shock and multiple organ failure.

Cytokines
Cytokines are signalling molecules that modulate the humoral immune response (such as several of the
interleukins) or the cellular immune response (tumour growth factor beta and interferon gamma), or both.
They are small proteins soluble in plasma and interstitial uid. Their e ects are to stimulate proliferation of
in ammatory cells, to make them secrete their own range of cytokines, They also stimulate growth of
epithelial cells (as does insulin-like growth factor 1, which can lead to colonic carcinoma in patients with
acromegaly) and cause the liver to secrete acute phase proteins such as C-reactive protein and serum
amyloid A (SAA) protein (principally by IL-1 and IL-6 from macrophages). Chemokines are cytokines that
are chemotactic.

Acute phase proteins

Acute phase proteins modulate the in ammatory response. C-reactive protein and SAA protein are
opsonins; ferritin, haptoglobin, and caeruloplasmin sequestrate iron and prevent its use by
microorganisms. C-reactive protein was named for its reaction with the C polysaccharide of the wall of
Streptococcus pneumoniae.
Macrophages
Macrophage is the generic term for the group of large phagocytic cells that have a part in the innate and
adaptive immune systems. The term includes the monocytes in the blood, histiocytes found in almost all
tissues, microglia in the CNS, Kup er cells in the liver, and osteoclasts in bone. Macrophage have several
functions, including migration, phagocytosis, digestion, antigen presentation, fusion to form multinucleate
giant cells, metabolism of vitamin D, and secretion.

Macrophage functions include:

Downloaded from https://academic.oup.com/book/31816/chapter/266636047 by University of Sydney user on 25 September 2022

◆ migration in response to cytokines

◆ phagocytosis assisted by opsonization by immunoglobulins, complement, and acute phase proteins

◆ destruction of microorganisms and digestion by enzymes and peroxides (‘respiratory burst’)

◆ multinucleate giant cell formation if the antigen is a particle too large for one macrophage to engulf or
if it is indigestible

◆ antigen presentation to other cells in the immune system, predominantly helper T cells

◆ secretion of interleukins, prostaglandins, leukotrienes, transforming growth factors, and tumour

necrosis factors

◆ metabolism of vitamin D.

Polymorphonuclear leucocytes or granulocyte

Granulocytes are formed from bone marrow stem cells which di erentiate into myeloid-erythroid
progenitor cells and common lymphoid progenitor cells. The rst di erentiate further into myeloblast,
megakaryocyte, and erythrocyte precursor cell lines. The myeloblasts mature by two main sequences:
granulocyte-precursor maturation into mature neutrophils, basophils, and eosinophils; and monocyte-
precursors which mature into macrophages and dendritic cells.

Neutrophils
Neutrophils are found in blood and tissues. They account for about 60% of white cells in the circulation,
9
about 5 × 10 neutrophils/L of whole blood. They have a life of 5–6 days, and once neutrophils leave the
circulation they do not return. They are larger than red cells at about 12 μm in diameter (a red cell is 7 μm in
diameter) and have polylobate nuclei with three to ve segments. The number of lobes increases with the
age of the cell and becomes particularly high in vitamin B12 de ciency.

Neutrophils are primarily phagocytic, especially of opsonized bacteria and other antigens. They secrete
proteins that recruit macrophages and others that kill bacteria by damaging their cell walls directly and by
creating free radicals around the organisms. A recently discovered further function is that neutrophils,
when they die, release DNA and proteases that trap and kill bacteria in blood vessels without phagocytosis,
so-called neutrophil extracellular traps (NETs).

Neutrophils and endothelial cells have been known to interact for some time. Adhesion molecules that bind
to neutrophils are present on endothelial cell membranes, and the endothelial lamentous protein actin
controls diapedesis. Intercellular adhesion molecules and vascular cell adhesion molecules on endothelium
and in vascular smooth muscle have been correlated with the possible damage caused by neutrophils in
atheroma and transplant vasculopathy. After margination and attachment, neutrophils take about 30
minutes to push through gaps between endothelial cells, force them apart, and move through the
thixotropic basement membrane collagen (a thixotropic material behaves as a solid at rest but as a liquid
when moved, like some non-drip paints). They then connect with smooth muscle cells in the vessel wall,
move into the extracellular matrix and follow chemotactic signals to the speci c site of injury.

Eosinophils
Eosinophils account for about 7% of granulocytes in the blood. Their main function is secretory rather than
phagocytic, especially attacking metazoan parasites such as helminths (Greek helmins, an intestinal worm).
These include nematodes, cestodes, and trematodes such as schistosomes. The secretory granules are

Downloaded from https://academic.oup.com/book/31816/chapter/266636047 by University of Sydney user on 25 September 2022

strongly eosinophilic, and contain major basic protein, eosinophil cationic protein, and eosinophil-derived
neurotoxin. These kill parasites and also induce apoptosis in human cells—there is evidence that malignant
tumours with a dense tissue in ltration of eosinophils have a better prognosis than those without.
Eosinophils are also antigen-presenting cells and interact with T-helper lymphocytes, B lymphocytes, and
other granulocytes; for example, basophils secrete IL-5 which stimulates eosinophil growth and
development.

Basophils
Basophils form about 0.1% of circulating granulocytes; the circulating numbers are increased in asthma and
other allergies, lymphomas and leukaemias, haemolytic anaemia, Crohn’s disease, and hypothyroidism.
Activation can be by surface IgE binding to antigen and by complement component C5a. Basophil granules
release histamine, heparin, and chondroitin, and proteolytic enzymes such as lipases and elastase.
Basophils also secrete lipid mediators like leukotrienes, and several cytokines including IL-4, important in
the development of allergies.

Hypersensitivity reactions
Hypersensitivity is generally classi ed into type I–IV hypersensitivity reactions. Autoimmune interactions
against aspects of the cell membrane speci cally, such as against hormone and other receptors, have been
put into a separate category, type V. These receptors can be stimulated because the antibody mimics the
e ects of the hormone cognate with the receptor, or they can be blocked because the binding of a ligand is
prevented. Examples include Graves’ disease and myasthenia gravis respectively. Many people regard this
cell membrane e ect to be encompassed by type II hypersensitivity rather than being a separate type of its
own, though there is no de ned cytotoxic e ect as in classical type II.

Type I hypersensitivity begins with linkage of two IgE molecules on a mast cell by an antigen, which results
in arachidonic acid breakdown products being formed. Prostaglandins and leukotrienes cause release of
mast cell contents such as 5-hydroxytryptamine, histamine, heparin, and chemokines from eosinophils.
Diseases from this type of hypersensitivity include asthma, allergic rhinitis, atopic eczema, and
gastrointestinal e ects such as eosinophilic gastroenteropathy in which there is dysphagia, abnormal
motility, and abdominal pain.

In a type II hypersensitivity reaction, an abnormal antibody is stimulated to a normal tissue component.

This can happen spontaneously or via a hapten. A hapten (Greek apteo, to fasten) is a small molecule that is
not intrinsically antigenic but that can react with, usually, a larger molecule such as a protein. This protein
would not itself normally stimulate antibodies but the attachment to it of a hapten increases its antigenicity
several-fold. The enhanced antigenicity is accounted for by activation of B lymphocytes and the production
by plasma cells of immunoglobulins against the hapten, and by recognition of the now-abnormal carrier of
the hapten by helper T lymphocytes.
The abnormal antibody circulates in the plasma and reacts speci cally against a component such as the cell
membrane or a cytoplasmic component of the target cell. Cell death is by phagocytosis by macrophages with
or without complement activation, or by destruction by natural killer T cells, or both. Diseases related to
type II hypersensitivity include complement-mediated haemolysis as in autoimmune haemolysis and blood
transfusion reactions, and drug interactions that cause immune reactions against red cells and platelets.

A type III hypersensitivity reaction involves the formation of intermediate-sized immune complexes that
activate complement and platelets. These stimulate tissue damage from ischaemia from thrombus
formation, membrane attack complexes, and enzyme release from in ammatory cells. The large immune
complexes are removed by macrophages and small complexes are ltered out by the glomeruli. Only

Downloaded from https://academic.oup.com/book/31816/chapter/266636047 by University of Sydney user on 25 September 2022

intermediate ones cause disease and circulate (serum sickness) or are found in tissues and cause disease
such as systemic lupus erythematosus (SLE).

A type IV hypersensitivity reaction is characteristically the tissue injury associated with granuloma
formation and T-lymphocyte reactions to microorganisms such as mycobacteria, fungi, and other
organisms. Organ transplant rejection has a type IV hypersensitivity component. The tissue reaction to
stitch material, other implanted surgical objects, beryllium, nickel, and many other chronic irritants is also
type IV.

Autoimmune diseases
Autoimmune diseases can be caused by humoral or cell-mediated mechanisms though the prime mover
appears to be the helper T lymphocyte, which mediates B-lymphocyte production of antibodies and
cytotoxic T-lymphocyte destruction of cells. It may be speci c or non-speci c. Speci c examples include
the development of antibodies against:

◆ thyroid-stimulating hormone (TSH) receptors on thyroid follicle cells in Graves’ disease resulting in
stimulation

◆ thyroid peroxidase, thyroglobulin, and TSH receptors with helper T-lymphocyte activation and
cytotoxic T lymphocyte destruction of follicle cells in Hashimoto’s thyroiditis. Transient
hyperthyroidism is caused by release of stored T4 from thyroglobulin from damaged follicles rather
than by TSH receptor stimulation

◆ intrinsic factor in gastric parietal cells in pernicious anaemia

◆ acetylcholine receptors at the postsynaptic neuromuscular junction in myasthenia gravis

◆ mature platelets in idiopathic thrombocytopenic purpura (megakaryocytes in the bone marrow are
normal).

Non-speci c examples of autoimmune diseases include the development of antibodies against:

◆ IgG in rheumatoid arthritis, of two types: there are IgM antibodies against IgG, which are large and
cannot leave the plasma so are unlikely to cause tissue e ects; and IgG antibodies against IgG (they
bind to themselves) which do leave the bloodstream and are probably more important in disease

◆ double-stranded DNA, histones, and other nuclear antigens in SLE, and against single-stranded DNA
in some patients with discoid lupus erythematosus

◆ smooth muscle in chronic active hepatitis: there is an overlap with primary biliary cirrhosis,
depending on the class of immunoglobulin—IgG class predominates in chronic active hepatitis and
IgM smooth muscle antibodies predominate in primary biliary cirrhosis
 ◆ pyruvate dehydrogenase in mitochondria and nuclear components in primary biliary cirrhosis.

Immunization
Immunity can be induced by active and passive means. Each of these can be achieved naturally and by
medical intervention. Natural active immunity follows infection by an organism that stimulates a reliable
immunological memory. Arti cial active immunity is achieved by vaccination. Natural passive immunity is
conferred on the fetus by placental transfer of IgG, which lasts for the rst few months of life, and arti cial
passive immunity by injection of preformed antibody from human donors or animals. Arti cial passive

Downloaded from https://academic.oup.com/book/31816/chapter/266636047 by University of Sydney user on 25 September 2022

immunity is used for patients exposed to blood that is positive for hepatitis B surface antigen and in
immunocompromised patients with shingles.

Immunization with live attenuated organisms usually results in long-lasting immunity. Examples include
the Sabin vaccine for polio, MMR vaccine for measles, mumps, and rubella, and BCG (bacillus Calmette–
Guérin) for tuberculosis. Live vaccines can be very dangerous in immunocompromised patients. Killed
organisms such as Bordatella pertussis for whooping cough result in a less intense immune response.
Tetanus toxoid is given not to prevent infection by Clostridium tetani but to abolish the lethal e ects of the
exotoxin that the organism produces.

Immunodeficiency
Patients can be immunocompromised from congenital and acquired conditions. Congenital
immunode ciency may be humoral, such as Bruton type hypogammaglobulinaemia, or cell-mediated as in
DiGeorge syndrome. Combined de ciencies with agammaglobulinaemia and stem cell de ciency are rare. A
speci c de ciency of the capacity of phagocytes to generate oxygen free radicals is present in chronic
granulomatous disease, in which patients (usually males as the commonest form is inherited as an X-linked
condition) su er from repeated, severe bacterial infections. Acquired conditions resulting in some degree of
immune compromise include HIV infection, long-term steroid therapy, and cytotoxic therapy. Patients with
diabetes have de cient neutrophil function which correlates directly with the degree of hyperglycaemia.

Malignant neoplasms of almost any type induce some degree of immunode ciency, and conversely
immune-compromised patients develop malignant disease more frequently than immunocompetent
people. A classic example is malignancy in patients with HIV infection (though not necessarily AIDS—only
cervical cancer, so-called Kaposi’s sarcoma, Burkitt’s lymphoma, immunoblastic lymphoma, and primary
cerebral lymphoma are on the list of AIDS-de ning criteria).

Neoplasms that characteristically arise in patients with HIV infection include:

◆ lymphoma, most commonly B-cell non-Hodgkin’s lymphoma (NHL) but occasionally T-cell NHL or
Hodgkin’s lymphoma

◆ squamous cell papilloma and carcinoma of skin

◆ SCC of cervix, vulva, and anus

◆ SCC of the larynx

◆ (Kaposi’s sarcoma is now thought to be a non-neoplastic reaction to human herpes simplex virus type
8).
Surgical haematology

Blood transfusion
Surgical use of donated blood accounts for about half of all blood transfusions, so a clear knowledge of the
hazards of transfusion is essential. Even simple precautions can save lives—for example, starting a
transfusion at night on a general ward should be avoided unless there is a complement of sta trained to
identify adverse reactions quickly. Acute transfusion reactions were the leading cause of transfusion
morbidity in 2011; the latest Serious Hazards of Transfusion (SHOT) report showed that many incidents

Downloaded from https://academic.oup.com/book/31816/chapter/266636047 by University of Sydney user on 25 September 2022

were potentially preventable, particularly all adverse events due to human errors, as might be expected.

The National Blood Service in England and North Wales (elsewhere in the United Kingdom there are the
Welsh Blood Service in South Wales, the Scottish National Blood Transfusion Service, and the Northern
Ireland Blood Transfusion Service) selects and tracks donors, and so excludes donors who can be identi ed
from their medical or social history as unsuitable. Donors must be unpaid volunteers in the United Kingdom.
The sta of the Service take blood by a set procedure into a solution of citrate, phosphate, and dextrose for
anticoagulation. In the processing laboratory the anticoagulated blood is separated and the packed red cells
resuspended in a solution of saline, arginine, glucose, and mannitol (SAGM).

Blood is tested for HIV-1, HIV-2, HTLV-1, HTLV-2, hepatitis B, hepatitis C, and syphilis. In some parts of
the world, tests for Trypanosoma cruzi (the cause of Chagas disease) and West Nile virus are also performed.
Some centres also test for CMV and other viral antibodies but this is not universal. Identi cation of other
organisms with the polymerase chain reaction is being developed. The blood is then typed for ABO, RhD, and
Kell blood groups. White cells are removed by specialized centrifugation and ltration to reduce the
theoretical possibility of transmitting prion disease.

The transfusion Services prescribe the conditions for storage. When the transfusion blood is used there is a
set procedure for checking that it is suitable for the recipient. Adverse reactions must be reported to the
relevant blood transfusion laboratory and to the patient’s consultant: a report will then be sent to SHOT. All
details of the transfused blood and blood products must be recorded in the patient’s notes so that they can
be traced.

The Services also supply blood components and blood products. A blood component is made from one
donation (or only a limited number of donations—platelet transfusions are components from pooled blood)
to limit antigenicity from blood groups and are wet blood components for transfusion. Examples include
packed red cells, platelets, fresh frozen plasma (FFP), and cryoprecipitate. A blood product is acellular and
produced from thousands of blood donations; these include albumin, coagulation factor concentrates, and
immunoglobulins, and are generally produced by industrial processes.

Almost all hospitals in the United Kingdom issue a Maximum Blood Order Schedule. This is an
internationally adopted scheme that reduces unnecessary transfusions, reduces clinical requests for
excessive amounts of blood for transfusion, and permits better stock control of blood for transfusion. It lists
surgical procedures that require cross-match against the number of units that are considered to be required
in the experience of the particular hospital. It is reviewed regularly and modi ed to include new procedures
and reassess existing ones. If a procedure does not appear on the list, a ‘group and antibody screen’ is
normally all that is needed. Patients must be judged individually and reasons given to the blood transfusion
laboratory if it might be necessary for the listed number of units to be exceeded. In a case of massive
13
haemorrhage, the UK blood transfusion and Tissue Transplantation Services guidelines are clear.

When blood is needed for transfusion, or will probably be needed because of the nature of the surgical
operation, a sample of the patient’s blood is sent to the blood transfusion laboratory. The sample labelling
 14
requirements are stringent.

This may be for ‘group and cross-match’ or ‘group and antibody screen’. Both are automated nowadays.
The latter is useful if blood for transfusion might be needed or might not, and permits rapid cross-matching
to be done if required at a later date. A sample can usually be stored for up to 3 months, though if the patient
is pregnant or has been transfused the sample has to be no more than 3 days before the actual transfusion.

For blood grouping, the patient’s red cells are mixed with monoclonal antibodies to determine the ABO and
RhD groups. An antibody screen tests the patient’s serum against a panel of red cells. Cross-matching tests
the bags of donated blood that will be used in this patient’s speci c case (categorized as being the correct

Downloaded from https://academic.oup.com/book/31816/chapter/266636047 by University of Sydney user on 25 September 2022

ABO and RhD groups) directly against the patient’s serum. This is to pick up antibodies raised by previous
transfusions or pregnancy, and antigenicity of minor blood groups. It also acts as a check that the donor
blood has been correctly labelled by the Service.

Platelets carry the same blood groups as red cells and so a platelet transfusion must be group-speci c for
the recipient. Injection of anti-D might be needed in women of child-bearing age who are RhD negative and
receive RhD-positive products. Platelets for transfusion are stored at room-temperature.

Albumin transfusion can be indicated in the emergency management of circulatory shock, severe
hypoproteinaemia, and burns. Its use nowadays is limited. Crystalloids or colloids are used instead as
volume expanders. Crystalloids such as dextrose-saline and Ringer’s solutions are not con ned by the blood
vessel walls and freely di use across: colloids have large molecules such as dextran or gelatin. Colloids have
more side e ects than crystalloids and are more expensive. There is no clinical evidence that colloid
solutions are more e ective.

Cryoprecipitate contains factors VIII and XIII, von Willebrand factor, brinogen, and bronectin but is
usually used as a source of brinogen, which might be needed for a patient with DIC after shock, sepsis, or
massive blood transfusion.

Indications for blood transfusion

Whether blood is needed for transfusion depends on the patient’s haemoglobin concentration and on the
estimated blood loss at operation. All e orts should be made preoperatively to optimize the patient’s
haemoglobin concentration and reduce the risk of bleeding. These might include iron supplements and
management of anticoagulant medication such as aspirin and warfarin.

The lowest normal concentration in a man is usually taken as 13 g/dL and in a woman 11.5 g/dL, but people
with haemoglobin concentrations well below these can be entirely asymptomatic and managed by
investigation with gradual reversal of the anaemia rather than by transfusion. In acute blood loss,
crystalloids or colloids are usually better, and in many cases postoperative iron therapy can be used instead
of transfusion.

A working scale for perioperative blood loss (expressed as the percentage of total blood volume) is:

◆ less than 15%, no treatment

◆ 15–30% loss, crystalloids or colloids

◆ 30–40% loss, crystalloids or colloids and red cells

◆ more than 40% loss, rapid replacement by blood transfusion with platelets and clotting factors if
indicated.
Alternatives to blood transfusion
Acute normovolaemic haemodilution is a type of autologous transfusion which can be used in patients with
normal haemoglobin concentrations. Two or three units of blood are taken from the patient in the
anaesthetic room and replaced with an equal volume of colloid or crystalloid solution. The patient’s red cell
mass is therefore diluted, which reduces the red cell mass lost during the operation. The blood taken at the
start is replaced at the end of the procedure when haemostasis has been achieved.

Preoperative autologous deposition of whole blood is no longer practised in the United Kingdom because of
the associated risks. In this procedure, blood is taken from patients who have normal haemoglobin

Downloaded from https://academic.oup.com/book/31816/chapter/266636047 by University of Sydney user on 25 September 2022

concentrations 4 weeks before elective surgery; up to a maximum of four units can be taken, each at
intervals of 1 week. The procedure should not be undertaken unless there is a guaranteed date for the
operation. In the United States where this procedure is commoner than in the United Kingdom, about half of
the deposited blood is discarded unused.

Intraoperative red cell salvage by automated systems may be useful in some instances, when anticipated
blood loss is more than two units. Blood from the operative eld is collected, ltered, and transfused back.
Some systems wash the blood to remove free haemoglobin and cell debris. Side e ects include DIC and air
embolism. This technique might be acceptable to patients who are Jehovah’s Witnesses but might not, and
this should be discussed.

Complications of blood transfusion

These can be classi ed into immediate and delayed. Immediate complications include:

◆ haemolysis from incompatibility with blood groups, a type II hypersensitivity reaction

◆ septicaemia from transfusion of infected blood, especially by Gram-negative organisms such as

coliforms

◆ bleeding diathesis: transfusion blood may be de cient in platelets and clotting factors, especially
factors V and VIII, though bleeding is usually the result of the underlying condition rather than any
de ciency in the contents of the transfused blood

◆ circulatory changes with hypertension from hypervolaemia and hypotension because of blood group
incompatibility; air embolus and other complications of venous access not speci c to transfusion can
also occur

◆ metabolic changes, classically hyperkalaemia from damaged red cells releasing potassium;
hypocalcaemia is rare nowadays as citrate is generally no longer used as a storage anticoagulant. The
patient may also develop acidosis

◆ temperature changes: hypothermia from rapid transfusion of chilled blood, and hyperthermia from a
transfusion reaction.

Delayed complications include:

◆ septicaemia from de ciency of the aseptic technique of connecting the intravenous lines usually
caused by Staphylococcus aureus or coliforms

◆ delayed haemolytic reactions from weak immunoglobulins in the patient’s plasma not detected at
antibody screening or cross-match

◆ impaired ability to reject transplanted organs such as renal transplants, especially if repeated
 transfusions are given. This, of course, might be a good thing

◆ infection (in unscreened donor blood) from hepatitis B, hepatitis C, HIV, CMV, malaria, and syphilis

◆ iron overload in patients who have had numerous transfusions, such as patients with thalassaemia.

Indications for platelet transfusion

Platelet transfusion may be indicated in patients with DIC, in patients who have had massive bleeding, and
in patients with thrombocytopenia. Patients who have been given aspirin will need a platelet transfusion

Downloaded from https://academic.oup.com/book/31816/chapter/266636047 by University of Sydney user on 25 September 2022

before a major operation such as aneurysm repair, abdominoperineal excision of rectum, and cardiac
bypass.

Indications for transfusion of fresh frozen plasma

These include severe DIC, massive blood transfusion, cardiac bypass surgery, and thrombotic
thrombocytopenic purpura. Patients on warfarin who require urgent operative surgery can be treated with
FFP to raise clotting factors II, VII, IX, and X to normal.

Anaemia

Anaemia is of great surgical importance. Surgically it is important to understand the signi cance of the
diagnosis of anaemia—surgeons manage patients with anaemia from di erent causes preoperatively,
perioperatively, and postoperatively and surgeons can cause anaemia by many operative procedures.

Iron-deficiency anaemia
Iron-de ciency anaemia is the commonest type of anaemia, related usually to chronic blood loss or a
de cient diet. It is commoner in women but not because they menstruate: menstruation is physiological. If a
woman develops menorrhagia, excessive menstrual loss, this will overwhelm the capacity of the alimentary
system to absorb enough iron compounds and for the bone marrow to convert them into haemoglobin.

The red cell precursors cannot make the proper amount of haemoglobin because of de ciency of iron but
have no abnormality in their nuclei and their capacity to multiply is unimpaired. The precursors undergo an
extra mitotic division which apportions the de cient cytoplasmic haemoglobin in one parent normocyte
between two smaller daughter cells. This increases the mean corpuscular haemoglobin concentration at the
expense of the mean corpuscular volume, though the concentration is still low. The blood lm shows
hypochromic, microcytic anaemia, as would be expected from this sequence.

This blood lm picture is not pathognomonic—it is also seen in patients with thalassaemia. Neither is the
serum iron particularly helpful: it is low in patients with rheumatoid arthritis and idiopathic in ammatory
bowel disease. The serum ferritin concentration is the best measure of iron status, but rises in acute and
chronic in ammatory diseases and should be interpreted in context. A low serum ferritin indicates low iron
stores.
Macrocytic and megaloblastic anaemia
The red cell maturation sequence in the normal bone marrow is from myeloblasts, myelocytes, early
normoblasts, and late normoblasts (all of which are nucleated) to reticulocytes and mature red cells (which
are not nucleated—the nuclear remnant has been extruded). Reticulocytes are large red cells that have a
‘reticule’ (a network or meshwork) of basophilic laments that are the remnants of RNA in the cell. On a
Coulter report, reactive reticulocytosis might speciously appear to be pathological macrocytosis.

Macrocytes are large red cells (without nuclei, and so are like mature normal red cell though too large)
which are present in the circulation. Because of the de ciency of absorption of vitamin B12 and folate the

Downloaded from https://academic.oup.com/book/31816/chapter/266636047 by University of Sydney user on 25 September 2022

developing red cells cannot divide e ciently and miss a division. Their progeny are therefore larger than
normal, which is re ected on the blood lm of a macrocytic anaemia. The lm will also show abnormal
polymorphs.

Megaloblasts are large, nucleated, abnormal precursors of macrocytes which are never found in normal
bone marrow; they are found predominantly in the bone marrow of patients with vitamin B12 and folate
de ciencies, and very occasionally can be found in a lm of peripheral blood. They have abnormal
metabolism of DNA precursors into DNA and so can be tetraploid or aneuploid. This nuclear abnormality is
present in all cells that have nuclei, so the cytology department will report abnormal nuclear changes on
specimens from these patients from, for example, the cervix, bronchus, and bladder. White cell maturation
is a ected re ected by hypersegmented neutrophils.

Macrocytosis and macrocytic anaemia without megaloblastosis are caused by alcohol ingestion,
hypothyroidism, and hepatic and renal failure. The commonest reason for macrocytosis in the United
Kingdom is drinking alcohol; most of these people do not develop anaemia. About 3 months of stores of
folate are held in the liver, and over 3 years of stores of vitamin B12. This is why pregnant women are given
folate supplements but not vitamin B12 supplements.

Folate and vitamin B12 are used in the cycle of DNA synthesis. The main driver is folate. Vitamin B12 acts at a
single methylation step which converts homocysteine into methionine and acts as a catalyst rather than a
substrate. Vitamin B12 is absorbed from meat, predominantly, in the diet. It attaches to intrinsic factor
(vitamin B12 was originally called extrinsic factor before its nature was known) and they are absorbed by
facilitated transport in the terminal ileum. The causes of vitamin B12 de ciency include:

◆ de ciency of intrinsic factor because of:

• pernicious anaemia from antibodies against parietal cells which secrete intrinsic factor into the
gastric lumen

• partial or total gastrectomy

◆ absence of vitamin B12 absorption because of disease in the terminal ileum such as tuberculosis and
Crohn’s disease.

Vitamin B12 can be absorbed by simple mass action in the jejunum but the patient would have to take several
tablets a day rather than one injection of hydroxocobalamin once every few months.

Folate de ciency is cause by dietary de ciency and by pregnancy from increased demands from the fetus.
Occasionally folate de ciency is caused by antifolate drugs such as methotrexate but this is almost always
closely monitored. Other drugs which interfere with DNA production include zidovudine and hydroxyurea.
Haemolytic anaemia
Haemolytic anaemia is a complex subject, most simply classi ed into inherited abnormalities and acquired
causes of haemolysis. Inherited causes are classi ed as:

◆ haemoglobin abnormalities:

• sickle cell disease, thalassaemia

• other rarer haemoglobinopathies such as HbC, HbD Punjab, HbE

Downloaded from https://academic.oup.com/book/31816/chapter/266636047 by University of Sydney user on 25 September 2022

◆ red cell membrane abnormalities:

• spherocytosis is the condition with the most surgical interest, as the symptoms can be cured by
splenectomy

• elliptocytosis is usually asymptomatic

• enzyme abnormalities such as glucose-6-phosphate dehydrogenase de ciency and pyruvate kinase

de ciency.

Acquired haemolytic anaemia can result from many causes. The principal ones of surgical importance are
immune mediated and mechanical. Immune-mediated causes can be autoimmune, such as from drug-
induced haemolysis, and isoimmune from ABO, RhD, and other blood group incompatibilities. Drugs that
stimulate antibodies against red cells with consequent haemolysis by complement include cephalosporins,
penicillin, levodopa and methyldopa, and some non-steroidal anti-in ammatory drugs. Mechanical causes
include damage to red cells from arti cial heart valves, especially metallic ones, and extracorporeal
circulation for cardiac surgery.

Haemolytic anaemia is diagnosed when a patient has a low haemoglobin concentration associated with the
typical haematological and biochemical changes below. This is characteristically a normochromic
normocytic anaemia as there is usually no iron, vitamin B12, or folate de ciency. The raised reticulocyte
count in the peripheral blood represents an attempt by the bone marrow urgently to inject mature red cells
and reticulocytes into the circulation to compensate for the haemolysis. Reticulocytosis can show on a
Coulter result as a specious macrocytic anaemia.

These patients may also have an excess serum concentration of unconjugated bilirubin because the liver’s
capacity to conjugate is exceeded. There is relative absence of urinary bilirubin and increased serum
methaemoglobin concentration.

Sickle cell disease

The clinical features of sickle cell disease are of surgical importance and are protean; the name given used to
be sickle cell anaemia, but the patients can su er severe disease without developing signi cant anaemia.
Sickle cell crises with thrombosis and infarction commonly presents as bone pain but can also cause
abdominal and chest pain; splenic infarction causes acute abdominal pain; priapism can be prolonged and
becomes a surgical emergency. Sequestration of sickled red cells causes hepatomegaly and splenomegaly,
though the spleen can also be small due to infarction. Haemolytic anaemia, especially if longstanding, can
cause congestive cardiac failure and pigment gallstones. Unusual infections such as pneumococcal
septicaemia and salmonella osteomyelitis can occur.

In sickle cell disease there is a biochemical abnormality of haemoglobin synthesis that results in a less
soluble than normal haemoglobin with consequently reduced red cell survival and polymerization of
haemoglobin with precipitation under low oxygen tension. There is a single amino acid error in the β-chain
at position 6: valine is substituted for the normal glutamic acid which causes polymerization and
precipitation of the haemoglobin in its deoxygenated state.

The β-chain genes are on chromosome 11 and act as autosomal co-dominants—each gene contributes about
half of the total amount needed for construction of haemoglobin molecules. Patients with sickle cell disease
are homozygous and have 90–100% HbS with small amounts of fetal haemoglobin, HbF. People with sickle
cell trait are heterozygous, and have only 20–40% HbS with the rest normally being HbA. They are
consequently usually asymptomatic.

Downloaded from https://academic.oup.com/book/31816/chapter/266636047 by University of Sydney user on 25 September 2022

The blood picture in sickle cell disease is of a normochromic lm showing sickled red cells. There is
reticulocytosis re ecting compensatory marrow hyperplasia, and features of splenic damage including
target cells and fragmented red cells.

Thalassaemia
The intrinsic problem in thalassaemia is defective globin chain synthesis. This results in abnormal
haemoglobin molecules and so abnormal red cell production. Alpha-chain thalassaemia a ects people in
China, Africa, and elsewhere in Asia but can a ect their dependants anywhere in the world. Beta-chain
thalassaemia is commoner and a ects patients especially in Mediterranean countries and the Middle East.

Patients with classical β-thalassaemia have a hypochromic, microcytic anaemia. They have reticulocytosis
and other abnormalities on a blood lm such as nucleated red cells. There is increased fetal haemoglobin
seen on electrophoresis: HbF continues to be produced in patients with thalassaemia as compensation for
the production of abnormal HbA. People with the heterozygous β-thalassaemia trait are asymptomatic and
have microcytosis without anaemia.

The complications of thalassaemia include marrow hyperplasia to compensate for the anaemia, iron
overload from the need for repeated blood transfusions, haemosiderosis with liver damage and endocrine
insu ciencies, and pancreatitis.

Splenectomy

Splenectomy is an important surgical procedure, and so it is important that the indication and
complications are understood. The most urgent indication is splenic trauma and rupture with
haemoperitoneum. Other more predictable indications include those for the treatment of haematological
conditions involving the spleen, treatment of some non-haematological conditions, and management of
the symptoms of splenomegaly. Splenectomy may be a necessary manoeuvre to permit access in operations
in the area of the spleen, such as gastrectomy, adrenalectomy from an anterior approach, left colectomy,
and Whipple’s operation.

Some haematological diseases respond well to the e ects of splenectomy. These include the management of
rare haemolytic disorders such as hairy-cell leukaemia and immune idiopathic thrombocytopenic purpura,
and the relief of haemolytic problems from hereditary spherocytosis. Splenectomy for the staging of
lymphoma has been superseded by computed tomography and positron emission tomography imaging.

Splenic cysts from hydatid disease may need to be excised: congenital splenic cysts are usually
asymptomatic. Other than lymphoma, primary and secondary neoplasms of the spleen are rare.
Splenectomy may give relief of the symptoms of massive splenomegaly caused by visceral leishmaniasis
(kala-azar), myelo brosis, and chronic myeloid and lymphoid proliferative disorders.
The e ects of splenectomy are re ected in red cell changes, platelet changes, and in white cell changes with
the immunological consequences of them. Red cell changes are from the incapacity of the spleen to monitor
degenerate red cells and abnormal red cell forms. Inclusion bodies in circulating red cells after splenectomy
may be Howell–Jolly bodies (which are nuclear remnants) and Heinz bodies (composed of denatured
haemoglobin). Abnormal forms include nucleated red cells and acanthocytes, distorted red cells with a spiky
shape. Changes in platelet include thrombocytosis, increased adhesiveness, and abnormal cell forms.

White cell changes that characteristically follow splenectomy include a transient neutrophilia followed by
permanent lymphocytosis and monocytosis. Immune changes include defective production of antibodies
that bind to antigens that have carbohydrate moieties, such as on the cell walls of capsulated bacteria. There

Downloaded from https://academic.oup.com/book/31816/chapter/266636047 by University of Sydney user on 25 September 2022

is also increased risk of contracting or reactivating malaria.

Splenomegaly
Splenomegaly is an abnormal increase in splenic size and weight, irrespective of function. The causes of
splenomegaly are numerous and mostly not of immediate interest to a surgeon but are important to know in
its di erential diagnosis.

In general, the causes of splenomegaly include:

◆ in ammation, which may be caused by a large number of infective agents of all sizes from viruses to
metazoa, or from non-infective causes of in ammation such as rheumatoid arthritis and sarcoidosis

◆ congestion of the spleen from complete or partial blockage of the splenic or portal veins by cirrhosis,
thrombosis, or involvement by carcinoma of the pancreas

◆ accumulation of amyloid material, or mucopolysaccharides as in Gaucher’s, Hurler’s, and Hunter’s

diseases and other mucopolysaccharide storage diseases

◆ congenital diseases such as congenital haemolytic anaemia and polycystic disease of the spleen

◆ neoplastic conditions: any almost any of the leukaemias and lymphomas, and in the
myeloproliferative disorders

◆ drug causes such as antibiotics and psychotropic drugs.

Hypersplenism
Hypersplenism is an abnormal increase in splenic function, almost always linked to size. All of the causes of
splenomegaly previously listed can cause hypersplenism. Features of hypersplenism include splenomegaly
with removal of red cells, white cells, and platelets whether appropriate or not. It is reversed by removal of
the cause of the splenomegaly or by splenectomy.

Polycythaemia

Polycythaemia is classi ed as primary, secondary, and relative.

Primary polycythaemia is polycythaemia vera (the term has been changed from polycythaemia rubra vera to
re ect the fact that white cells and platelets are also raised). It is one of the myeloproliferative diseases, the
others being chronic myeloid leukaemia, myelo brosis, and essential thrombocythaemia. The serum
erythropoietin concentration is low in primary polycythaemia. It is characterized by the presence of a
mutation in the Janus kinase 2 pathway in 98% of cases, and this is now the diagnostic test for the
condition.

In secondary polycythaemia the serum erythropoietin concentration is high. This can be appropriate,
stimulated by high altitude, cigarette smoking, lung disease such as emphysema, congestive cardiac failure,
and haemoglobinopathies with high-a nity haemoglobins which hold on to oxygen and result in tissue
hypoxia.

Secondary polycythaemia due to inappropriate erythropoietin excess is typically caused by excess eutopic
secretion from a neoplasm, such as renal parenchymal cell carcinoma and hepatocellular carcinoma, or

Downloaded from https://academic.oup.com/book/31816/chapter/266636047 by University of Sydney user on 25 September 2022

excess ectopic secretion such as by cerebellar haemangioblastoma, phaeochromocytoma, and prostatic
adenocarcinoma. Relative polycythaemia occurs when there is a reduction in plasma volume, in which there
is no increase in total red cell mass.

Haemostasis

Platelets
Platelets are of great clinical importance in the control of bleeding, especially from capillaries. Patients with
thrombocytopenia present with internal bleeding in the skin (petechiae and ecchymoses) and in the retina.
External bleeding, which may be profuse, may come from the alimentary tract, the female genital tract, and
the upper respiratory tract as epistaxis. Conversely, patients with thrombocytosis present with coronary
thrombosis and digital ischaemia from thrombosis, and with splenomegaly.

Platelets are cytoplasmic fragments of megakaryocytes that are regulated by growth factors such as
thrombopoietin. Platelets have no nuclei and no ability to synthesize enzymes, so a continuous supply is
9
needed. The normal concentration in blood is 150–400 × 10 /L and they have a lifespan of 7–10 days. About
two-thirds of platelets stay in the general circulation; the rest are held in the spleen and exchanged with
ones from the circulation. In cases of hypersplenism the splenic pool enlarges but the platelet lifespan is
unchanged.

Platelets release clotting, vasoactive, and other substances locally to manage a breach in an endothelial cell
surface. Platelet cell membranes have proteins that attach to brinogen and to von Willebrand factor, which
carries factor VIII. The platelet cytoplasm contains:

◆ storage granules:

• alpha granules: clotting factors V, VIII, brinogen, and von Willebrand factor; platelet factor 4, a
heparin antagonist; and platelet-derived growth factor

• dense granules: 5-hydroxytryptamine (serotonin), ADP, catecholamines, calcium

• glycogen granules, which provide the energy source for platelet reactions

• other granules containing thromboxane and prostaglandins

◆ actin and myosin bres that cause clot retraction.

When there is a breach in an endothelial surface, collagen is exposed to the bloodstream. Platelets attach to
it by membrane proteins and von Willebrand factor, a very large molecule that bridges spaces among
platelets and between platelets and collagen. The shape of the platelets changes from discoid to spherical by
rearrangement of microtubules. There is release of platelet granules with binding of circulating platelets
nearby to brinogen which polymerizes to brin. Other clotting factors are also bound to the surface of
platelets, including factors V and VIII. The platelet plug is stabilized by thromboxane and prostaglandins,
and further consolidated when pseudopodia from platelets in the clot link and their actin and myosin bres
contract.

Aspirin blocks the actions of cyclooxygenase (COX) enzymes. These are essential for the formation of
thromboxane and prostaglandin in platelets and endothelial cells. The block is permanent in platelets as
they have no nuclei to regenerate more COX: in contrast, regeneration is rapidly possible in endothelial cells.
New platelets take about a week to repopulate the circulation in adequate numbers.

Downloaded from https://academic.oup.com/book/31816/chapter/266636047 by University of Sydney user on 25 September 2022

Blood coagulation
This is achieved by a cascade of pro-enzymes (the clotting factors) and enzymes (the activated clotting
factors). Most of the clotting factors are made in the liver (not just factors II, VII, IX, and X, which are the
vitamin K-dependent factors). The bene ts of the coagulation cascade are that the severity of acute
haemorrhage, and to some extent chronic haemorrhage, is limited. The clotting cascade has more e ect in
venous or capillary haemorrhage rather than arterial. The same factors contribute to localization of acute
infection in an abscess.

The cascade was classically divided into the intrinsic and the extrinsic systems but this is no longer
considered useful. The intrinsic system has no role in vivo. The governing factor is factor VII. With tissue
factor this activates factors IX and X. Activated factors IX with activated factor VIII also activate factor X.
This, with activated factor V, splits prothrombin to thrombin, which splits brinogen to brin.

Factors XII and XI are unnecessary—patients with complete absence of factor XII are asymptomatic—but
both factors have a small role at sites of major tissue injury. Both are needed for the activated partial
thromboplastin time (aPTT test) to be normal. The other main test of clotting is the prothrombin time (PT),
which is usually expressed as the international normalized ratio. The PT is prolonged in warfarin treatment,
liver disease, DIC, and vitamin K de ciency. The aPTT is prolonged in heparin treatment, haemophilia, DIC,
and liver disease. Another test which can be useful is the thrombin time, prolonged in heparin treatment,
DIC, and abnormalities of brinogen.

Haemophilia syndromes

Men with haemophilia A (and very rarely homozygous women with two abnormal X chromosomes) su er
from repeated haemarthroses, intracranial haemorrhages, and subperiosteal haemorrhages resolving into
so-called pseudotumours of bone with new bone formation. The classic form of haemophilia is inherited as
an X-linked condition but about one-third are spontaneous mutations. The condition a ects 1 in 100 000
men and results in low plasma factor VIII concentrations of variable severity. Patients are classi ed as
severe if their plasma concentration is less than 1% of normal; moderate if they have 1–5% of normal; and
mild if they have 6–40% of normal.

Christmas disease or haemophilia B is factor IX de ciency. It is also X-linked but only one- fth as common
as haemophilia A. The clinical picture is the same as haemophilia A. Treatment for both types is replacement
of speci c clotting factors. Arginine vasopressin (DDAVP) can be used to stimulate secretion of von
Willebrand factor with a consequent increase in factor VIII binding and survival in patients with mild
haemophilia A but not haemophilia B.
Thrombocytosis

Thrombocytosis (or thrombocythaemia) may be neoplastic in essential thrombocytosis or part of another

myeloproliferative disorder such as myelo brosis, polycythaemia vera, and chronic myeloid leukaemia.
Thrombocytosis can also be secondary to:

◆ in ammation and operative surgery

◆ iron-de ciency anaemia

Downloaded from https://academic.oup.com/book/31816/chapter/266636047 by University of Sydney user on 25 September 2022

◆ splenic de ciency:

• splenectomy and congenital absence of the spleen

• hyposplenism

• sickle cell disease, thalassaemia, lymphomas, and coeliac disease

• splenic irradiation before bone marrow transplantation.

Thrombocytopenia and thrombasthenia

Thrombocytopenia is a reduction below normal of the number of platelets. Thrombasthenia is a reduction
below normal of the function of platelets. These conditions are not mutually exclusive. The causes of
thrombocytopenia are failure of platelet production, increased platelet consumption, and dilutional or
artefactual thrombocytopenia.

Failure of production includes conditions such as:

◆ aplastic anaemia

• congenital: Fanconi’s anaemia

• iatrogenic from:

■ drugs: cytotoxics, drugs causing hypersensitivity states

■ radiotherapy

• autoimmune causes with no known aetiology

• other: virus infections, pregnancy, accidental radiation exposure

◆ megaloblastic anaemia

◆ myelodysplastic syndromes other than idiopathic thrombocythaemia

◆ bone marrow replacement by metastatic carcinoma

◆ HIV and other virus infections unrelated to aplastic anaemia

◆ other congenital causes (rarely):

• May–Hegglin anomaly

• Bernard–Soulier syndrome
 • osteopetrosis with obliteration of the marrow.

Increase in consumption in conditions such as:

◆ thrombotic thrombocytopenic purpura

◆ splenomegaly and hypersplenism

◆ DIC

◆ immunological causes:

Downloaded from https://academic.oup.com/book/31816/chapter/266636047 by University of Sydney user on 25 September 2022

• in a blood transfusion reaction (‘post-transfusion purpura’)

• idiopathic thrombocytopenic purpura

• heparin-induced thrombocytopenia

• diseases such as SLE and antiphospholipid syndrome

• drug reactions

◆ infections: malaria, glandular fever, schistosomiasis.

Relative thrombocytopenia, which may be:

◆ dilutional from transfusion of stored blood low in platelets, or of large transfusions of uid such as
dextrose saline

◆ artefactual thrombocytopenia: patients may have antibodies that cause aggregation of platelets in
glass.

The causes of thrombasthenia are rare; they can be congenital or acquired. Congenital defects include
glycoprotein abnormalities of the platelet membrane, such as Glanzmann’s disease and Bernard–Soulier
syndrome, or abnormalities of platelet storage granules. Stored platelets have de cient dense granules,
alpha granules, or both.

Acquired causes of thrombasthenia include chronic renal and hepatic diseases and drug interactions with
platelets. Aspirin blocks the actions of COX enzymes and so inhibits prostaglandin synthetase and prevents
release of ADP and thromboxane A2; other drugs causing thrombasthenia include frusemide, sympathetic
nerve system blockers, clo brate, non-steroidal anti-in ammatory drugs, and heparin.

Heparins and warfarin

Unfractionated heparin is a sulphated polysaccharide with a mean molecular weight of 15 kDa that is
produced by hepatocytes (hence the name) and by mast cells. It inhibits the actions of thrombin by binding
it to naturally occurring antithrombin III, which is also made in the liver. The length of the polysaccharide is
important—18 or more saccharide units are essential if the heparin linking chain is to bridge between
antithrombin and thrombin. By inhibiting thrombin, heparin prevents conversion of brinogen to brin,
and inhibits thrombin activation of factor V, factor VIII, and platelets. The heparin–antithrombin complex
also inhibits activated factor X but does not bind to it. As a consequence the heparin chain length can be as
small as ve units.

Low-molecular-weight heparin (LMWH) has a mean molecular weight 5 kDa. It has less capacity than
unfractionated heparin to inactivate thrombin because of the smaller polysaccharide length, but inhibits
activated factor X to the same degree. The advantage of LMWH is that it binds to plasma proteins less than
unfractionated heparin and so has a more predictable dose-related half-life, a longer plasma half-life, and
a lower risk of heparin-induced osteopenia and thrombocytopenia. The e ects of both types of heparin are
reversed by protamine sulphate. Heparins do not cross the placenta.

Warfarin antagonizes the e ects of vitamin K, which is necessary for the formation of the calcium-binding
forms of factors II, VII, IX, and X. Vitamin K in the liver modi es the precursor factor molecules by
carboxylating them and this is blocked by warfarin. Protein C and protein S synthesis are also a ected.
Protein S is a co-factor in the activation of protein C, which acts against activated factors V and VIII to
decrease the e ects of thrombin. Depletion of all these factors takes several days—warfarin has a half-life

Downloaded from https://academic.oup.com/book/31816/chapter/266636047 by University of Sydney user on 25 September 2022

of 60 hours—and overlap with heparin should be considered if anticoagulation is urgent. Warfarin crosses
the placenta and so cannot be used in pregnancy.

Bridging protocols for patients on anticoagulants have been developed and are regularly scrutinized. When
and whether to use bridge anticoagulation will depend on the patient’s risk of thromboembolus. This will
depend on the indication for long-term warfarin therapy, such as previous deep vein thrombosis with
embolus, or heart disease with atrial brillation, or a prosthetic valve. Warfarin might not need to be
discontinued in patients having minor surgery in which bleeding is likely to be minimal or can easily be
staunched. Speci c operative risks have been studied—discontinuation of antiplatelet treatment in patients
15
who need to have a coronary artery stent increases the chance of stent thrombosis.

Disseminated intravascular coagulopathy

A surgical knowledge of DIC is clinically important because patients with massive trauma can develop DIC
and its complications; patients can present with DIC as a complication of a surgically treatable condition;
surgical procedures can cause DIC; and postoperative infections can cause DIC.

Causes of DIC include:

◆ infections such as Gram-negative septicaemia; Gram-positive septicaemia by meningococci and

clostridia; systemic candidiasis and aspergillosis; and malaria

◆ massive tissue injury from burns, major physical trauma, and extensive surgical procedures

◆ haematological disorders such as sickle cell disease and other causes of intravascular haemolysis

◆ vascular and perfusion disorders such as aneurysms, prosthetic grafts, coarctation of the aorta,
vasculitis, and occasionally myocardial infarction

◆ neoplasms such as carcinomas of the bronchus, prostate, ovary, and pancreas

◆ obstetric complications such as amniotic uid embolism, eclampsia, and premature separation of the
placenta

◆ other causes including liver failure, acute pancreatitis, hypothermia, amphetamines and other drugs,
and snakebites.

The clinical diagnosis of DIC is con rmed by nding a low platelet count, a low plasma brinogen
concentration, increased PT and aPTT, and brin degradation products in urine and serum. Haemolysis and
fragmented red cells are usually present to some degree.
Biochemical disorders

Calcium disorders

Hypercalcaemia
The normal serum calcium concentration is in the range of 2.15–2.55 mmol/L with small variations between
biochemistry laboratories. Hypercalcaemia is considered to be a corrected serum calcium concentration

Downloaded from https://academic.oup.com/book/31816/chapter/266636047 by University of Sydney user on 25 September 2022

above 2.60 mmol/L. The commonest cause is recognized or undiagnosed parathyroid disease—about 1% of
the population in the United Kingdom has mild primary hyperparathyroidism with consequently raised
serum calcium levels.

Hypercalcaemia in relation to malignant disease is also well recognized. Metastatic carcinoma in bone can
produce mild or severe hypercalcaemia. Parathyroid hormone-related protein (PTHrP) is secreted by all
normal cells as a paracrine communicator, and the plasma concentration of PTHrP increases when there is
widespread metastatic carcinoma; this causes generalized demineralization of bone. Carcinomas can also
have ectopic secretion of parathyroid-like hormone, such as SCC of bronchus and occasionally oat cell
carcinoma. Patients with myeloma, leukaemia, and lymphoma develop hypercalcaemia by several
16
mechanisms including stimulation of osteoclasts by the tumour cells.

Other endocrine diseases associated with hypercalcaemia include phaeochromocytoma, adrenal failure, and
severe hyperthyroidism. Phaeochromocytoma that is not part of multiple endocrine adenopathy (MEA) II
causes hypercalcaemia by an unknown mechanism; the calcium concentration reverts to normal when the
phaeochromocytoma is excised. Iatrogenic causes include prolonged immobilization such as in patients in
the intensive care unit and high dependency unit and in patients with Paget’s disease of bone. Drugs such as
thiazides, lithium, oestrogens, tamoxifen, and overdosage of vitamins A and D also contribute.

Familial causes include hypophosphatasia, idiopathic hypercalcaemia of infancy, and hypocalciuric

hypercalcaemia. Other rare causes include severe chronic granulomatous diseases such as sarcoidosis and
occasionally tuberculoid leprosy: macrophages hydroxylate vitamin D to its active forms.

The classical and important e ects of hypercalcaemia include:

◆ bone pain, joint pain, and pathological fractures

◆ depression, confusion, neuroses and psychoses, fatigue, and lethargy

◆ nausea and vomiting, peptic ulcers, pancreatitis, and constipation

◆ polyuria and polydipsia, renal calculi, nephrocalcinosis, and renal failure

◆ in longstanding cases, hypertension, cardiac arrhythmias, and metastatic calci cation.

Metastatic calcification
Calci cation is classi ed as normal and abnormal—orthotopic and heterotopic. Orthotopic calci cation
occurs in bones, teeth, and otoliths. Heterotopic calci cation is divided into dystrophic, metastatic, and
age-related from no apparent dystrophic or metastatic mechanism.

It is important not to read the word metastatic (Greek metastasis, change or removal) in this context as
referring to involvement by the spread of malignant disease. It means a change in condition from
normocalcaemia to hypercalcaemia, calci cation secondary to hypercalcaemia rather than dystrophic
calci cation. Metastatic calci cation occurs around the renal tubules as nephrocalcinosis, in alveolar walls
in the lungs, around the gastric glands, and in the cornea.

Dystrophic calcification
This is calci cation in dead or damaged tissues in the presence of a normal circulating calcium
concentration, such as calci cation in tissue damage caused by tuberculosis, atheroma, and parasites.

Plasma proteins

Downloaded from https://academic.oup.com/book/31816/chapter/266636047 by University of Sydney user on 25 September 2022

Disorders of proteins
Plasma proteins are paradoxically measured in the biochemistry laboratory as serum proteins. Plasma
contains all of the constituent proteins in the circulation: serum is plasma depleted of clotting factors. The
importance of removing brinogen from the plasma before using it for protein electrophoresis is that it
forms polymers of itself. There are therefore large numbers of molecules of very many molecular weights
and these obscure the bands of the other plasma proteins.

The highest and tightest peaks on electrophoresis are albumin and pre-albumin. The globulin peaks follow:
the α-1 band carries α-1-antitrypsin, now called protease inhibitor enzymes, and high-density lipoprotein
(HDL); the α-2 band carries α-2 macroglobulin and haptoglobin, a haemoglobin-binding protein important
in haemolytic anaemia; the β-1 and β-2 bands carry low-density lipoprotein (LDL), transferrin, and β-2
microglobulin; and the γ band has the immunoglobulins.

Bilirubin

Bilirubin and jaundice

Bilirubin is derived principally from the haem moiety in red cells, with much smaller amounts derived from
myoglobin and cytochrome enzymes. Red cells are degraded in the spleen and the consequent bilirubin is
carried in plasma strongly bound to albumin. In the liver, bilirubin is conjugated with glucuronide. Bilirubin
glucuronide is excreted in bile. In the colon, conjugated bilirubin is deconjugated by bacterial
glucuronidases and reduced to stercobilinogen, which is excreted in the faeces as stercobilin. A small
amount of stercobilinogen is absorbed by the colon, recycled by the liver, and excretion in bile. A very small
amount of stercobilinogen leaks into the plasma; it is water-soluble and so is excreted in urine as
urobilinogen.

Classification of jaundice
Jaundice is classi ed into haemolytic and other prehepatic causes, hepatocellular causes, and post-hepatic,
obstructive causes. In haemolytic diseases the excess of unconjugated bilirubin, which is rmly bound to
albumin, is unable to escape through glomerular ltration and so the patient has ‘acholuric’ jaundice
without bile in the urine. In the newborn, the excessive amounts of unconjugated bilirubin such as from RhD
incompatibility can attach to lipid-rich areas in the brain such as the basal ganglia and cause kernicterus.

In hepatocellular jaundice there is excess of conjugated and unconjugated bilirubin because the diseased
hepatocytes cannot conjugate bilirubin adequately. There may also be failure to excrete in the bile the
bilirubin that has been successfully conjugated.
In obstructive jaundice, there is excess of conjugated bilirubin in the plasma because it cannot be excreted in
bile and so must be excreted in the urine which is consequently dark. There are less-than-normal amounts
of stercobilin production in the colon and so the faeces are pale.

Serological tests for the investigation of a patient with jaundice include full blood count, lm, reticulocyte
count, erythrocyte sedimentation rate, and C-reactive protein measurement. Other investigations,
depending on the clinical picture, may be investigations of clotting function, virological investigations, liver
function tests including albumin and total protein measurements, and an autoantibody screen.

Gout

Downloaded from https://academic.oup.com/book/31816/chapter/266636047 by University of Sydney user on 25 September 2022

A knowledge of gout is of surgical importance for several reasons. The most important is that gout causes
acute and chronic arthritis. It is one of the crystal arthropathies (along with the arthropathies caused by the
crystals of calcium pyrophosphate, hydroxyapatite, and oxalate deposition in joints). It is in the di erential
diagnosis of septic arthropathy and, as in any repeated or chronic joint injury, eventually causes
osteoarthritis.

Urological surgeons may diagnose calculi and other diseases caused by urate crystal deposition.
Reconstructive surgeons might be asked to treat gouty tophi on visible parts of the body. All surgeons
involved with cytotoxic drugs and radiotherapy should know that they can cause or exacerbate
hyperuricaemia and clinical gout.

Urate is derived from metabolism of purines (the name was given from the Latin for ‘pure urate’). Purines
(adenine and guanine) are metabolized to urate; pyrimidines (uracil and thymine in DNA, and uracil and
cytosine in RNA) are not, and are eventually degraded to urea, a far simpler molecule than uric acid.

Classification of hyperuricaemia
Primary hyperuricaemia is a congenital abnormality of a phosphoribosyl transferase that causes a defect in
the normal recycling of purine breakdown products into new purines. As a consequence, they must be
further deconstructed through xanthine and hypoxanthine. The excretory point of their metabolism in
human beings is uric acid.

Secondary hyperuricaemia is either from increased cell destruction or decreased urate excretion by the
kidneys. The rst is caused by increased cell turnover states such as myeloproliferative diseases, leukaemia,
psoriasis, and chemotherapy. The second follows decreased excretion of urate as a consequence of chronic
renal failure and diuretics such as thiazides and frusemide which modify tubular urate excretion.

Alcohol-related diseases
Ingestion of ethyl alcohol primarily a ects the CNS and the stomach, pancreas, larynx, and liver. The CNS is
a ected the earliest, only minutes after ingestion, by psychological e ects such as loss of inhibition and
judgement, and physical pharmacological e ects of sedation and loss of coordination. The commonest
alcohol-related injury in young adults is trauma such as skin lacerations and abrasions, head injuries with
intracranial haemorrhage, and long bone fractures. Late complications include cirrhosis, carcinomas of the
larynx, stomach, and elsewhere, cerebellar degeneration, encephalopathy, and psychoses. On a practical
note, obtaining a clear surgical history from a patient who has ingested alcohol, whether acutely or
chronically, may be impossible.

Ethyl alcohol is metabolized principally by the liver and to a lesser extent by the kidney, stomach, and brain.
The main pathway is through the microsomal ethanol oxidizing system enzymes, with smaller amounts
metabolized by alcohol dehydrogenase and the catalase reaction. All of these have acetic acid as the end
result, which is metabolized partly to acetyl-CoA and partly to carbon dioxide in heart, brain, and skeletal
muscle cells. Methyl alcohol ingestion is toxic because it is metabolized through formaldehyde to formic
acid, both of which have severely deleterious e ects on most tissues of the body. Ingestion of as little as 10
mL of methanol can cause blindness and 30 mL can be fatal.

The liver changes on histology as a consequence of long-term alcohol ingestion re ect the degree of
hepatocyte damage:

◆ steatosis with fatty change but no signi cant in ammation. This usually resolves unless the alcohol

Downloaded from https://academic.oup.com/book/31816/chapter/266636047 by University of Sydney user on 25 September 2022

challenge continues

◆ steatohepatitis, which has progressed from steatosis to steatitis with an acute in ammatory cell
in ltrate. This can result in brosis

◆ alcoholic hepatitis with demonstrable hepatocyte damage, severe active in ammation, and
cholestasis. Some cases are fatal

◆ progressive hepatic brosis with linking brosis and early hepatocyte regeneration

◆ cirrhosis, which is brosis of the liver with nodular regeneration. This is classically micronodular
unless the patient subsequently gives up drinking, when it can progress to mixed and then
macronodular cirrhosis

◆ in about 5% of cases of alcoholic cirrhosis, hepatocellular carcinoma develops.

Gastric diseases associated with alcohol consumption include acute and chronic gastritis with enhancement
of the e ects of Helicobacter pylori infection if present, gastric erosions and ulcers, and gastric carcinoma.

The pancreas may develop acute pancreatitis, repeated attacks of acute pancreatitis, chronic pancreatitis,
and carcinoma of the pancreas. Pancreatic atrophy may occur and sometimes gives no symptoms of
abdominal or back pain, only symptoms and signs related to malabsorption.

Alcohol-induced diseases of the larynx are especially associated with consumption of undiluted spirits
rather than beer or wine. These patients develop chronic laryngeal in ammation and SCC of the larynx.
Other diseases in this group include SCCs of the pharynx and oesophagus.

Surgically important endocrine gland disordersThyroid

diseaseHyperthyroidism
The three thyroid hormones are T3, T4, and calcitonin. Excess of plasma calcitonin, such as in medullary
carcinoma of thyroid, has no apparent deleterious e ect though the carcinoma itself has a poor prognosis.
By convention hyperthyroidism refers only to the iodinated hormones. A patient can be found to have
normal thyroid function because it is driven by an elevated TSH concentration, and so in some cases
measurement of TSH is important.

Hyperthyroidism and thyrotoxicosis are terms used interchangeably. In mild hyperthyroidism there may be
no apparent toxicity. Some of these patients feel full of energy and might become unacceptably lethargic if
returned to normal thyroid hormone function. The clinical and biochemical diagnosis of hyperthyroidism
gives only a small indication of the underlying disease process.

Biochemically, the synthesis of thyroid hormones requires the coordinated action of several enzyme
systems. Iodination of the amino-acid tyrosine provides mono-iodotyrosine and di-iodotyrosine. Coupling
of these results in triiodothyronine and tetraiodothyronine, T3 and T4 (the name change re ects the fact
that tyrosine has one benzene ring and thyronine has two). The reactions depend on the supply of plasma
iodine salts, and can be excessive if iodine is in large supply. The tissue causes of hyperthyroidism are varied
but all result in excess secretion of T3 or T4, or both.

Hyperplasia of the gland is the commonest cause of hyperthyroidism in the United Kingdom. This can be
di use as in Graves’ disease, or focal as in a multinodular goitre in which a hyperactive, toxic nodule
develops. In Graves’ disease (named for Robert Graves who described the disease in 1835) the gland is
di usely enlarged, dark red, and beefy because of hyperplasia and hypertrophy of the follicular cells and
increase in the blood supply. There have been rare reports of Hashimoto’s disease developing in patients

Downloaded from https://academic.oup.com/book/31816/chapter/266636047 by University of Sydney user on 25 September 2022

with treated Graves’ disease. It is impossible to identify on routine histopathological sections which of the
nodules of a multinodular goitre are oversecreting: there is no relation to size, cellularity, or thyroglobulin
content.

Neoplasia of the thyroid can cause hyperthyroidism if the tumour cells are di erentiated and
hypermetabolic. A follicular adenoma can secrete excess T3 and T4. Di erentiated carcinomas of the thyroid
(papillary and follicular carcinomas) can also secrete T3 and T4. Another neoplasm rarely associated with
hyperthyroidism is a cystic teratoma (benign dermoid cyst) of the ovary with monophyletic di erentiation
into thyroid tissue. Surgical removal can cause abrupt hypothyroidism in the patient with hypotension and
bradycardia.

Much rarer than all of the neoplasms mentioned above is a TSH-secreting adenoma of pituitary, which
occurs with a prevalence of less than 2% of functioning pituitary neoplasms, which they themselves are
rare. This can be diagnosed by a raised serum TSH concentration in a patient with an increased serum T4
concentration.

There are several iatrogenic reasons for hyperthyroidism. There may be overtreatment with thyroxine
during replacement after thyroidectomy or treatment of hypothyroidism. Several drugs such as amiodarone
contain large amounts of iodine as do radiological investigations using iodine-based contrast media.

Hypothyroidism
Hashimoto’s thyroiditis (for Hakaru Hashimoto who described the condition in 1912) is an autoimmune
chronic lymphocytic thyroiditis in which the follicular cells are damaged by antibodies and cell-mediated
immune reactions. Antibodies are typically against thyroglobulin, thyroid peroxidase, and cell structures
including TSH receptors. The cell-mediated damage is by CD4 and CD8 T cells and macrophages, as a type IV
hypersensitivity reaction though granulomas are not typical of Hashimoto’s disease.

In early Hashimoto’s disease there is no hyperplasia but active destruction of the thyroid follicles, which
release stored T3 and T4 from thyroglobulin and can cause transient hyperthyroidism before the destructive
process results in atrophy. Unlike in Graves’ disease, in Hashimoto’s thyroiditis the gland is enlarged but
pale because of the large in ltrate of lymphocytes and developing brosis. A rare complication is the
development of NHL of B cell type.

Other thyroiditides
Riedel’s thyroiditis ( rst described by Bernard Riedel in 1896) is a rare focal condition characterized by a
very dense brotic mass that extends beyond the thyroid capsule into surrounding structures such as the
strap muscles. The surgical signi cance is that it closely mimics thyroid carcinoma, and that about one-
third of patients with the condition have hypothyroidism. There is no apparent association with the
development of brosarcoma.
De Quervain’s thyroiditis (Fritz de Quervain, 1902) is a rare granulomatous thyroiditis linked with viral
infections such as adenovirus and Coxsackie virus. The patient may present with hyperthyroidism in the
early stages and hypothyroidism in the later stages. The disease is usually self-limiting but operative
surgery may be required to make the diagnosis.

Thyroid neoplasms
The ve thyroid neoplasms most commonly seen in general surgical practice are papillary, follicular,
medullary, and anaplastic carcinoma, and thyroid lymphoma. The order given for the carcinomas relates to

Downloaded from https://academic.oup.com/book/31816/chapter/266636047 by University of Sydney user on 25 September 2022

prevalence and prognosis. Other rare neoplasms include thyroid teratoma and lymphangiosarcoma. In view
of the high blood supply of the thyroid, metastatic carcinoma to the gland is surprisingly rare.

Papillary carcinoma
Papillary carcinoma accounts for about 80% of thyroid carcinomas and is multifocal in about half of cases
(the multifocality can a ect both lobes and the isthmus). It is an incidental nding of no signi cance in
about 2% of postmortem examinations in patients with no other malignancy. There is no benign
counterpart.

The tumour is related to thyroid irradiation, nowadays more commonly from escape of radioactive iodine
from nuclear power plants than from direct radiation used with the intention of therapy. The histological
appearance of papillary carcinoma is not directly related to its behaviour in terms of invasiveness except for
the tumour size: small tumours of about 0.5 cm diameter are associated with nodal metastases in about half
of cases, larger tumours in 80% of cases. It has a prognosis overall of about 90% after 5 years.

Follicular carcinoma
Follicular carcinoma accounts for about 15% of thyroid carcinomas. In contrast to papillary carcinoma it is
rarely multifocal, rare as an incidental nding at postmortem, and rarely related to radiation exposure. It
metastasizes through the bloodstream to bone marrow and lungs.

The histological appearance is usually of a well or moderately di erentiated carcinoma. Diagnosis depends
on the behaviour of the tumour cells rather than their appearance—thyroid adenomas can have mitoses and
pleomorphic cell forms. Demonstration of capsular or vascular invasion at the periphery of the tumour, or
both, is diagnostic. Follicular carcinoma has a prognosis of about 70% after 5 years.

Medullary carcinoma
Medullary carcinoma of thyroid is a malignant neoplasm of C cells; there is no benign counterpart. It has a
prevalence of about 5% of thyroid carcinomas overall. When it arises spontaneously, in about three-
quarters of cases, it tends to be unilateral. When associated with MEA II syndromes and so genetically
determined, it accounts for the other third of cases and is almost always bilateral in the thyroid.

Medullary carcinoma derives from thyroid C cells which make calcitonin. Calcitonin from the tumour cells
accumulates within it and has a distinct histological appearance. The deposits of calcitonin among the
tumour cells stain with Congo red and have apple-green dichroic birefringence, and so ful l the simple
de nition of amyloid material. These amyloid deposits are strongly positive on immunostains for
calcitonin.

Metastasis is characteristically to lymph nodes and bone marrow, and is often extensive by the time of
diagnosis. Medullary carcinoma has a 5-year prognosis of about 90% if at excision it is completely con ned
to the thyroid; of about 70% if there are local lymph node metastasis; and about 20% if other tissues are
involved. Overall there is a 5-year survival of about 60%.

Anaplastic carcinoma
Anaplastic carcinoma accounts for about 2% of thyroid carcinomas. These characteristically arise in iodine-
de cient areas or in a multinodular goitre. Dedi erentiation of a di erentiated carcinoma, such as a
follicular carcinoma into an anaplastic carcinomas, has almost the same prognosis as the anaplastic type.
Metastases of anaplastic carcinoma are early to distant sites through lymphatic and blood vessels. Local,
fatal invasive and compressive e ects in the neck, especially with retrosternal extension and massive

Downloaded from https://academic.oup.com/book/31816/chapter/266636047 by University of Sydney user on 25 September 2022

haemorrhage, may preclude the antemortem diagnosis of metastatic spread. It has a 1-year survival rate of
almost zero. Young men who develop thyroid carcinoma, which is very rare, almost always develop
anaplastic carcinoma.

Diagnosis of thyroid cancer

This depends on clinical examination, ne-needle aspiration cytology (FNAC) and in equivocal cases,
diagnostic thyroid lobectomy. Ultrasound of the neck should precede FNAC to exclude vascular and other
causes of the neck mass.

All of the ve histological types of thyroid cancer can be diagnosed on FNAC except one:

◆ Papillary carcinoma: all papillary neoplasms are malignant: there is no entity of papillary adenoma.
They can be diagnosed on FNAC provided that tumour papillae are present on the cytology slide.

◆ Follicular carcinoma: no follicular thyroid lesion can be given a de nite diagnosis on FNAC. The
di erential diagnosis includes normal thyroid parenchyma, follicular adenoma, follicular carcinoma,
a dominant nodule in a multinodular gland, and a colloid thyroid nodule. An enlarged parathyroid
gland, which also may have follicles and which may be intrathyroid, may also have been sampled.

◆ Medullary carcinoma: this is usually easy to diagnose, with regular polyhedral cells in an amyloid
matrix that can be seen on the cytology preparation.

◆ Anaplastic carcinoma: this is usually easy to diagnose; the severe anaplasia is usually very obvious. A
possible di erential diagnosis is high-grade thyroid lymphoma.

◆ Thyroid lymphoma: this can usually be di erentiated from severe lymphocytic thyroiditis because of
the monomorphism of the cells of the neoplasm.

The diagnosis of follicular carcinoma depends on the histological demonstration of invasion of the capsule
or peripheral vessels. This requires a well- xed excision specimen of a solitary thyroid mass or of the entire
thyroid gland. The concern regarding frozen-section examination is that handling of the fresh tissues can
transpose tumour cells artifactually into vessels and outside the capsule. Even on numerous well-orientated
sections from xed tissue this can be a problem. It is resolved by nding an endothelial cell covering of
tumour cells in vessels, indicating that this had occurred in vivo. This subtlety is very di cult on frozen
sections, which are usually at least ve times the thickness of a para n-wax section.

Lymphomas that involve the thyroid are of NHL type in almost all cases. The development of NHL is
associated with Hashimoto’s disease and more rarely with Graves’ disease. Given a rm diagnosis of NHL,
surgery is not indicated: chemotherapy without excision can give a 5-year prognosis of 85%.
Parathyroid diseaseHyperparathyroidism
Almost all cases of excess secretion of parathyroid hormone (PTH) are from eutopic secretion from a
parathyroid neoplasm or from parathyroid hyperplasia, which is idiopathic. Frozen section diagnosis has no
proper place in the identi cation of parathyroid disease, only in the con rmation that the tissue sampled is
parathyroid. The tissue could be a thyroid nodule, a lymph node, the thymus, a strap muscle, or other
tissues. Parathyroid adenocarcinoma is very rare and would usually not be diagnosed on frozen section.

In primary hyperparathyroidism, the disease is an adenoma in 85% of cases, hyperplasia in 15%, and
carcinoma in very much less than 1%. Primary hyperparathyroidism is common and often asymptomatic. It

Downloaded from https://academic.oup.com/book/31816/chapter/266636047 by University of Sydney user on 25 September 2022

causes hyperparathyroid bone disease by generalized stimulation of osteoclasts with bone resorption and of
osteoblasts with inadequate mineralization of osteoid, both of which can lead to pathological fractures.

Secondary hyperparathyroidism results from hypocalcaemia, usually from chronic renal failure in which
there is abnormal tubular loss of calcium and retention of phosphate, and failure of 1-hydroxylation of
vitamin D in the kidney to its active form. Other causes include dietary de ciency of vitamin D, especially
aggravated by a long winter with little sunlight. Vitamin D inhibits the transcription of DNA for PTH and so a
decrease in plasma vitamin D will result in secondary hyperparathyroidism even without hypocalcaemia. In
pregnancy, there are increased demands from the developing fetus which can cause hypocalcaemia. In
tertiary hyperparathyroidism, there is adenoma development in one or more of the hyperplastic glands of
secondary hyperparathyroidism.

Hypoparathyroidism
Hypoparathyroidism is largely a medical, endocrinological disease but there are important surgical reasons
for being aware of the condition. In terms of symptoms, a patient may present surgically with severe
abdominal pain or bone pain. The patient may have head injuries because of epileptic ts, bronchospasm
causing anaesthetic di culties, and cardiac arrhythmias, so it is important that hypoparathyroidism is
considered.

Operative surgery on the neck for many reasons may result in hypoparathyroidism. In addition to the well-
recognized complications of partial parathyroidectomy and bruising or infarction of the remaining gland or
glands, there have been cases in which the patient has had hypercalcaemia treated by excision of three
glands, and subsequently has needed a partial thyroidectomy for an unrelated reason. About 10% of
parathyroid glands are intrathyroid, and so the result can be inadvertent removal of the remaining glands.

Autoimmune destruction in patients who have parathyroiditis, autoantibodies to other endocrine glands
such as the thyroid, adrenals, and ovaries can occur. The severe chronic in ammation results in destruction
of the parathyroids. Congenital reasons for hypoparathyroidism include T-cell de ciency such as in
DiGeorge syndrome, in which the parathyroid glands are hypoplastic or aplastic.

Magnesium is essential for PTH secretion. De ciency can result from excessive alcohol intake, especially if
combined with a poor diet because of vomiting and diarrhoea, and from diabetes mellitus. The
hypoparathyroidism is reversed by correction of the hypomagnesaemia.
Adrenal gland diseaseCushingʼs disease and syndrome
Hypercortisolaemia de nes both the disease and the syndrome. Harvey Williams Cushing (1896–1937) was
a neurosurgeon in Boston, Massachusetts. He published his widely recognized paper on pituitary adenoma
in 1932, though had published before that on the same subject over the previous 15 years. Cushing’s disease
is a neoplasm of the pituitary gland which is almost always an adenoma. Cushing’s syndrome is the
collection of symptoms and signs that result from hypercortisolaemia from any cause including, rarely, a
pituitary adenoma.

The external and internal features of a patient with severe Cushing’s syndrome include:

Downloaded from https://academic.oup.com/book/31816/chapter/266636047 by University of Sydney user on 25 September 2022

◆ cortisol e ects such as:

• change in adipose tissue distribution, such as central obesity which with reduction of muscle tone
results in a pendulous abdomen; increase in adipose tissue between the scapulae; and reduction of
adipose tissue in the limbs with muscle wasting

• skin changes such as acne; purple striae and ecchymoses from capillary fragility; furuncles and
carbuncles related to the diabetogenic properties of cortisol

• other changes of diabetes mellitus

• osteoporosis with the risk of compression fracture

◆ aldosterone-like e ects of cortisol, such as generalized and localized oedema; when this a ects the
head it gives a rounded face augmented by adipose tissue deposition

◆ testosterone-like e ects of cortisol, responsible for male pattern baldness and hirsutism in women,
and amenorrhoea from suppression of ovarian hormone secretion.

The causes of Cushing’s syndrome are numerous. The commonest is iatrogenic, usually from treatment
with steroids such as prednisolone; adrenocorticotropin hormone (ACTH) is sometimes used instead of
steroids in children as it has less e ect on growth. Neoplastic causes include eutopic secretion of cortisol
from an adrenal adenoma and carcinoma; pituitary adenoma secreting ACTH stimulating the adrenals
bilaterally; and ectopic secretion of an ACTH-like substance from atypical carcinoid, oat cell carcinoma, and
islet cell tumour of pancreas.

Connʼs syndrome
Conn’s syndrome is primary hyperaldosteronaemia, whether from bilateral adrenal hyperplasia of the zona
glomerulosa cells of the adrenal cortex (in 65% of cases) or an adrenal adenoma which is usually unilateral
(in 35% of cases). Other causes, such as adrenal carcinoma and ectopic secretion of aldosterone, are rare. It
is named for Jerome W. Conn who described the condition in 1955. Secondary hyperaldosteronism is caused
by congestive cardiac failure with a rise in renin secretion from the juxtaglomerular apparatus of the kidney.

The sodium retention by the kidney as a result of the excess mineralocorticoid causes expansion of the
plasma volume and hypertension. The latter results in suppression of renin from the juxtaglomerular
apparatus. If the patient has Conn’s syndrome, the aldosterone:renin activity ratio can be measured to
con rm this.

Surgery is usually curative of a solitary adenoma, provided that there is no concomitant hyperplasia of the
zona glomerulosa cells adjacent to the neoplasm which might indicate bilaterality. Patients who have
bilateral hyperplasia can be treated with spironolactone or other suppressive agents, or by bilateral
adrenalectomy and steroid replacement therapy.

Addisonʼs disease
Addison’s disease (named for Thomas Addison, who described the disease in 1849 and 1855: his patients had
bilateral adrenal tuberculosis) is a rare endocrine disorder in which the adrenal glands are severely
damaged. This may be due to infection, in ammation from other causes, or failure of adequate
development. The hormone de ciency that results predominantly is from inadequate steroid hormone
production rather than inadequate catecholamine production.

Downloaded from https://academic.oup.com/book/31816/chapter/266636047 by University of Sydney user on 25 September 2022

The most common symptoms are non-speci c and can be di cult to diagnose; President J. F. Kennedy had
undiagnosed Addison’s disease for some time. Dizziness, muscle pain and weakness, pyrexia, weight loss,
postural hypotension, nausea and vomiting, diarrhoea, sweating, and swings in mood and personality are
all features and all non-speci c. Hyperpigmentation of the skin, especially in sun-exposed sites, skin
creases, and the skin of genitalia and nipples can occur as the result of pituitary overproduction of pro-
opiomelanocortin, the precursor of ACTH (as a reaction to the hypocortisolaemia) and of melanocyte-
stimulating hormone.

Waterhouse–Friderichsen syndrome, in which the adrenal glands are destroyed characteristically in

meningococcal septicaemia but also in any severe haemorrhagic diathesis, is not considered to be Addison’s
disease. Autoimmune endocrine organ destruction of the thyroid and pancreas, such as type 1 diabetes and
Hashimoto’s thyroiditis, occur more frequently in patients with Addison’s disease. Autoimmune adrenalitis
is the commonest cause of Addison’s disease in the Western world.

Congenital causes of Addison’s disease include adrenal agenesis or hypoplasia, and inborn errors of
metabolism in terms of steroidogenesis. The commonest form of the rare condition of congenital adrenal
hyperplasia (CAH) is 21-hydroxylase de ciency (95% of cases) followed by 11-hydroxylase de ciency (5%
of cases). The other enzymes involved in steroidogenesis are much less commonly implicated. The surgical
signi cance of CAH is that the consequent increase in ACTH drive will a ect ectopic adrenal cortical gland
rests below the capsule of the kidney and below the tunica of the testis. The diagnosis of a testicular mass as
a Leydig cell tumour in a young man should raise the question of CAH as the hyperplastic ectopic
adrenocortical cells can closely resemble neoplastic Leydig cells (which are also steroidogenic).

Drugs such as ketoconazole and other azole antifungals suppress the enzymes for steroid synthesis. Others
stimulate liver enzymes that facilitate its capacity to metabolize steroids, such as phenytoin and some
antituberculosis drugs.

Pituitary gland diseaseAcromegaly

Acromegaly is the name for the range of clinical e ects of excess growth hormone in an adult body, that is,
in a patient beyond the age at which bone and other normal growth has ceased.

The cause of acromegaly is almost always hGH excess secreted from a somatotroph adenoma of the anterior
pituitary gland. Very rarely there can be ectopic secretion of hGH from a carcinoma of the pancreas,
bronchus, or small intestine.

Diseases of surgical importance caused by acromegaly include:

◆ osteoporosis and pathological fractures

◆ an increased incidence of neoplastic large bowel polyps and adenocarcinoma of large bowel: hGH acts
 on the liver to cause it to secrete insulin-like growth factors, which stimulate mucosal cells in the
large bowel to divide

◆ an increased incidence of gallstones and gall bladder disease, hernia, and of the complications of
diabetes mellitus

◆ abnormality of bite from increase in size of the mandible.

Eutopic and ectopic hormone secretion by neoplasms

Downloaded from https://academic.oup.com/book/31816/chapter/266636047 by University of Sydney user on 25 September 2022

Eutopic tumour secretion of hormones is from tissues that normally secrete hormones, by neoplasms that
are su ciently di erentiated to do so. These include di erentiated neoplasms of the:

◆ adrenal: adrenal adenoma and carcinoma

◆ thyroid: follicular adenoma (papillary adenoma does not exist) and papillary and follicular carcinoma

◆ pituitary: adenomas of the cells of the anterior pituitary, many of which are very rare, and carcinomas
which are rarer

◆ liver: hepatocellular carcinoma can secrete erythropoietin (5% of plasma erythropoietin is provided
by the normal liver)

◆ ovary: granulosa cell tumour and thecoma.

Ectopic secretion of hormones is from tumours of tissues that do not normally secrete such hormones:

◆ the small intestine and respiratory system can develop carcinoid tumours, atypical carcinoids and oat
cell carcinoma, all of which are neuroendocrine neoplasms that can secrete 5-hydroxytryptamine, 5-
hydroxytryptophane, and polypeptide sequences with the biological activity of antidiuretic hormone
and adrenocorticotrophic hormone

◆ neoplasms of the lung, breast, kidney, pancreas, colon, and adrenal can secrete PTH-like polypeptide
sequences with biological activity

◆ liver neoplasms, especially hepatocellular carcinoma, can secrete beta-human chorionic

gonadotrophin

◆ pancreatic islet cell neoplasms can secrete gastrin, which is not a normal part of the repertoire of the
pancreas

◆ medullary thyroid carcinoma, paragangliomas, prostate cancer, and islet cell neoplasms can secrete
ACTH

◆ breast, bronchial, renal, and prostate tumours can secrete PTHrP, which is a small peptide in which 8
of the rst 16 amino acids are homologous with PTH

◆ lymphomas can produce 1,25-dihydroxycholecalciferol.

Multiple endocrine adenopathy

Multiple endocrine adenopathy is the name for a collection of syndromes involving endocrine organs. The
diseases in these organs can be hyperplasia, adenoma, or carcinoma. The syndromes run in families and
tend to breed true: a family with MEA I would not be expected to develop phaeochromocytoma more often
than chance. In any extended family some members might get one or two aspects of a syndrome, or in
severe cases, all.

MEA I

Downloaded from https://academic.oup.com/book/31816/chapter/266636047 by University of Sydney user on 25 September 2022

This comprises some or all of:

◆ adenoma or carcinoma of the pancreatic islet cells

◆ adenoma (very rarely an aggressive tumour) of the pituitary

◆ hyperplasia of the parathyroid glands.

MEA IIa
◆ Medullary carcinoma of thyroid

◆ Phaeochromocytoma of adrenal, which may be benign or malignant and has a higher prevalence of
bilaterality than in phaeochromocytomas not related to MEA II

◆ Hyperplasia of the parathyroid glands.

MEA IIb
◆ Medullary carcinoma of thyroid

◆ Phaeochromocytoma of adrenal, which may be benign or malignant and has a higher prevalence of
bilaterality than in phaeochromocytomas not related to MEA II

◆ Submucosal neuro bromas of the palate

◆ Hyperplasia of the parathyroid glands.

Vascular diseases of surgical importance

Atheroma

Cholesterol handling
Most cholesterol in the body is made by human cells—only about 1 g/day of preformed cholesterol is
absorbed from food. Cholesterol is needed in general for plasma membrane synthesis, for steroid hormone
production in the adrenal cortices and gonads, and for vitamin D synthesis in the skin.

The plasma cholesterol concentration is controlled by cytochrome P450-mediated oxidases in the liver; the
cholesterol is metabolised into the bile acids cholic acid and chenodeoxycholic acid. These are then
conjugated principally with glycine and tauric acid to form bile salts. Normal bile contains cholesterol, bile
acids, and bile salts. Almost all of the cholesterol metabolites are reabsorbed in the small intestine linked to
lipids from the diet, with which they form micelles necessary for lipid digestion.

Bacterial enzymes in the large bowel dehydroxylate the small proportion of cholesterol metabolites that are
not absorbed into secondary bile acids, deoxycholic acid and lithocholic acid; cholic acid becomes
deoxycholic acid, chenodeoxycholic acid becomes lithocholic acid. All four bile acids can be reabsorbed and
resecreted by the liver.

Low-density lipoprotein

Downloaded from https://academic.oup.com/book/31816/chapter/266636047 by University of Sydney user on 25 September 2022

An LDL particle is formed of an apolipoprotein molecule linked with phospholipids synthesized in the liver.
This has a hydrophobic layer which wraps around over 1000 cholesterol molecules. Because LDL particles
can also transport cholesterol into the artery wall, increased levels are associated with atheroma. The lipid
is xed in the intima by macrophages that engulf the LDL particles and start the formation of plaques.

High-density lipoprotein
HDL particles are smaller than LDL particles—they contain the highest ratio of apolipoprotein to
cholesterol. They internalize cholesterol from cell cytoplasm and from other lipoproteins and transport it to
the liver and steroid-producing organs. They can remove cholesterol from an atheromatous plaque and
carry it to the liver for excretion. Patients with high levels of HDL have relatively low rates of cardiovascular
disease, those with low levels of HDL have higher.

HDLs and their contents have antioxidant properties, mediate anti-in ammatory e ects, and inhibit
platelet aggregation. The acute phase apolipoprotein serum amyloid A (SAA) protein is produced by the liver
in response to stress in response to interleukins released from macrophages at an in amed site. It carries
glucocorticoids from the adrenal to sites of in ammation, where it is chemotactic and stimulatory for
leucocytes. In its usual low and temporary plasma concentrations, SAA protein is soluble and harmless, but
in severe unremitting chronic in ammatory conditions such as rheumatoid arthritis and bronchiectasis, the
prolonged exposure causes polymerization of SAA protein in the tissues into insoluble amyloid material.

Atheroma/atherosclerosis
Atheroma or atherosclerosis is the term used for arterial-wall deposits of lipid material which may progress
to pools of lipid in the intima and sometimes deeper into the media called atheroma. Many people use these
two terms interchangeably for the whole disease process. Atheroma is a disease of elastic and medium-sized
muscular arteries down to 1 mm in diameter. The abdominal aorta and the left anterior descending coronary
artery (LAD) are the commonest sites of atheroma; the LAD is the commonest site to develop complications
of atheroma. The changes in sequence classically begin with endothelial cell interactions with leucocytes,
platelets, and myo broblasts. There is endothelial cell injury from free radical formation from several
factors: LDL and the cholesterol carried by it impair the ability of the smooth muscle cells in the wall to
contract and dilate, and the antioxidant properties of the endothelial cells is exceeded; hyperglycaemia and
chemicals from cigarette smoke damage the metabolism of endothelial cells; and in ammatory mediators
17
from leucocytes cause further damage.

Macrophages derived from monocytes in the circulation enter the intima and phagocytose LDL cholesterol
to form characteristic cells with intracellular lipid called foam cells. They secrete cytokines which injure the
endothelium further and add to in ammation in the a ected intima. As well as the build-up of LDL
cholesterol and phospholipids, calcium is deposited and there is developing brosis leading to plaque
formation with a lipid pool under the brous plaque. The ow of blood in the artery is increasingly deranged
contributing to platelet deposition and surface thrombosis.

18
The American Heart Association has classi ed the changes into six stages leading to the development of
full-blown atheromatous disease:

Stage Scattered foamy macrophages in the arterial intima

I

Downloaded from https://academic.oup.com/book/31816/chapter/266636047 by University of Sydney user on 25 September 2022

Stage Fatty streaks in the intima visible to the naked eye, in which there are more closely aggregated foamy macrophages
II

Stage Scattered collections of extracellular lipid in the intima

III

Stage Pools of extracellular lipid that in time coalesce into a single pool
IV

Stage Fibroblasts around the lipid pool secrete tropocollagen which trimerizes into fibrous tissue; dystrophic calcification
V starts to become common

Stage Complicated atheromatous disease develops with endothelial cell loss and surface thrombus formation;
VI embolization of this and of atheromatous lipid from a ruptured plaque can occur; calcification can become severe.

Reproduced from Stroke, Volume 43, Issue 12, Karen L. Furie et al., Oral Antithrombotic Agents for the
Prevention of Stroke in Nonvalvular Atrial Fibrillation: A Science Advisory for Healthcare Professionals
From the American Heart Association/American Stroke Association, pp. 3442–53, 2012. With permission
from Wolters Kluwer Health.

Risk factors in general include being a man, having a family history of atheroma or a complication of it
(such as a stroke or myocardial infarct), and having one of the high-risk familial hyperlipidaemias. More
speci c risk factors include a high plasma concentration of LDL and a low concentration of HDL;
hypothyroidism, for example, causes plasma LDL and cholesterol concentrations to rise. The e ectiveness
of drugs intended to lower cholesterol is debated. Hypertension per se increases the risk of atheroma, as do
diabetes mellitus and cigarette smoking. Other factors that probably contribute to some extent include lack
19
of exercise, obesity, high dietary saturated fats, and gout.

The serious complications of atheroma include ischaemia from gradual occlusion of the artery from
accumulation of lipid in the plaque; haemorrhage into or rupture of a plaque causing rapid thrombus
formation; embolus from a plaque, which may be thrombus from the surface or lipid from the lipid pool;
and eventually aneurysm formation.

Aneurysms

An aneurysm is an abnormal localized dilatation of a blood vessel including arteries, the heart, arterioles,
and veins in descending frequency. Aneurysmal dilatation of lymphatic vessels may rarely occur.
They are classi ed variously into:

◆ congenital or acquired: congenital causes include full malformation of vessels, such as veins as in a
cirsoid aneurysm of scalp; or malformation of part of a vessel wall, such as in a berry aneurysm of the
anterior communicating branch of the circle of Willis, in which there is a congenital de ciency in the
media of the artery which manifests as an aneurysm only in adult life

◆ true or false: whether all three layers of the wall are present in the aneurysm or only some,
respectively

◆ by shape: saccular if only part of the circumference is involved, fusiform if the entire circumference is

Downloaded from https://academic.oup.com/book/31816/chapter/266636047 by University of Sydney user on 25 September 2022

involved, and dissecting when the arterial media is de cient

◆ by cause, probably the most informative classi cation

• atheroma: descending aorta below the renal arteries below the renal arteries, and the LAD

• syphilis: dissecting aneurysm of the aorta because of thrombosis of the vasa vasorum in which the
Treponema pallidum organisms live

• Erdheim’s cystic medionecrosis and Marfan’s syndrome from damage to the aortic media. Both of
these conditions are autosomal dominant

• mycotic: low-grade bacterial infection or rarely fungal infection

• in ammatory other than the above listed: polyarteritis nodosa, aortitis in ankylosing spondylitis

• ischaemic: ventricular aneurysm after myocardial infarction

• traumatic: from a penetrating injury, deceleration trauma, and subclavian artery damage from a
cervical rib

• hypertension: microaneurysms in the lenticulosriate artery

• iatrogenic: arteriovenous aneurysm in a dialysis shunt.

The complications of an aneurysm are internal and external. Internal complications include thrombosis
with ischaemic e ects, and embolism. External complications usually occur later: from pressure e ects in
the thorax from an aneurysm of the arch of the aorta on the oesophagus, vertebral column, and sternum, or
from an abdominal aortic aneurysm compressing the inferior vena cava; and external haemorrhage from
rupture with or without dissection.

Compartment syndrome

Compartment syndrome is caused when the pressure in a closed anatomical space exceeds the perfusion
pressure of the blood passing through it. The consequent reduction or cessation of circulation may cause
temporary or permanent ischaemic damage to muscles, tendons, and nerves. Acute compartment syndrome
comprises recurrent pain and disability on exercise which subside when the exercise is stopped. The pain is
induced by passive movement and is intense, out of proportion to the physical clinical changes on
examination of the a ected part. Late changes indicative of permanent damage are pallor and pulselessness.
There is a chronic counterpart of the acute syndrome, in which the volume of the compartment is
permanently restricted because of thickened fascia and muscle hypertrophy.
Causes of acute compartment syndrome can be divided into those from external restriction and those from
internal restriction. The rst include direct physical trauma to a compartment; iatrogenic causes, such as
tight fascial closure and tight splints or plaster casts; burns with formation of tight eschar; and very tight
clothing. Internal causes include acute bleeding after direct trauma, fractures, or operative surgery;
bleeding diatheses; crush injuries and deep burns; and any cause of severe rhabdomyolysis such as drug
overdose and snake bite.

Sites typically a ected by acute compartment syndrome are the limbs. The forearm has two related
compartments, the leg four, and the foot several. The abdomen can develop compartment syndrome after
repair of an abdominal aortic aneurysm. A ected indirectly are the kidneys, by acute tubular necrosis from

Downloaded from https://academic.oup.com/book/31816/chapter/266636047 by University of Sydney user on 25 September 2022

myoglobinaemia, and the heart from the related hyperkalaemia.

Ischaemia reperfusion injury

Ischaemia reperfusion injury is the damage that results from sudden re-introduction of oxygenated blood
to an area of ischaemia. There is cellular damage from oxygen free radicals, DNA breaks, and enzyme
disruption. Activation of prostaglandins and the complement system causes further in ammatory e ects
including platelet–leucocyte aggregation, leucocyte–endothelial cell adhesion, and increased vascular
permeability. These changes can a ect any reperfused tissues, such as muscles in compartment syndrome
and after prolonged tourniquet use, the heart after cardiopulmonary bypass, and the liver during liver
surgery and transplantation.

Treatment is often di cult. Possible approaches include:

◆ ischaemic preconditioning where appropriate

◆ controlled reperfusion

◆ antioxidant therapy

◆ prostaglandin inhibition by indomethacin.

Injury and mechanical abnormalities

Endogenous

Herniation
A hernia is a protrusion of tissue from the body compartment in which it is anatomically correct into
another body compartment. Predisposing factors include increased pressure in the donor compartment
coupled with an actual or incipient weakness in the boundary of the compartment. In the abdomen, this can
result in inguinal, femoral, and obturator hernias, and diaphragmatic hernias such as hiatus hernia and
those of Morgagni and Bochdalek. In the CNS, increased intracranial pressure can result in herniation of the
cingulate gyrus underneath the falx, of the uncus through the tentorium, and of parts of the cerebellum
through the foramen magnum.

Other predisposing factors are that there might be congenital absence of normal tissue at a site, such as
congenital diaphragmatic hernia with aplastic muscle, or weakness of tissues with normal pressure in the
donor compartment, as in an incisional hernia. General factors such as nutrition and immunode ciency are
also important.

The complications of herniation are mainly from pressure e ects. There may be obstruction of a hollow
viscus such as the small and large intestines (including the appendix) in lower abdominal hernias, and with
incarceration and ischaemia or infarction. In the upper abdomen, the e ects might be on the upper
alimentary system, such as re ux or obstruction, or might be on adjacent organs and cause respiratory
compromise and cardiac arrhythmias. In the CNS, the complications are not usually the loss of function of
the herniated element but of the part of the brain compressed as a consequence: in the list above these
would be the corpus callosum, the midbrain, and the brainstem, respectively.

Downloaded from https://academic.oup.com/book/31816/chapter/266636047 by University of Sydney user on 25 September 2022

Diverticula
A diverticulum is an abnormal outpouching of a hollow viscus. Diverticula are classi ed as congenital and
acquired, true and false, and pulsion and traction. True diverticula have all of the components of the wall
and are usually the result of congenital malformation, for example, Meckel’s diverticulum in the ileum and
duodenal diverticula. False diverticula have only part of the wall of the viscus present and tend to be
acquired, such as sigmoid, bladder, and oesophageal diverticula.

The complications of diverticula are characteristically the consequences of abnormal anatomy and the
predisposition to in ammation and infection: haemorrhage, abscess and stula formation, and perforation.
In ammation may lead to metaplasia, dysplasia, and malignant change, as in a bladder diverticulum. There
may be ectopic gastric and pancreatic tissues in a Meckel’s diverticulum, with ulceration as a consequence
of the former, and a small tendency to torsion because of the abnormal anatomy. Duodenal diverticula may
become colonized by bacteria and result in the blind loop syndrome with vitamin de ciencies.

Exogenous

Fractures and fracture healing

20
Fractures are classi ed by :

◆ location: by the name of the fractured bone and the position of the fracture within that bone, such as
fracture through the neck of the femur

◆ fracture line:

• transverse, when the line is at 90° to the long axis of the bone

• oblique when the line is at a straight angle

• spiral when the line curves, usually resulting from a twisting force

• comminuted, when more than two fragments are present—this might be segmental, in which the
bone is fractured at two separate levels

• impacted, when the ends are driven together

• compressed, as in vertebral body fracture

• depressed, by a localized force that moves one aspect of the fracture site inwards or downwards

◆ displacement: when bone fragments have moved and are not in alignment.
Fracture healing
From the moment of fracture, there are seven typical stages in the healing of a fracture of a long bone. The
rst is haematoma formation, the size of which is limited by arterial contraction and by the pressure of the
periosteum when it is intact. The second, in ammatory phase follows the usual processes of acute
in ammation with vasodilatation, exudate formation, and polymorph in ltration. The demolition phase
begins when the in ammatory process becomes chronic: local and recruited macrophages digest the
haematoma and with osteoclasts remove dead bone fragments. Organization follows with granulation tissue
extending from below the periosteum and out of the fractured bone ends.

Downloaded from https://academic.oup.com/book/31816/chapter/266636047 by University of Sydney user on 25 September 2022

In the later stages there is rst early callus formation, in which osteoid bres (a form of collagen) are laid
down rapidly and randomly and mineralize to form woven bone, so-called because the pattern of bres
resembles felt, with no organized Haversian canals at this stage. There may also be cartilage formation. Late
callus formation follows, when the woven bone is slowly and precisely absorbed by osteoclasts, and
osteoblasts lay down lamellar bone with Haversian systems. The nal stage, which can take months or
years, is remodelling during which the normal shapes of the bone and bone marrow are resumed.

Abnormalities of fracture healing are essentially defects in union of the bone. The most severe is non-union,
usually as a consequence of interposition between the bone ends of connective tissues, such as muscle or
fascia, and sometimes a foreign body. Delayed union may result from infection, particularly in compound
fractures; movement of the fracture site; presence of a foreign body; and ischaemia which especially a ects
fractures of the neck of the femur, the shaft of the tibia, and the scaphoid bone. Malunion refers to healing
that has not followed the usual processes; an example is brous union when there is excessive brous tissue
between the fracture ends that permits movement, possibly after repeated fractures at the same site. In
some of these pseudarthroses can develop. Osteoarthrosis in the joints above and below the fracture site is
the commonest long-term outcome of abnormal union.

Pathological fractures
A pathological fracture is one through a previously abnormal bone, irrespective of the force of the physical
trauma. The underling bone disease can be anything that weakens the bone. The two commonest diseases
associated with pathological fracture are osteoporosis and metastatic carcinoma. Less common are
metabolic bone diseases such as vitamin D de ciency causing rickets with greenstick fractures and
osteomalacia, and bone diseases seen in chronic renal failure and primary hyperparathyroidism. Primary
bone neoplasms, Paget’s disease of bone, and radionecrosis after radiotherapy also cause pathological
fracture. Probably the rarest cause is congenital bone disease such as osteogenesis imperfecta.

Burns

Many injurious agents can cause some of the tissue changes found in burns of the skin, but the
characteristic causes are thermal injury producing cell damage by protein coagulation, chemical damage
destroying cell membranes and organelles directly, and ionizing radiation inducing free-radical formation.
Thermal injury could be from the e ects of excessive heat, for example, from re, hot solids like kettles, hot
liquids such as water or fat, and from severe friction. Electric current of a high voltage also produces
thermal burns.

Chemical injury may be from spillage of corrosives such as acids, alkalis and other industrial products, and
from naturally-occurring irritants like the sap of Rhus typhina, which cause mild burns in some people but
severe burns in many people if they are exposed to sunlight at the same time as the sap
(photophytodermatosis). Ionizing radiation causes burns by providing the energy for free-radical
formation and also DNA damage.

There are classically three zones of overlapping but recognizable histological change in a burn. In the
central part is the coagulation zone, of dead tissue in which the proteins have coagulated and the DNA
destroyed. Around this and deep to it is the zone of ischaemia, in which the tissues are viable but subject to
su cient vascular damage that they will die after some days if untreated. Around both of the rst two zones
is the hyperaemic zone, in which the tissues are not fatally injured and develop vasodilatation from the
vascular e ects of in ammatory mediators.

Downloaded from https://academic.oup.com/book/31816/chapter/266636047 by University of Sydney user on 25 September 2022

Classification of burns
Skin burns are classi ed in terms of the extent of the burn, the depth of tissue destruction, the prognostic
outcome, and by the risk to speci c people in a population.

The extent of burns is determined by the percentage of body area involved, estimated by the ‘rule of 9s’:

◆ head and neck 9%

◆ upper limb each 9%

◆ front of thorax and abdomen 18%

◆ back of thorax and abdomen 18%

◆ lower limb each 18%

◆ genitalia 1%.

In young children, the head is proportionately much bigger and the lower limbs smaller than in adults. Their
percentages are reversed—the head and neck in children 18%, the lower limbs each 9%. In terms of risk, the
high-risk group includes children under 10 years and adults over 50 years and the low-risk group, patients
21
aged 10–50 years.

A rst-degree burn involves only the epidermis. It may have the three zones on histology just described but
the central necrotic zone can be very small or missing. The burn is hot, erythematous, and oedematous but
does not blister. It remains painful for 2–3 days and usually heals within a week without treatment; lasting
tissue damage like brosis is rare but pigmentation changes can take months to resolve.

A second-degree burn involves the epidermis and the dermis but not the subcutis. The depth of dermal
damage has prognostic importance. The burn has a variegated appearance: it is usually dark red with blister
formation and shiny from exudate, with areas of pale grey necrotic tissue. Pain lasts for more than a week.
The degree of scarring depends on whether the burn involves super cial dermis alone or the deep dermis as
well. In general, super cial second-degree burns heal in about 3 weeks, deep second-degree burns take
longer than that.

A third-degree burn destroys tissue at least as far as subcutis. The burn is painless as the dermal nerve-
endings are necrotic or vaporized, and is usually pale, dry and rough or black with eschar (Latin eschara, a
hearth, hence the mark left by a burn). These burns do not heal without debridement and skin coverage, and
even then are prone to severe scarring.

In terms of risk and prognosis, burns can be assessed by a combination of several variables.

◆ Minor burns include:

 • partial thickness burns involving less than 15% of body surface area (BSA) in low-risk patients

• partial thickness burns involving 10% of BSA in high-risk patients

• full thickness burns of less than 2% of BSA with no other injuries.

◆ Moderate burns include:

• partial thickness burns of 15–25% of BSA in low-risk patients

• partial thickness burns of 10–20% of BSA in high-risk patients

Downloaded from https://academic.oup.com/book/31816/chapter/266636047 by University of Sydney user on 25 September 2022

• full thickness burns of 3–10% of BSA with no other injuries.

◆ Major burns include:

• partial thickness burns of more than 25% of BSA in low-risk patients

• burns involving the face, hands, feet, or perineum

• burns involving major joints of a limb

• burns complicated by:

■ severe electrical damage

■ inhalation injury

■ fractures.

Apart from the direct tissue damage, complications of burns include compartment syndrome, renal damage
from myoglobinaemia, hypoproteinaemia, and hypovolaemia, and laryngeal oedema.

Nerve injuries

Nerve injuries are classi ed in general as Neuropraxia, axonotmesis, and neurotmesis. Neuropraxia (Greek
praxis, acting on) is a relatively minor injury to a nerve that recovers complete function. The damage
involves only the myelin sheath while the extent of the axon remains intact and so there is no Wallerian
degeneration. Axontmesis (Greek tmesis, a cut) refers to injury to the myelin sheath and to the axon but the
rest of the nerve remains with an intact endoneurial sheath and Schwann cell continuity. There is Wallerian
degeneration distal to the injury but the axon will normally regrow along the sheath. In neurotmesis the
whole nerve or nerve bundle is cut across and normal axonal regeneration cannot occur—worse, brosis
occurs within the nerve sheath and forms a barrier to axonal regeneration. Complete recovery is therefore
unlikely.

Nerves can be damaged by several mechanisms of surgical importance, the commonest being trauma. This
can be from intentional penetrating injuries from knives or bullets and accidental penetrating injuries from
car crashes, falling glass, and tin-opener mishaps. Nerve injury from fractures is uncommon but a
recognizable complication, especially in the upper limb: radial nerve damage is caused by fracture of the
humerus, and fracture-dislocation of the elbow causes ulnar nerve discontinuations. In the compartment
syndrome (which may itself be due to trauma) there may be nerve compression and discontinuity.
Compression injury to nerves is also caused by scar contraction and nerve trapping, and in stretch injury
there is typically axonotmesis with disruption of axons over long segments.
Degenerations and accumulations

Cyst formation
A cyst is an abnormal uid- lled cavity characteristically lined by epithelial cells. Amoebic cysts of the liver
and spleen have no speci c epithelial cell lining but are still called cysts. The cysts of cysticercosis are the
intermediate stage in the life cycle of Taenia solium and consist of the organism itself with no human
epithelial covering. The so-called cysts reported radiologically in diseases such as osteoarthritis are usually
solid but transradient and have no speci c lining.

Downloaded from https://academic.oup.com/book/31816/chapter/266636047 by University of Sydney user on 25 September 2022

Cysts can be congenital or acquired and arise from several processes:

◆ congenital cysts are usually from failure of a duct system to develop properly, such as
pancreaticobiliary and renal cysts, or in the case of thyroglossal and branchial cysts, failure to regress
properly. Less commonly, extraneous tissue can be included in developmental infoldings, as with
dermoid cysts of the face and head

◆ in ammatory cysts are also often the result of obstruction of a ductal system by the in ammatory
process. Examples include hydrosalpinx and true pancreatic cyst formation in chronic pancreatitis (as
opposed to pseudocyst formation in the lesser sac). Speci c organisms such as Echinococcus granulosus
(causing hydatid disease) and Taenia solium have cystic forms in human beings

◆ ischaemia can cause cystic degeneration in leiomyomas and cerebral infarcts but these have no
speci c epithelial lining

◆ traumatic implantation of surface epithelium can result in cyst formation, as in implantation

epidermal cyst and dermal cyst of skin

◆ cysts may be found in hyperplastic tissues such as the endometrium and breast

◆ neoplasia especially in the ovary and pancreas. Large parathyroid adenomas are almost always cystic,
though there is no speci c epithelial lining.

Calculi
A calculus (Latin calculus, a pebble or small stone) is an abnormal mass of solid material precipitated in a
duct or bladder. They can be primary, from an increase in the concentration of solute in a solution beyond
the capacity for the solvent to carry it. This occurs, for example, in the urinary system in gout when urate
calculi form, and in the gallbladder with pigment calculi as the result of haemolytic anaemia. Secondary
calculi are secondary to decrease in solvent, stasis, change of pH, nidus formation, or any combination of
these. For example, in pyelonephritis the nidus might be a necrotic fragment of a renal papilla and the
infecting organism (such as Proteus spp.) which causes the urinary pH to rise, resulting in a staghorn
calculus that exacerbates the condition with stasis.

Given the conditions for primary or secondary calculus formation, in theory they can develop in any ductal
system, but the classic sites are the prostatic ducts, the pancreaticobiliary system, the urinary system, and
the salivary ducts, especially the submandibular duct. Corpora amylacea in the prostate ducts are almost
universal in men over 65 years and are the commonest kind of calculi, formed of inspissated secretions. In
the biliary system, calculi are characteristically derived from cholesterol metabolism or bilirubin
metabolism, with a small proportion composed of calcium carbonate. In the kidney, secondary calculi of
calcium, magnesium, and ammonium salts are the commonest; primary calculi include urate, oxalate,
cysteine, and xanthine stones.

Complications of calculi in general include haemorrhage, obstruction, and tendency to infection. There may
be physical obstruction in the pancreaticobiliary system, obstructed by brous stricture, and in rare cases
gallstone ileus from obstruction of the small bowel after stulation from the gall bladder to the duodenum.
In the urinary tract, there can be obstruction by the calculus itself or as a consequence of brosis from
in ammation caused by the calculus, which leads to hydronephrosis, hydroureter, and a predisposition to
ascending infection. In ammation also causes squamous metaplasia generally, and carcinoma of the
bladder if the calculus is present for some time.

Downloaded from https://academic.oup.com/book/31816/chapter/266636047 by University of Sydney user on 25 September 2022

Amyloidosis
The term amyloid was rst used in 1839 to describe a semigelatinous starch-like thickening in seeds, and
rst used to describe a substance in human organs of similar appearance by Rokitansky 3 years later. It is
not one substance but a collection of disparate proteins, all of which have a beta-pleated sheet structure
(cross-beta structure). Most mammalian systems have no enzymes that will denature these proteins. On
Congo red stain histologically, most of the proteins in this group have apple-green birefringence (dichroic
birefringence) under polarized light; polarization is important as Congo red stains many tissues, but only
the amyloids have the green dichroic colour change. Several recently described amyloids do not stain well
with Congo red but do have the expected tertiary structure. Amyloid is not only a human product: it is
present in spider silk, some Escherichia coli bacteria, and some fungi.

Amyloid used to be classi ed as primary or secondary, but there was a large overlap between these groups
and they took no account of localized deposition. Classi cation is now by the speci c protein deposited. AL
(previously primary) amyloid and AA (previously secondary) amyloid produce generalized disease. Aβ or AH
amyloid is found adjacent to the neuro brillary tangles in Alzheimer’s disease. Tumour amyloid deposits
are found in medullary carcinoma of the thyroid, in which the amyloid is calcitonin; in renal cell carcinoma,
mesothelioma, Hodgkin’s disease, and some other lymphomas the amyloid is AA type. Deposition of
amyloid material around invasive lobular carcinoma of breast has been reported but this was not typed.

AL amyloid, also called light-chain amyloid, used to be called primary amyloid. The disease is found in
patients with myeloma, especially IgG and IgA myelomas, and is the result of polymerization in the tissues
of immunoglobulin light chains, especially lambda chains. AL amyloid deposits predominate in the heart
causing restrictive heart muscle disease; in arteriole walls in skin and deeper tissues related to carpal tunnel
syndrome; and in nerves generally or with speci c involvement at certain sites causing sweating
abnormalities and impotence.

AA amyloid is produced as part of chronic in ammation that persists for years. Stimulated macrophages
secrete IL-1 and IL-6 which cause hepatocytes to release SAA, the soluble amyloid precursor. This is a
normal, soluble acute phase protein (an apoprotein) that has immunomodulatory e ects but polymerizes
over time into insoluble amyloid AA. Deposits are found predominately in the kidney, in the glomeruli, renal
arterioles, and renal tubules causing nephrotic syndrome; in the spleen, where function is rarely a ected;
and in the liver in the space of Disse where function is also rarely a ected.

Chronic in ammatory diseases causing AA amyloidosis continue for many years. These can include
tuberculosis, leprosy, chronic osteomyelitis, bronchiectasis, and Whipple’s disease. Rheumatoid arthritis is
the commonest cause of AA amyloidosis in the United Kingdom. Familial Mediterranean fever is a
congenital chronic in ammatory condition in which IL-1 is unsuppressed and so is permanently higher
than normal and raises the SAA concentration. The neoplasms associated with amyloidosis were mentioned
earlier; it is likely that the amyloid arises from in ammatory mediators with macrophage stimulation in
these cases except for medullary carcinoma of the thyroid.

Deposits of amyloid unassociated with neoplasia can be found rarely in the thyroid, where it di usely
surrounds follicles. It is more commonly seen in the pancreatic islets in patients with diabetes mellitus,
where it is composed of calcitonin gene-related peptide and other peptides. Rounded masses of amyloid can
occur idiopathically anywhere in the urinary and respiratory tracts and can cause obstruction.

Disorders of di erentiation and growth

Downloaded from https://academic.oup.com/book/31816/chapter/266636047 by University of Sydney user on 25 September 2022

Deficiencies of initial growth

Agenesis, aplasia, hypoplasia, and atresia

Agenesis is complete failure of an organ or tissue to develop. For example, agenesis of one or more branchial
pouches can cause absence of the thymus and parathyroid glands; agenesis of part of a lung in a fetus will
cause compensatory emphysema of the formed lung in the neonate, but if more severe will be fatal—
neonates must have two lungs to survive, unlike adults.

Aplasia is when there is recognizable tissue present but no indication of di erentiation. Hypoplasia is the
failure of an organ or tissue to reach a proper size or function. Atresia is the failure of the development of a
lumen in a normally hollow structure such as the bile ducts, alimentary system, or choanae, and is a type of
aplasia.

Changes in growth in formed tissues

Atrophy
Atrophy is the degeneration of a tissue from its normally developed state to one in which there is a decrease
in the normal cell size, cell number, or both. Essentially atrophy is the result of the rate of cell death
exceeding the rate of cell proliferation. It is classi ed into physiological and pathological types.
Physiological atrophy occurs in the developing fetus and neonate in the ductus arteriosus, hypogastric
arteries, thyroglossal duct, branchial clefts, and notochord. In later life, the thymus normally undergoes
atrophy, as does lymphoid tissue generally, and after the menopause there is atrophy of the uterus, vagina,
and breasts.

Pathological atrophy is caused by starvation of general nutrients and speci cs such as proteins and
vitamins. Atrophy of localized parts may be due to disuse from neuropathies; immobilization; fracture;
obstruction to a drainage system; and pressure e ects such as of an aortic aneurysm on vertebral bone.
Some tissues may atrophy for unknown reasons, such as the testis and eye.
Hyperplasia and hypertrophy
Hyperplasia is an increase of the size of an organ or tissue because of an increase in the number of its cells.
Hypertrophy is an increase in the size of an organ or tissue because of an increase in the size of its cells.
They can occur together, as in the thyroid gland in Graves’ disease and in the prostate in nodular prostatic
enlargement. Both can be caused by physiological and pathological stimuli. In pregnancy, there is
hyperplasia of the breasts and hypertrophy of the uterus (and in late pregnancy a small degree of
hyperplasia); the thyroid in pregnancy is stimulated by human chorionic thyrotropin from the placenta and
develops hyperplasia and hypertrophy, usually only to a small degree; the lactotrophs of the pituitary
undergo hyperplasia because of stimulation by placental oestrogen and increased prolactin secretion.

Downloaded from https://academic.oup.com/book/31816/chapter/266636047 by University of Sydney user on 25 September 2022

Skeletal muscle undergoes hypertrophy from exercise.

Pathological hyperplasia and hypertrophy can be idiopathic or be caused by a known stimulating process.
Idiopathic examples of hyperplasia include parathyroid hyperplasia from an unknown cause in primary
hyperparathyroidism and hyperaldosteronism from idiopathic adrenal hyperplasia. The smooth muscle
hypertrophy that accompanies hyperplasia in nodular prostatic enlargement is also idiopathic. Known
causes of hyperplasia include excess hormone drive, in ammation, and drugs. The hormone drive on some
of the e ector organs includes, for example, excess oestrogen from an ovarian granulosa cell tumour or
thecoma causing endometrial hyperplasia, and a pituitary adenoma secreting excess ACTH and very rarely
TSH and follicle-stimulating hormone causing adrenal, thyroid and ovarian hyperplasia. Chronic gingivitis
can cause gum hyperplasia, as can antiepileptic drugs. Pathological hypertrophy of cardiac muscle occurs as
a consequence of hypertension and several congenital diseases a ecting blood ow and direction.

Metaplasia
Metaplasia is de ned as a change of one fully di erentiated cell type into another fully di erentiated cell
type. The commonest type is epithelial metaplasia—connective tissue metaplasia is much more rarely
encountered. Metaplasia is named for the new epithelial type after the change. Squamous metaplasia forms
in glandular and transitional cell epithelia; it develops characteristically in the bladder after calculi and
schistosoma infection; in the prostate after transurethral resection, and also in men on antiandrogen
therapy for carcinoma. Glandular metaplasia can be found in the bladder as cystitis glandularis, and in
glandular organs when there is change from one fully di erentiated glandular mucosal type into another—
intestinal metaplasia is common in the stomach associated with Helicobacter pylori infection; and apocrine
metaplasia in the breast is true metaplasia as the breast is a modi ed eccrine sweat gland.

The surgical signi cance of metaplasia is that dysplastic and neoplastic change can occur in areas of
metaplasia. In the bladder, squamous metaplasia from infection by Schistosoma haematobium and
occasionally S. mansoni in the bladder can develop into SCC. Squamous metaplasia in the bronchus is caused
by smoking and inhalation of industrial gases, and if the stimulus for the metaplasia persists and is
carcinogenic the patient can develop squamous dysplasia and SCC. In the cervix at puberty, the endocervical
glandular mucosa everts and becomes exposed to the acidic milieu of the vagina; the squamous metaplasia
that results is more prone to infection by human papilloma virus (HPV) infection and to develop cervical
intraepithelial neoplasia and SCC.

Patients with Barret’s oesophagus are more likely to develop adenocarcinoma of the oesophagus than
carcinoma of the oesophagus. In Barrett’s oesophagus, there is metaplasia to gastric mucosa or intestinal
mucosa with acid mucin demonstrable in goblet cells (the normal stomach has neutral mucin and no goblet
cells). The risk of malignant change appears to be less than originally considered; a recent series of 11 000
patients with Barrett’s oesophagus found that in those without dysplasia the risk was 1 case in 1000 patient-
years rising to 5.1 cases in 1000 patient-years when dysplasia is present.
Another aspect of surgical importance is that metaplasia can be misdiagnosed. Cystitis glandularis can be
misdiagnosed clinically and histologically as dysplastic epithelium and sometimes adenocarcinoma if there
is signi cant in ammatory atypia with hyperchromatism of the metaplastic cells. Florid changes in a
Barret’s oesophagus can be mistaken for carcinoma on endoscopy.

The principal examples of connective tissue metaplasia are osseous, chondroid, and myeloid metaplasias.
The rst two can form hard nodules in an abdominal scar many years after bowel resection and so be
clinically suspected of being metastatic deposits. A focus of osseous metaplasia can arise in the bladder wall
in association with previous surgery at that site. Myeloid metaplasia occurs in the liver, spleen, and lymph
nodes if the marrow is unable to function because of widespread bone involvement by myelo brosis.

Downloaded from https://academic.oup.com/book/31816/chapter/266636047 by University of Sydney user on 25 September 2022

Hamartoma and choristoma
A hamartoma (Greek hamartanein to err), is a non-neoplastic malformation composed of a haphazard
arrangement of di erent amounts of the tissues normally found at that site. A choristoma is the same but
formed of tissues not normally found at that site. In almost all cases, hamartomas and choristomas stop
growing when the patient is about 20 years old, and may regress spontaneously. In surgical practice, both of
these defects cause the symptoms and signs of benign neoplasms, they can be mistaken for malignancy, and
they can develop malignancy.

Hamartomas occur in the alimentary system classically in Peutz–Jeghers syndrome, an autosomal

dominant condition in which there is the development of small and large bowel polyps composed of
mucosa, lamina propria, and a tree-like pattern of muscularis mucosa. The last element distinguishes these
polyps from neoplastic polyps, irrespective of the presence or absence of dysplasia in the epithelium of the
polyp. They are associated with patchy pigmentation (lentigines) around the lips, gingiva, and anus.
Hamartoma of the bronchus (called chondroadenoma though it is not a neoplasm) is usually symptomless
and found incidentally on chest radiography but can sometimes obstruct the bronchus and adjacent airways.
Splenic hamartoma is usually asymptomatic but is very vascular and can spontaneously rupture.
Rhabdomyoma of the heart is associated with tuberous sclerosis, in which there are multiple hamartomas in
the CNS. Hamartoma of the hypothalamus causes epilepsy, pressure features, and precocious puberty.
Malignant change in a hamartoma is rare; a Peutz–Jeghers polyp can become adenocarcinoma,
neuro brosarcoma can supervene in a patient with von Recklinghausen’s disease, and chondrosarcoma can
arise in an osteochondroma (cartilage-capped exostosis) especially when the cartilage does not regress
after the patient is 20 years old.

Choristomas most commonly present with pressure e ects. They are commonest in the central and
peripheral nervous systems, such as on the facial and trigeminal nerves and in the posterior pituitary. The
anterior pituitary may develop a neuronal choristoma, which is classically associated with growth hormone
secretion and acromegaly. Choristomas composed of salivary gland acini and ducts can be found in the
middle ear.

Dysplasia
Dysplasia is failure of maturation of a tissue associated with a tendency to aneuploidy and pleomorphism
but without the capacity for invasive spread. Severe dysplasia has all of the characteristics of malignancy but
with no stromal invasion. At speci c sites, such as the colon and rectum, dysplastic epithelium can become
polypoid and form a neoplastic polyp of large bowel. As this part of the gastrointestinal system has few
lymphatic channels, even if the dysplastic epithelium appears to invade the lamina propria it will behave in
a biologically benign fashion (though follow-up is important).
There is therefore no concept of carcinoma in situ of the large bowel. Only when invasion through the
muscularis mucosae has occurred will the neoplastic cells meet lymphatics and gain metastatic potential.
This situation does not apply to severe gastric dysplasia and gastric carcinoma in situ, as the stomach
mucosa has extensive lymphatic drainage.

Histological changes characteristic of dysplasia are pleomorphism and hyperchromatism because of

aneuploidy, loss of cohesion between cells, and increased numbers of normal mitoses, and abnormal
mitoses such as starburst mitoses, tripolar mitoses, and bizarre mitoses. In the squamous epithelium of a
at or elevated epithelium severely infected by HPV the basal levels are indistinguishable from the highest
levels, and there is cell shedding because cohesion is lost. A cuboidal epithelium may develop multilayering.

Downloaded from https://academic.oup.com/book/31816/chapter/266636047 by University of Sydney user on 25 September 2022

By similar virus, irritant and other e ects other tissues can be involved.

In some organs, such as the stomach, the severity of these changes might indicate carcinoma in situ, but for
a diagnosis of dysplasia there must be no invasion into the underlying connective tissues.

Sites in the body of surgical importance at which dysplasia is relatively common include the stomach in
patients with Helicobacter pylori infection and intestinal metaplasia; the large bowel when it is extensively
and unremittingly in amed with ulcerative colitis; the bronchus in patients who smoke; and in the
oesophagus in patients with Barrett’s mucosa and glandular dysplasia, or with candidiasis and squamous
dysplasia. The cervix is by far the commonest site in the body involved by dysplasia as cervical
intraepithelial neoplasia, but this is unlikely to come to general surgical attention (unlike frank carcinoma
of the cervix). The causes of dysplasia are essentially those of neoplasia in general.

Neoplasia

‘A neoplasm is an abnormal mass of tissue, the growth of which exceeds and is uncoordinated with that of
the normal tissues, and persists in the same excessive manner after cessation of the stimuli which evoked
the change’ (R.A. Willis, 1952). The common word ‘tumour’ should be used only when the context is clear,
such as when it is obvious that a benign or a malignant neoplasm is being referred to. The word is often used
when there is no neoplasm at all: nodular prostatic enlargement is sometimes called a ‘tumour’. Conversely,
some neoplasms such as leukaemia do not form a recognizable mass or tumour. Used without context,
‘tumour’ simply means a mass or swelling and implies no predictions of behaviour.

Properly used, the terms ‘benign’ and ‘malignant’ refer only to neoplasms—if a swelling is not a neoplasm,
the terms are meaningless. No-one would call a mass malignant if it was not a neoplasm, but many non-
neoplastic masses are called benign. In general usage, a corpus luteum cyst of ovary is called a benign
ovarian cyst but it is not neoplastic, has no neoplastic potential, and can behave in a very non-benign way if
it ruptures. The common enlargement of the prostate is called benign prostatic hyperplasia, though it is not.

Carcinogenesis

Physical carcinogenesis
The relation between ionizing radiation and heat with DNA and RNA damage has been dealt with earlier
above.
Chemical carcinogenesis
Chemical carcinogens act through charged molecules that form covalent bonds with DNA, RNA, and
proteins. They are classi ed traditionally into remote, proximate, and ultimate carcinogens. A remote
carcinogen is a precursor of a carcinogenic agent that might be found in food, the environment, by exposure
to certain chemicals and physical agents, and in infective organisms. A proximate carcinogen is the
metabolite or metabolites of a remote carcinogen that have some carcinogenic potential but may be
modi ed further in the body into an ultimate carcinogen. An ultimate carcinogen is the active carcinogen
that interacts with DNA and other aspects of the cell, and causes neoplasia.

Downloaded from https://academic.oup.com/book/31816/chapter/266636047 by University of Sydney user on 25 September 2022

Carcinogenesis is usually a multistep process through initiation and promotion. Initiators are classically
mutagens that alter DNA. They tend to be rapid and dose related. Most initiators are procarcinogenic and
require activation, especially by cytochrome P450-dependent oxygenase enzymes. Initiators that are not
activated do not cause neoplasia. A promoter a ects normal cells and initiated cells and causes changes that
lead to altered gene expression. In most cases the activity of the promoter only a ects initiated cells with
abnormal DNA; only then does the altered gene expression result in a preneoplastic or a neoplastic cell.
Promoters cannot usually induce neoplasia alone but only after an initiator has altered a cell and caused
permanent DNA damage in that cell and its progeny. Promoters lead to proliferation which exposes cells to
further mutations, and more than one promoter event may be necessary to induce neoplasia.

Hormones and neoplasia

Hormones can cause neoplasia by acting as promoters. Most hormones act by stimulating growth and
secretion of the target organ. Some are inhibitory: dopamine used to be called prolactin-inhibiting factor,
and so may be considered a hypothalamic hormone; progesterone inhibits proliferation in endometrial
cells, but it does support secretion.

Tamoxifen is a drug used to treat breast cancers that express oestrogen receptors on the cell surface by
blocking. It works by binding rmly to the receptors and so decreasing the rate of proliferation. Tamoxifen
is not an antioestrogen but a partial oestrogen agonist; the agonist e ect is negligible in the breast but
potent in the endometrium, where it stimulates rst hyperplasia, then atypical hyperplasia and
adenocarcinoma.

Oestrogen stimulates many tissues in the body but especially the female reproductive system and is a known
contributor to the development of endometrial and breast carcinoma. Methylated steroid hormones such as
molecules in the testosterone family cause liver neoplasms.

Irrespective of being themselves carcinogenic, hormones may support the growth of malignancies that have
arisen spontaneously or from other causes. The rate of growth of breast carcinoma is dependent on
oestrogen, and that of prostate carcinoma on testosterone. Growth of papillary and follicular carcinomas of
the thyroid is stimulated by TSH from the pituitary. The risk of TSH induction of malignancy in thyroid-
irradiated rats is high but in human beings with high plasma TSH levels, even if lifelong, there is only a very
small risk. Patients with dyshormonogenetic goitre, in whom there is thyroid insensitivity to TSH because
of enzyme errors of metabolism, have a lifelong low thyroxine production and so constantly high TSH
levels. These patients very rarely develop malignancy. Papillary and follicular carcinomas have been
recorded but only as very occasional case reports and it is not known whether statistically the neoplasms
could have occurred by chance.

Hormones or their antagonists may be used to treat neoplasms:

◆ tamoxifen (a partial agonist) and gonadotrophin hormone-releasing hormone (GnRH) partial

agonists such as goserelin are used to treat breast adenocarcinoma
 ◆ progestogens are used to treat endometrial adenocarcinoma by suppressing mitoses

◆ antiandrogens such as utamide, and GnRH partial agonists such as goserelin or leuprolide, are used
to treat prostate carcinoma

◆ thyroxine can be used to manage thyroid carcinoma, particularly papillary and follicular carcinomas,
by suppressing pituitary secretion of TSH.

Viruses and neoplasia

Downloaded from https://academic.oup.com/book/31816/chapter/266636047 by University of Sydney user on 25 September 2022

As with hormones, viruses have a strong association with neoplasia. This can be by causing a neoplasm
directly, by stimulating the growth of an existing neoplasm, by causing a disease such as HIV and so
immunosuppression that predisposes to neoplasia, or simply by providing a new population of neoplastic
cells that can become vicariously infected by viruses.

Viruses that cause neoplasia include:

◆ HPV causing SCC of the cervix, vulva, perineum, and skin. Herpes simplex virus type II was originally
said to be causative, then thought to be an incidental passenger, and is now considered to be
facultative for HPV-induced neoplasia

◆ Epstein–Barr virus (EBV) causing Burkitt’s lymphoma with the cooperation of malarial infection

◆ EBV causing nasopharyngeal carcinoma

◆ HTLV1 and HTLV2 causing lymphoma.

Viral infections that contribute to neoplasia but are not considered to be directly causative include:

◆ HIV which causes an immunode ciency state that is permissive for HPV and for the development of
lymphoma

◆ hepatitis B virus infection causing chronic active hepatitis which may progress to cirrhosis and
hepatocellular carcinoma. Hepatitis D (which is an incomplete virus, called a virusoid) is a co-factor
especially in South East Asia.

Asbestos
Asbestos was used extensively in building ships, houses, and institutions such as prisons and hospitals 50–
80 years ago, and was still used in the construction of o ce blocks in the 1950s. Asbestos, especially blue
asbestos (crocidolite) but to some extent most of the numerous compounds in the asbestos family, is now
known to be related to an increased risk of several malignancies.

A di culty in taking out asbestos from buildings, especially public buildings, is that the process of removal
increases the asbestos bre concentration in the air inside the buildings by 100-fold or more, and this stays
high for decades afterwards. Occupations most at risk include shipworkers, laggers, builders, industrial
plumbers, architects, and workers in old hospitals that have insulation that was installed over 50 years ago.
A problem with rare diseases such as mesothelioma is that tying the cause of the disease to a chance
exposure to asbestos that could have happened 20 or 30 years before (because of the latent period) can be
almost impossible except presumptively.

Diseases considered to be caused by asbestos include:

 ◆ asbestosis, a brosing lung disease that is dose-exposure related

◆ carcinoma of bronchus, usually SCC, which might be dose related

◆ malignant mesothelioma of pleura, pericardium, and peritoneum, which is not dose related and can
occur after a single chance exposure over 20 years later

◆ chronic bronchitis as from any dust-related disease, which is dose related

◆ misdiagnosis of pleural brous plaques (which might be the result of a number of pathogens) as
pleural malignancy with consequent morbidity.

Downloaded from https://academic.oup.com/book/31816/chapter/266636047 by University of Sydney user on 25 September 2022

Genetic causes of neoplasia

General aspects of cancer genetics

Malignant neoplasms can arise spontaneously and sporadically, in families and from speci c genetic
abnormalities. Sporadic malignancies account for most cases overall. They arise by chance in patients with
no identi able family history and no apparent genetic abnormalities.

Familial cancer is multifactorial, from abnormalities in several genes in members of the family, not all of
which would be present in each person. Environmental factors also play a part. The chance of developing a
malignancy is determined by the number of inherited genetic abnormalities, the environmental risk factors,
and how all of these act together. There is therefore no entirely predictable way of knowing which family
members will develop cancer. For example, the risk of developing carcinoma of the lung is doubled if a
person has a rst-degree relative who has or had lung cancer, and increased by a third if he or she has a
second-degree relative with lung cancer.

Cancers can rarely arise as a consequence of a single gene abnormality, irrespective of environmental
in uences. The mode of inheritance will depend on whether the abnormal gene is dominant or recessive,
but in clinical practice this can be an oversimpli cation. Retinoblastoma is inherited as an autosomal
recessive condition—children born with one RB retinoblastoma gene are normal. Early in life the normal RB
gene in retinoblasts can spontaneously mutate, resulting in loss of heterozygosity and development of the
neoplasm.

There are two ways in which a genetic predisposition to cancer can be inherited. One is by inheriting one (or
sometimes two) copies of an abnormal gene that will result in malignancy developing. The other is by
inheriting an abnormal gene which a ects the capacity of a cell to multiply (or to be prevented from doing
so), or to repair its DNA adequately. Both apply in many tumours.

Abnormal function of the growth inhibitor gene p53 is important in many neoplasms. Normally DNA
damage in a cell causes the p53 gene to transcribe RNA for p53 protein. This stops the cell cycle by increasing
the concentration of p21 protein, which is a CDK inhibitor; this prevents damaged DNA being replicated.
Specific genetic abnormalities in common diseases

Colorectal carcinoma
Adenocarcinoma of the colon and rectum is usually sporadic. The normal to adenoma to carcinoma
sequence involves at least seven major molecular aberrations. Chromosomal abnormalities account for most
cases, the earliest detectable being deletions in the growth inhibitor APC gene which is followed by
abnormalities developing in the p53 gene. Microsatellite instability accounts for about 15%; microsatellites
are repeating DNA units which mutate and persist in the cell line because chromosome repair is defective.

Downloaded from https://academic.oup.com/book/31816/chapter/266636047 by University of Sydney user on 25 September 2022

The APC gene on chromosome 5 codes for a protein that regulates cell adhesion and signal transmission;
most defects in the gene are insertions, deletions, and nonsense mutations which cause frameshifts and
abnormal positioning of stop codons.

Hereditary non-polyposis colonic carcinoma accounts for about 5% of cases; the genetic abnormality is in
DNA repair genes and not the APC gene. Familial adenomatous polyposis (FAP) accounts for about 1% of
cases of large bowel cancer. Much rarer are Lynch II and Li–Fraumeni syndromes which include colonic
carcinoma. FAP is inherited as an autosomal dominant condition, though variants have been identi ed—
there is an attenuated form with fewer polyps and a lower incidence of malignant change, and a non-
classical form in Western Jewish populations. FAP may sometimes present with abnormalities outside the
large bowel including:

◆ desmoid tumours

◆ dental abnormalities, such as supernumerary teeth, unerupted teeth, congenital absence of teeth,
dentigerous cysts, and odontomas

◆ congenital hypertrophy of the retinal pigment epithelium

◆ malignant tumours of the thyroid, liver, bile ducts, and CNS

◆ metaplasia, adenoma, and adenocarcinoma of the ileum: adenoma and adenocarcinoma have also
been reported in ileal pouches in patients with FAP who have had total proctocolectomy.

Breast carcinoma
About 10% of women with breast cancer in Western countries have a genetic predisposition, with a pattern
of inheritance of autosomal dominant with limited penetrance; this means that the abnormal gene or genes
can be transmitted by an apparently normal family member. Women who have an inherited breast cancer
gene tend to develop malignancy at a younger age and to have more a ected rst-degree relatives than
those with spontaneous mutations. They are also more likely to have bilateral disease. A ected families
have a higher incidence of carcinoma of the ovary, colon, prostate, and elsewhere, which has been
attributed to the same inherited gene mutation.

The total number of genes that predispose to breast cancer is unknown. The two most studied are the
abnormalities of BRCA1 on the long arm of chromosomes 17 and BRCA2 on the long arm of chromosome 13.
One or both of these are present in most high-risk families.

In general terms, a woman is at risk who has:

◆ one rst-degree female blood-relative who has bilateral breast cancer or breast and ovarian cancer

◆ one rst-degree female blood-relative who has breast cancer under 40 years
 ◆ one rst-degree male blood-relative who has breast cancer diagnosed at any age

◆ two rst- or second-degree blood-relatives who have breast cancer diagnosed under 60 years or
ovarian cancer at any age

◆ three rst or second blood-relatives with breast and ovarian cancer.

Mutations in other genes are also associated with familial breast cancer, in particular abnormalities of
growth inhibitor genes. In Li–Fraumeni syndrome, there is inheritance of a mutated, defective p53 gene in
an autosomal recessive manner. This appears to be autosomal dominant because there is loss of
heterozygosity of p53 early in the person’s life with the development of two abnormal p53 genes—the same

Downloaded from https://academic.oup.com/book/31816/chapter/266636047 by University of Sydney user on 25 September 2022

sequence as occurs in retinoblastoma. The normal inherited p53 gene copy mutates early in perhaps one cell
in several organs so that functional p53, the protein product of p53, is absent from the cell line. There is then
a considerable reduction in the inhibition of replication of abnormal DNA, and so a greatly increased risk of
malignancy in the a ected tissues. Most often associated with Li–Fraumeni syndrome are breast
carcinoma, osteosarcoma, and soft tissue sarcoma. Other cancers in this syndrome include astrocytoma,
leukaemia, and adrenocortical carcinoma. In Cowden’s syndrome of multiple hamartomas, several genes
are abnormal including PTEN, which is also a growth inhibitor gene. Patients with this condition have an
increased risk of carcinoma of the breast, thyroid, and endometrium and more rarely of the colon and
kidney.

Melanoma
Nodular, super cial spreading and acral lentiginous melanomas have a predictable abnormality on
chromosome 6. In familial melanoma, chromosome 9 is usually abnormal with deletion of p16, a growth
inhibitor gene. In many melanomas there are confounding genetic variables such as the MC1R gene for red
hair and pale skin, and the abnormal nucleotide repair genes in xeroderma pigmentosum, both of which
predispose to melanoma.

Diagnosis of neoplasia

Cytology and histology

Cytology often precedes histological examination of the tissues. The commonest type of cytology is
exfoliative; its main use is by gynaecologists and screeners for cervical neoplasia. It is also used by plastic
surgeons for diagnosis of skin lesions in aesthetically sensitive areas such as the face. Endoscopic brushings
from the stomach or bronchi are also exfoliative though more invasive.

Fluid cytology is used extensively for diagnosis in surgery. Natural uids of diagnostic value include urine
for malignant cells and schistosome ova; sputum for malignant cells such as SCC and oat cell carcinoma;
and CSF for malignant glial cells. Unnatural uids can be helpful, such as ascites and pleural e usion uid
for malignant cells, and bronchial lavage uid recovery for the same. Aspiration of cyst uid from the
pancreas or thyroid, and the ovary by gynaecologists, can permit the diagnosis of benign and malignant
tumours with a high degree of certainty.

Handling of the uid for cytology is important if a diagnosis is to be achieved or relied upon. Pleural and
ascitic uid must be anticoagulated so that the clotting factors in the uid will not solidify it and make
centrifugation di cult. Urine intended for examination for malignant cells should be a random catch during
the day and not an early-morning specimen—left overnight, even normal transitional cells decay in the
urine and can look alarming.
FNAC is used principally for the diagnosis for breast tumours, thyroid tumours, and lymph nodes. Imprint
cytology, where the fresh specimen is dabbed onto a histology slide, is used for rapid examination of a
lymph node or spleen suspected of having lymphoma; some pathologists have experience enough to
diagnose melanoma this way.

Tissues are sent for histological examination by incisional and other biopsies and by excision specimens,
which can be small for a benign skin tumour on the face and very large for a hind-quarter amputation or
pelvic exenteration. A biopsy is usually for diagnostic reasons rather than therapeutic, and ranges in size
from scraping or shave biopsy of skin diseases through wide-bore needle core biopsy and punch biopsy to
diathermy loop and deeper biopsies. Sometimes the object of the biopsy is diagnostic though the hope is

Downloaded from https://academic.oup.com/book/31816/chapter/266636047 by University of Sydney user on 25 September 2022

therapeutic—a large cone biopsy of the cervix, for example, is primarily to establish the extent of
involvement by cervical intraepithelial neoplasia but hopefully is curative of it. Excision specimens are
usually by cutting diathermy, loop diathermy, or scalpel excision.

The only essential similarity between the two modalities of tissue sampling, cytology and histology, is that
in both, the number of cells sampled is large. In cytology, the eld sampled is usually large and poorly
de ned; in histology, it is small and focused. The architecture of the tissue is absent from a cytological
sample, unless there is evidence of papillary carcinoma or other speci c features; in histology, the
architecture is preserved and so invasion of local tissues can be assessed. Cytology is for the most part non-
invasive and repeatable; histology by de nition must be invasive, and when the specimen is removed it
cannot be removed again. Both modalities can be used to diagnose most types of malignancy but the
reliability is higher on histology. Cost and speed of both are di cult to assess. Cytology can be quick and
cheap, but the great volume of specimens tends to make it slow. Histology takes 24 hours, which can be
much faster than routine cytology, and permits multiple sections for special chromatic stains and
immunostains.

Frozen section diagnosis

The indications for asking for a frozen section (FS—rapid intraoperative section) are limited, and it is
important to appreciate the limitations and hazards of FS diagnosis. The indications include:

◆ tissue identi cation, for example to establish that a parathyroid gland is not a thyroid nodule or a
lymph node

◆ as an intraoperative diagnostic tool in very limited circumstances. The patient’s immediate

management must depend on the result of the FS and the issue in question must be within the remit of
the pathologist who examines the FS. (For example, FS can be useful simply in diagnosing whether a
neoplasm is benign or malignant but would largely be useless for distinguishing one malignant
lymphoma from another.)

◆ examination of excision margins to establish whether a carcinoma has been excised completely,
especially when the least amount of excision may be preferable as in laryngectomy and glossectomy.

The limitations of FS examination are that the process is destructive: a small specimen can be destroyed
completely by ice-crystal artefact. There will inevitably be sampling problems and so the result may be
misleading. There will be false negatives and false positives, more frequently than in routine
histopathological practice. The diagnosis will usually be simpli ed rather than the ne-tuned diagnosis
possible from properly processed tissues. FS is expensive as it disrupts the normal work in the laboratory.
Worst of all, the diagnosis might be completely wrong because of the artefacts induced by the process—
there are examples of tuberculosis in a lung FS being diagnosed as sarcoma. Surgeons must accept that there
are four proper responses, in general, on a FS report: ‘it is parathyroid (for example)’, it is benign’, ‘it is
malignant’, and ‘wait until tomorrow for the diagnosis on para n-wax slides’.

Immunohistochemistry
Immunohistochemistry staining (immunostaining) gives an indication not just of what a cell looks like but
what it contains. This is of course predicated on proper xation to prevent cell constituents dissolving
during processing, or translocating into misleading parts of the section. Immunostains are an essential part
of diagnostic pathology and in use daily all over the developed world. Thirty years ago when techniques were

Downloaded from https://academic.oup.com/book/31816/chapter/266636047 by University of Sydney user on 25 September 2022

still being formulated, fresh tissue was needed to ensure that the technique was reliable; nowadays all
commercially available antibodies work very well on routine formalin- xed, para n-wax processed blocks
and slides. Microwave heating has been established to reveal antigens ‘hidden’ by processing and is very
successful.

The main uses of immunostaining are for distinguishing:

◆ among a carcinoma, sarcoma, and lymphoma

◆ among all of the lymphoma types

◆ among speci c carcinomas, such as papillary carcinomas of the thyroid, ovary, and pancreas, all of
which as a lymph node metastasis can be very di cult on routine stains

◆ between connective tissue components such as laminin and CD10

◆ the di erent hormone-containing cells in pituitary, testicular, and other endocrine organs in
normality and disease

◆ tumours with a low proliferation index from those with a high index.

Di culties in interpreting immunostains can be considerable but overcomeable. For example, cytokeratins
are positive in epithelial neoplasms but can occasionally be positive in leiomyomas and some lymphomas.
There are often so-called edge e ects, in which there is peripheral staining of the tissues which can lead to
false-positive staining and misinterpretation. Negative immunostaining does not indicate that a tissue is
not synthesizing a substance—it might be excreting it rapidly so that none remains for staining.

Formalin and its e ects on tissues

A 40% solution of formaldehyde in water, abbreviated to formalin, is used almost universally as the routine
xing agent. It is very cheap, versatile, and e ective. Formalin xes almost all tissues well. All of the
commercially available immunostains work on formalin- xed tissues. It works by cross-linking tissue
components in place, so preserving relations. The water content of the solution prevents dehydration, and
the formaldehyde component is a potent microbicide. Formalin is compatible with haematoxylin and eosin
(H&E) staining, and as both are used in all countries of the world, routinely stained H&E sections from
anywhere can be assessed by all histopathologists.

The problem with formalin is its toxicity. It is severely irritant in solution and as a vapour and can cause
severe skin rashes. If insu cient formalin is used to x specimens, especially large specimens, the tissue
will decay and gases may be produced. When the specimen pot is opened the formalin may spray into the
laboratory assistant’s or the pathologist’s eyes.
Tumour markers
A tumour marker is a substance reliably found in the circulation of a patient with neoplasia which is directly
related to the presence of the neoplasm (though is not stoichiometric), falls away when the neoplasm is
treated and rises again when the neoplasm recurs at the primary site or as metastases. The main use of
tumour markers is to aid diagnosis rather than make the diagnosis, and they are particularly used to
monitor persistence of the tumour after operation or recurrence. The level of a tumour marker does not
directly re ect the volume of tumour present, except for the plasma concentration of carcinoembryonic
antigen which reliably changes in proportion.

Downloaded from https://academic.oup.com/book/31816/chapter/266636047 by University of Sydney user on 25 September 2022

Tumour markers are grouped mostly as hormones, isoenzymes, and oncofetal and other antigens.
Hormones may be produced by tumours eutopically or ectopically. Tumours of endocrine organs are often
di erentiated enough to secrete the appropriate hormone, such as thyroid hormones secreted by papillary
and follicular carcinomas of thyroid. Isoenzymes as tumour markers include placental alkaline phosphatase
for neoplasms of germ cells which is sometimes also raised in carcinoma of the pancreas, colon, and
bronchus.

Prostatic acid phosphatase analysis was used as a diagnosis for carcinoma of the prostate but has now been
largely superseded by prostate-speci c antigen (PSA). The danger of PSA is that many normal activities
cause a signi cant rise in PSA. For example, riding a cycle will raise the PSA; ejaculating will raise the PSA.
Patients must be advised not to have a PSA measurement for several days after a rectal examination, or
intercourse, or ejaculation—the result will be high and might be unnecessarily alarming.

Screening
A screening programme is de ned as a codi ed search for unsuspected disease in a population of apparently
healthy people. Success depends on two main modalities: the features of the disease and the variables of the
screening test.

The disease should be an important health problem and so be common; asymptomatic or with only non-
speci c symptoms; and one with a reliably long premorbid latent period. It should be detectable at an early
stage in the latent period, and it should be treatable, preferably at the time of detection. The screening test
should be non-invasive and acceptable to people, with no signi cant harm in terms of the test and the
information that the test provides. It should be sensitive and speci c, cost-e ective, and auditable.

The longest-established screening test in the modern sense is for cervical carcinoma and its precursor
lesions. Screening for breast carcinoma in the general population has also become routine in most countries
(women with a strong family history of breast cancer or a mutation in one or both BRCA genes undergo
surveillance rather than screening). Colorectal carcinoma screening is now being introduced for people over
60 years. Screening for abdominal aortic aneurysm is less widespread.
General types of neoplasm

Benign neoplasms
A benign neoplasm is one that is characteristically slow-growing, has no in ltrative growth or capacity to
metastasis, and does not recur after complete excision. Benign neoplasms grow either on a surface, such as
from the skin or into the lumen of a duct or anatomical tract, or within solid tissues such as the thyroid or
adrenal gland. The commonest growth patterns from surface epithelium are papillomas which may be
pedunculated or sessile, and adenomas which may be tubular, villous, or mixed patterns of these (and also

Downloaded from https://academic.oup.com/book/31816/chapter/266636047 by University of Sydney user on 25 September 2022

pedunculated or sessile). There can be mixed tissue components, as in pleomorphic adenoma of parotid
gland. Many benign neoplasms of glandular tissue are cystic, especially ovarian neoplasms such as serous
cystadenomas which can present with torsion and acute abdominal pain. A benign neoplasm can have mixed
elements of epithelium and connective tissue proliferations, such as broadenoma of breast, and
adenolymphoma of salivary gland.

A benign neoplasm can cause the death of a patient by many processes, including:

◆ thrombosis and infarction that can lead to severe haemorrhage from a large bowel or endometrial
polyp; torsion of a benign ovarian cyst or subserosal leiomyoma can cause haemoperitoneum

◆ infection of an ulcerated large bowel adenoma that can result in septicaemia; biliary tract infection
can complicate stasis from an adenoma of the biliary system

◆ obstruction of a ductal system, such as biliary obstruction as above; intussusception can be caused by
a benign neoplastic polyp of large bowel. A meningioma in the posterior cerebral fossa can obstruct
the ow of CSF, or if in the spinal meninges can obstruct the nerve supply to a tissue. A large
retrosternal adenoma of the thyroid can obstruct the venous return from the head and neck

◆ biochemical abnormalities that are life-threatening, such as eutopic hormone and ectopic secretion,
and electrolyte and protein loss from polyps in the large bowel

◆ pathological fracture through a benign bone tumour such as an osteoid osteoma or osteoblastoma

◆ malignant change

◆ misdiagnosis with consequent mortality.

Malignant neoplasms
A cancer is the generic term for any malignant neoplasm. It is useful when writing about neoplasms of, say,
the thyroid: there are four classical carcinomas but ve classical cancers, as this term includes lymphoma. A
cancer with both carcinomatous and sarcomatous di erentiation is called a carcinosarcoma, as in the
uterus, ovary, and lung. A di erentiated teratoma can have a malignant element, such as adenocarcinoma of
a glandular element or SCC of a skin element, or be malignant ab initio and composed of immature
elements.

Neoplasms have abnormal proliferation, di erentiation, and relation of their cells to each other and the
surrounding tissues. This results in an abnormal growth pattern with distortion of architecture and
compression with or without in ltration of adjacent structures. There may be the cardinal histological
features of neoplastic cells, especially in malignant tumours, such as hyperchromatism from accumulation
of DNA and its precursors in neoplastic nuclei leading to a raised nuclear/cytoplasmic ratio and nuclear
pleomorphism. Aneuploidy, an abnormal and usually raised amount of nuclear DNA, contributes to
hyperchromatism and to tripolar, tetrapolar, and starburst mitoses as metaphase and telophase cannot
proceed normally.

Loss of normal maturation leads to the disruption of a squamous epithelium and multilayering of a
glandular epithelium. The development of abnormal ductal systems can cause cyst formation. Disruption of
poorly formed new blood vessels in a neoplasm causes haemorrhage or thrombosis which leads to necrosis,
as does compression of blood vessels by expansile growth in a con ned space, such as in a meningioma.

The rate of growth of a neoplasm is proportional to the rate of cell multiplication measured by the growth

Downloaded from https://academic.oup.com/book/31816/chapter/266636047 by University of Sydney user on 25 September 2022

fraction of actively proliferating cells, and inversely proportional to the rate of cell death, whether due to
spontaneous apoptosis, apoptosis induced by immune mechanisms, or necrosis. The growth rate depends
on the blood supply, general nutrition, local and circulating growth factors, the intensity and type of
immune response to the neoplasm, and the degree of resistance to invasion by surrounding tissues. The
growth fraction can be increased by debulking tumours with an initially low growth fraction, such as
colorectal cancer. Tumours with a high growth fraction usually respond better to treatment with cytotoxic
drugs.

Molecular changes in neoplasia

Tumour cell spread by detachment from the parent mass, invasion of and transport through lymphatics or
blood vessels, attachment to vessels at distant sites, and passage through the vessel’s basement membrane
into the extracellular matrix. Malignant cells have laminin and receptor integrins over the whole surface,
not just at the basement membrane aspect. Matrix metalloproteinases are secreted by tumour cells and they
stimulate stromal cells also to secrete matrix metalloproteinases, which degrade collagen. Tumour cells can
escape immune recognition as they have altered MHCs or immunoglobulin superfamily expression on their
surfaces. Tumour cells that survive adhere to endothelial cells with integrins and secrete matrix
metalloproteinases to move into extravascular tissues by proteolysis.

Angiogenesis begins only when the mass of neoplasm is more than 2 mm in diameter as the cells within
begin to become hypoxic and react by secreting vascular endothelial growth factor and other angiogenesis
factors. Microvessel density correlates with the potential to metastasize. Another factor that encourages
angiogenesis, in normal cells and tumour cells, is the plasma membrane molecule CD44. This also has a role
in many other aspects of cell behaviour, such as cell-to-cell adhesion and cell-to-connective tissue matrix
adhesion, cell di erentiation, proliferation, capacity for motility, and presentation of growth factors and
cytokines to their receptors. High expression of CD44 by tumour cells is usually associated with aggressive
features but in some cancers the reverse is true, and there is at present no de nite correlation with
22
prognosis.

Cardinal variables for all cancers

The four features of prime importance in management and prognosis of cancer are the site, type, grade, and
stage of the neoplasm. Irrespective of the other three variables, the site of origin of the tumour is crucial. An
SCC of skin, for example, will behave very di erently from an SCC of oesophagus or SCC of cervix.

The type of a neoplasm is indicated by its cell line. A carcinoma is a malignant tumour of epithelial cells. A
sarcoma is a malignant tumour of connective tissue cells; by this de nition lymphomas and leukaemias are
sarcomas but are always considered as a separate group. Most carcinomas are classi ed simply as SCC,
adenocarcinomas, and transitional cell carcinomas and undi erentiated (anaplastic) carcinomas, but some
cancers have speci c appearances and behaviour; melanoma, choriocarcinoma, nasopharyngeal carcinoma,
and adenoid cystic carcinoma have speci c names as they behave in their own speci c ways. Mixed
carcinomas such as adenosquamous carcinomas of the uterus and transitional cell/SCC of the bladder are
uncommon but likely to be encountered. Mixed malignancies of epithelial and connective elements such as
malignant mixed Müllerian tumour are rare.

The grade of the neoplasm is based on its degree of di erentiation, or lack of it, which refers to the
closeness of resemblance to the non-neoplastic normal tissue at the site. This is graded into well
di erentiated, moderately di erentiated, and poorly di erentiated. There is no grade of moderately well
di erentiated; of course more than one pattern may be present, when the tumour would be called partly

Downloaded from https://academic.oup.com/book/31816/chapter/266636047 by University of Sydney user on 25 September 2022

well di erentiated and partly moderately di erentiated. A carcinoma is graded as undi erentiated when
there is no di erentiation that permits recognition as a poorly di erentiated SCC, adenocarcinoma, or
transitional cell carcinoma. Anaplastic simply means undi erentiated, though some writers reserve the
term for particularly pleomorphic tumours with bizarre tumour giant cells. If a neoplasm cannot be
recognized as a carcinoma or sarcoma, it is an undi erentiated cancer. Nowadays some degree of
di erentiation into epithelial and connective tissue cell lines can usually be demonstrated by
immunohistochemistry.

The stage of a cancer refers to the extent of spread, both local and distant. The principles of any staging
system are that it should be simple to understand, apply, and reproduce reliably. The system should
establish a clear ranking of the distribution through the di erent stages, and must be valuable in the
management and prognosis of the patient. Examples of staging systems are given later (see ‘Staging of
cancer’).

Factors that determine the extent of local spread of a neoplasm include:

◆ the tumour site, type and grade: for example, an adenocarcinoma of anus behaves di erently from to
an SCC of anus of the same grade

◆ the capacity of the tumour cells to in uence the extracellular matrix through which they spread

◆ local factors around the tumour such as the blood supply and the presence of tissue planes of least
resistance

◆ the presence of tissues resistant to in ltration such as cartilage, because of lack of blood supply and
secretion of inhibitors of hyaluronidase

◆ the extent and type of the humoral immune response to the tumour by circulating and local
immunoglobulins, and the cellular immune response by lymphocytes and macrophages such as in the
spleen, in which metastases of carcinoma are rarely found.

Metastatic spread of cancer

As well as expansion locally, cancers spread metastatically. A metastasis is a deposit of malignant tumour
cells away from and unconnected with its site of origin.

The six classical routes of metastasis are via lymphatic vessels, blood vessels, through one or more of the
coelomic cavities, through perineural spaces (which may in fact be lymphatics), through the CSF, and
through iatrogenic intervention. Most carcinomas spread by lymphatics, which have no type IV collagen or
laminin in their walls and so are considered to be more susceptible to invasion, but other factors must also
be in play. Sarcomas classically spread via the bloodstream.
The routes of blood spread are into the new vessels stimulated by the tumour cells, into native vessels
around the tumour, and into the left subclavian vein by way of the thoracic duct. The number of cells
released in a given time into the bloodstream does not correlate with the development of metastases—for
example, a renal parenchymal cell carcinoma can grow directly into the renal vein and sheds millions of
cells per hour, but characteristically forms solitary or only few metastases.

Transcoelomic spread can be through the peritoneal cavity, the pleura, and, rarely, the pericardium. All
three are derived from the embryonic coelome (Greek koilos, hollow). In the peritoneum, the commonest
cancers to spread by this route are colon and stomach, both of which spread throughout the peritoneal
serosa but especially a ect the ovaries. Bilateral nodular involvement of the ovaries by metastases from

Downloaded from https://academic.oup.com/book/31816/chapter/266636047 by University of Sydney user on 25 September 2022

anywhere are called Kruckenberg tumours (Kruckenberg, 1896). Lung cancers, especially peripheral ones,
can metastasize to the upper surface of the diaphragm transcoelomically, and occasionally spread through
the pericardial cavity. Perineural spread is most often seen in adenoid cystic carcinoma of the salivary
glands. Aggressive tumours of the CNS such as medulloblastoma can spread through the CSF to involve the
spinal cord.

Iatrogenic spread of a cancer may be because a neoplastic cyst, such as in the pancreas or ovary, is ruptured
during excision. Chondrosarcoma of the pelvis can be seeded widely at operation; malignant chondroblasts
have a very low metabolic requirement and can survive on di used nutrients in the normal small amount of
peritoneal uid.

Grading systems
Most malignant tumours are graded by eye by the histopathologist, without any basis except experience of
conformity, into the four grades discussed earlier. Formalized, structured grading systems have been
developed for some common tumours. The two in common use are the Elston–Ellis system for breast
carcinoma and the Gleason system for prostate carcinoma.

Breast carcinomas are assessed on tubule formation (a grade of 1 means that there is clear tubule formation,
3 that there is not), mitotic count per high power eld (1 is few, 3 many) and nuclear pleomorphism (1 little,
3 severe). A combined score of 3–5 is considered low grade, 6–7 intermediate, and 8–9 high grade. These
23
combined scores correlate well with prognosis.

24
Adenocarcinoma of the prostate is graded by the Gleason system of patterns of growth :

1. The adenocarcinoma of the prostate closely resembles normal prostate tissue—the glands are small,
well formed, and closely packed.

2. The adenocarcinoma has well-formed glands but they are larger and have more connective tissue
between them.

3. The adenocarcinoma has recognizable glands but the glandular cells are hyperchromatic and begin to
invade the surrounding tissues.

4. The adenocarcinoma has few recognizable glands and many foci of invasion are present.

5. The adenocarcinoma has no recognizable glands and forms sheets of neoplastic cells.

Gleason system reprinted from Human Pathology, Volume 36, Issus 4, Henrik Helin et al., Web-based virtual
microscopy in teaching and standardizing Gleason grading, pp 381–386, Copyright © 2005, with
permission from Elsevier, http://www.sciencedirect.com/science/journal/00468177
In the United Kingdom, Gleason pattern 3 is the commonest reported. The histopathologist examines the
biopsy specimen microscopically and gives a score to two patterns: the rst is called the primary grade,
which is that found in most of the tumour; the secondary grade is based on the appearances of the second
most prevalent aspect of the adenocarcinoma. These grades are added together to form the nal Gleason
score. This cannot be less than 2 or more than 10, and re ects the prognosis.

Staging of cancer

TNM staging

Downloaded from https://academic.oup.com/book/31816/chapter/266636047 by University of Sydney user on 25 September 2022

The TNM staging system was developed to indicate the prognosis of a malignant neoplasm, to assist in
management of it, and to formalize data collection so that di erent treatments and clinical trials could be
compared. The system is based partly on the anatomical extent of spread and partly on clinical features,
such as those found on physical examination, endoscopy, imaging, biopsy, surgical exploration, and other
25
relevant procedures performed before treatment. The latter are called the cTNM data.

The T category indicates the extent of the primary tumour. The N category documents the presence or
absence of regional lymph node metastases; involvement of nodes other than regional nodes is included in
the M category. These do not have to be distant metastases: a carcinoma of the hepatic exure of the colon
that has metastases in the liver only a few centimetres away has an entry in M.

The T category of local involvement by the tumour includes:

• TX: the primary tumour cannot be assessed

• T0: there is no evidence of the primary tumour (such as after radiotherapy)

• Tis: carcinoma in situ

• T1–T4: the size and local extent of the tumour

The N category of regional lymph node involvement includes:

• NX: the regional nodes cannot be assessed

• N0: there are no regional node metastases

• N1–N3: the extent of regional node involvement

The M category of metastases other than in regional lymph nodes includes:

• MX: the presence or absence of distant metastases cannot be assessed

• M0: there are no distant metastases

• M1: distant metastases are present (their site is stated here).

Reproduced with permission from Wittekind C, Greene FL, Hutter RVP, Klimp nger M, Sobin LH, TNM Atlas:
Illustrated Guide to the TNM Classi cation of Malignant Tumours, Fifth Edition, Wiley-Liss, Copyright © 2008
Wiley.
Other staging systems

Dukesʼ staging of colorectal carcinoma.

The Dukes’ staging system (Cuthbert Esquire Dukes, 1890–1977) for colorectal carcinoma was derived from
Dukes’ earlier work on staging of rectal carcinoma. The earliest evidence that an adenomatous polyp has
become an adenocarcinoma is when neoplastic glands are identi ed on the submucosal side of the
muscularis mucosae. The grade of the epithelium in the neoplasm is immaterial in terms of Dukes’ staging.

Dukes’ stage A is when the neoplasm has invaded through the muscularis mucosae but has not reached the

Downloaded from https://academic.oup.com/book/31816/chapter/266636047 by University of Sydney user on 25 September 2022

outermost aspect of the muscularis propria (Dukes could not use the anatomical level of the serosa as a
marker as the lower rectum does not have a serosa). Dukes’ stage B is when the carcinoma has extended
through the outermost aspect of the muscularis propria. Dukes’ stage C is when there are lymph node
metastases. The staging system has been modi ed since it was introduced to refer to proximal and distant
lymph node involvement, C1 and C2. The carcinoma can spread by lymphatics from an apparently stage A
26
tumour into lymph nodes and so become stage C without breaching the muscularis propria.

The Dukes’ staging has been useful for many years but it does not address several aspects of prognostic
importance. These include whether the tumour is completely excised, whether there is invasion of major
veins in the specimen, and whether the tumour extends close to excision margins. Subsequent staging
systems, such as the Jass system, include data on the growth pattern of the tumour—whether it is
in ltrative or growing as blunt extensions—and whether there is an in ammatory cell in ltrate, both of
which are prognostic indicators.

Clarkʼs staging system for melanoma and the Breslow thickness.

Clark’s levels is a system of grading melanoma by the extent to which it has spread into the dermis and
27
subcutis :

Level 1: tumour cells only within the epidermis

Level 2: tumour cells invade the papillary dermis only

Level 3: tumour cells reach the junction between the papillary and the reticular dermis

Level 4: tumour cells invade the reticular dermis

Level 5: tumour cells invade the subcutis.

Adapted with permission. Copyright © Cancer Research UK 2014.

This staging system takes no account of the normal variation of the thickness of the dermis in di erent
parts of the body: on the nose and eyelid the dermis is very thin and would be breached by a small
melanoma; on the lower back the dermis is considerably thicker and would be breached only by a sizeable
tumour. Clark’s levels are still used but the Breslow thickness has been found to correlate better with
prognosis.

The Breslow thickness of melanoma is not a staging system. It makes no attempt to identify the extent of
spread of the melanoma but instead addresses only its thickness, which is measured in millimetres from the
granular layer of the epidermis overlying the melanoma to the deepest identi able tumour cell—there is no
requirement to identify where in the dermis or subcutis this is. The Breslow thickness is modi ed if the
tumour is ulcerated; the measurement is taken from the most super cial aspect of the melanoma to the
deepest malignant cell and the presence of ulceration is clearly recorded. An exophytic nodular melanoma
might have a large Breslow thickness and a Clark’s level of only 2. It will have a poor prognosis.

Prognostic features of melanoma include the:

◆ type of melanoma—a nodular melanoma has a worse prognosis than the other types

◆ Breslow thickness

◆ Clark’s level, to some extent

Downloaded from https://academic.oup.com/book/31816/chapter/266636047 by University of Sydney user on 25 September 2022

◆ presence of ulceration, indicating a poor prognosis

◆ presence or absence of satellite nodules and lymph node metastases

◆ histological features of the tumour, such as a high mitotic count and large tumour volume

◆ site of the tumour: for a given Breslow thickness, tumours on the extremities have a worse prognosis

◆ sex of the patient: men have a worse prognosis

◆ age of the patient: older patients have a worse prognosis.

Paraneoplastic syndromes

A paraneoplastic syndrome is one in which the patient develops symptoms and signs because of a neoplasm
which are not due to the direct presence of the neoplasm or its metastases or associated cachexia, and not
due to secretion of hormones or other substances that the neoplasm would be predicted to secrete.

A thyroid follicular carcinoma secreting T4 with the symptoms and signs that follow is not considered
paraneoplastic but logically neoplastic. Only ectopic secretions and their e ects are considered
paraneoplastic. A gastrinoma of the pancreas and its e ects would be a paraneoplastic syndrome as the
pancreatic islets do not normally secrete gastrin: an insulinoma secreting insulin would not be.

These symptoms and signs may be the presenting features of a neoplasm and so it is surgically important to
recognize the possibility. Some are vague but can themselves cause morbidity or mortality irrespective of
the presence of the causative neoplasm. Some can be misleading, such as hypercalcaemia which might be
taken to indicate bone metastases and lead to up-staging of the neoplasm. Paraneoplastic syndromes fall
into four classical groups:

◆ Haematological:

• a tendency to thrombosis, with or without thrombophlebitis migrans and sterile thrombotic

endocarditis

• thrombocytopenia

• polycythaemia

• DIC.

◆ Endocrine:

• ectopic hormone secretion—eutopic secretion is excluded by the de nition.

◆ Neuromuscular:

• demyelinating disorders

• cerebellar degeneration with myasthenic features (Lambert–Eaton syndrome)

• myopathies without myasthenic features

• polymyositis.

◆ Dermatological:

Downloaded from https://academic.oup.com/book/31816/chapter/266636047 by University of Sydney user on 25 September 2022

• clubbing of ngers and toes

• related to changes in blood ow and also growth factors secreted from the lungs such as
prostaglandins

• acanthosis nigricans

• dermatomyositis

• erythroderma

• erythema gyratum repens

• pemphigus

• hypertrichosis.
References

1. Vermeulen K, van Bockstaele DR, Berneman ZN. The cell cycle: a review of regulation, deregulation and therapeutic targets
in cancer. Cell Prolif 2003; 36:131–49. 10.1046/j.1365-2184.2003.00266.x
Google Scholar WorldCat Crossref PubMed Web of Science

2. Malumbres M, Barbacid M. To cycle or not to cycle: a critical decision in cancer. Nat Rev Cancer 2001; 1:222–
31. 10.1038/35106065
Google Scholar WorldCat Crossref Web of Science

Downloaded from https://academic.oup.com/book/31816/chapter/266636047 by University of Sydney user on 25 September 2022

3. Müller H. Dominant inheritance in human cancer. Anticancer Res 1990; 10(2B):505–11.
Google Scholar WorldCat PubMed

4. Rather LJ. Disturbance of function (functio laesa): the legendary fi h cardinal sign of inflammation, added by Galen to the
four cardinal signs of Celsus. Bull N Y Acad Med 1971; 47:303–22.
Google Scholar WorldCat PubMed

5. Williams GT, Williams WJ. Granulomatous inflammation—a review. J Clin Pathol 1983; 36:723–33. 10.1136/jcp.36.7.723
Google Scholar WorldCat Crossref PubMed Web of Science

6. Little MP. Risks associated with ionizing radiation: environmental pollution and health. Br Med Bull 2003; 68:259–
75. 10.1093/bmb/ldg031
Google Scholar WorldCat Crossref PubMed

7. Valko M, Leibfritz D, Moncol J, et al. Free radicals and antioxidants in normal physiological functions and human disease.
Int J Biochem Cell Biol 2007; 39:44–84. 10.1016/j.biocel.2006.07.001
Google Scholar WorldCat Crossref PubMed Web of Science

8. Wood KE. Major pulmonary embolism: review of a pathophysiologic approach to the golden hour of hemodynamically
significant pulmonary embolism. Chest 2002; 121:877–905. 10.1378/chest.121.3.877
Google Scholar WorldCat Crossref PubMed Web of Science

9. Roberts KE, Hamele-Bena D, Saqi A, et al. Pulmonary tumor embolism: a review of the literature. Am J Med 2003; 115:228–
32. 10.1016/S0002-9343(03)00305-X
Google Scholar WorldCat Crossref PubMed Web of Science

10. National Institute for Clinical Excellence. Nutrition Support in Adults: Oral Nutrition Support, Enteral Tube Feeding and
Parenteral Nutrition. Clinical Guideline 32. London: NICE; 2006. http://www.nice.org.uk/CG032

11. Eming SA, Krieg T, Davidson JM. Inflammation in wound repair: molecular and cellular mechanisms. J Invest Derm 2007;
127:514–25. 10.1038/sj.jid.5700701
Google Scholar WorldCat Crossref PubMed Web of Science

12. Male D, Brosto J, Roth D, et al. Immunology (8th ed). Philadelphia, PA: Saunders; 2013.
Google Scholar Google Preview WorldCat COPAC

13. Mahambrey T, Pendry K, Nee A, et al. Critical care in emergency department: massive haemorrhage in trauma. Emerg Med
J 2013; 39:9–14. 10.1136/emermed-2011-201061
Google Scholar WorldCat Crossref Web of Science

14. http://www.transfusionguidelines.org.uk/docs.pdfs/”www.transfusionguidelines.org.uk/docs.pdfs
WorldCat

15. Douketis JD, Berger PB, Dunn AS, et al. The perioperative management of antithrombotic therapy: American College of
Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133(suppl 6):299S–339S.
PubMed

16. Bilezikian JP. Management of acute hypercalcaemia. N Engl J Med 1992; 326:1196–203. 10.1056/NEJM199204303261806
Google Scholar WorldCat Crossref PubMed

17. Epstein PH, Ross R. Mechanisms of disease: atherosclerosis—an inflammatory disease. N Engl J Med 1999; 340:115–
26. 10.1056/NEJM199901143400207
Google Scholar WorldCat Crossref PubMed Web of Science

Downloaded from https://academic.oup.com/book/31816/chapter/266636047 by University of Sydney user on 25 September 2022

18. Furie KL, Goldstein LB, Albers GW, et al. Oral antithrombotic agents for the prevention of stroke in nonvalvular atrial
fibrillation: a science advisory for healthcare professionals from the American Heart Association/American Stroke Association.
Stroke 2012; 43(12):3442–53. 10.1161/STR.0b013e318266722a
Crossref Web of Science

19. Lusis AJ. Atherosclerosis. Nature 2000; 407:233–41. 10.1038/35025203

Google Scholar WorldCat Crossref PubMed Web of Science

20. Singh AP. Classification of Bone Fractures, Feb 16 2016. http://www.boneandspine.com

WorldCat

21. Jeschke MG, Herndon DN. Burns in children: standard and new treatments. Lancet 2014; 383:1168–78. 10.1016/S0140-
6736(13)61093-4
Google Scholar WorldCat Crossref Web of Science

22. Ponta H, Sherman L, Herrlich PA. CD44: from adhesion molecules to signalling regulators. Nature Rev Mol Cell Biol 2003;
4:33–45. 10.1038/nrm1004
Google Scholar WorldCat Crossref PubMed Web of Science

23. Elston CW, Ellis IO. Pathological prognostic factors in breast cancer: I. The value of histological grade in breast cancer:
experience from a large study with long-term follow-up. Histopathology 1991; 19:403–10. 10.1111/j.1365-2559.1991.tb00229.x
Google Scholar WorldCat Crossref PubMed

24. Gleason DF. Histologic grading of prostate cancer: a perspective. Hum Pathol 1992; 23(3):273–9. 10.1016/0046-
8177(92)90108-F
Google Scholar WorldCat Crossref PubMed Web of Science

25. Wittekind C, Greene FL, Hutter RVP, et al. TNM Atlas: Illustrated Guide to the TNM Classification of Malignant Tumours (5th
ed). New York: Wiley-Liss; 2008.
Google Scholar Google Preview WorldCat COPAC

26. Cserni G. The influence of nodal size on the staging of colorectal carcinomas. J Clin Pathol 2002;55:386–
90. 10.1136/jcp.55.5.386
Crossref

27. Cancer Research UK. Stages of Melanoma. 2014. [Online] http://www.cancerresearchuk.org/about-

cancer/type/melanoma/treatment/stages-of-melanoma#clark
WorldCat

© Oxford University Press