Ebook Muir''s textbook of pathology (15th edition): Part 1

MUIR’S
TEXTBOOK

OF PATHOLOGY

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MUIR’S
TEXTBOOK

OF PATHOLOGY
Fifteenth Edition
Edited by
C Simon Herrington MA DPhil FRCP(Lond) FRCP(Ed) FRCPath
Professor of Pathology, University of Dundee and Consultant Pathologist,
Ninewells Hospital and Medical School, Dundee, UK

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CRC Press
Taylor & Francis Group
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CONTENTS

Contributorsvii
Prefaceix
Preface to 14th edition xi

SECTION 1 CELLULAR AND MOLECULAR MECHANISMS OF DISEASE
1 Applications of pathology........................................................................................................................................3
2 Normal cellular functions, disease, and immunology..............................................................................................11
3 Clinical genetics....................................................................................................................................................31
4 Cell injury, inflammation, and repair.....................................................................................................................49
5 Cancer and benign tumours...................................................................................................................................77

SECTION 2 SYSTEMIC PATHOLOGY
6 The cardiovascular system...................................................................................................................................105
7 The respiratory system........................................................................................................................................165
8 The lymphoreticular system and bone marrow....................................................................................................197
9 The gastrointestinal system..................................................................................................................................231
10 The liver, gallbladder, and pancreas......................................................................................................................273
11 The nervous systems and the eye.........................................................................................................................295
12 The locomotor system.........................................................................................................................................347
13 The kidneys and urinary tract..............................................................................................................................391
14 The female reproductive system..........................................................................................................................421
15 The breasts..........................................................................................................................................................443
16 The male reproductive system.............................................................................................................................463
17 Endocrine system................................................................................................................................................475
18 The skin..............................................................................................................................................................501

19 Infections.............................................................................................................................................................537
Index577

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CONTRIBUTORS TO
15TH EDITION

Jonathan N Berg MSc MD FRCP(Ed)

Senior Lecturer in Clinical Genetics, University of Dundee
and Consultant in Clinical Genetics, Ninewells Hospital and
Medical School, Dundee, UK
Daniel M Berney MB B Chir MA FRCPath
Professor of Genito-Urinary Pathology and Consultant
Histopathologist, Department of Cellular Pathology,
Bartshealth NHS Trust, London, UK
Alastair D Burt BSc MD FRCPath FSB FRCP
Dean of Medicine and Head of School of Medicine,
University of Adelaide, Australia
Francis A Carey BSc MD FRCPath
Consultant Pathologist and Professor of Pathology,
Department of Pathology, Ninewells Hospital and Medical

School, Dundee, UK
Runjan Chetty DPhil FRCPA FRCPC FCAP FRCPath
Professor of Pathology and Consultant Pathologist, University
Health Network and University of Toronto, Canada
Cathy Corbishley FRCPath
Consultant Urological Histopathologist,
Hospital, London, UK

St

George’s

Ian O Ellis BMedSci FRCPath

Professor of Cancer Pathology and Consultant Pathologist,
Faculty of Medicine and Health Sciences, Department
of Histopathology, City Hospital Campus, Nottingham,
University Hospitals NHS Trust, Nottingham, UK
Alan T Evans BMedBiol MD FRCPath
Consultant Dermatopathologist, Department of Pathology,
Ninewells Hospital and Medical School, Dundee, UK
Stewart Fleming BSc MD FRCPath
Professor of Cellular and Molecular Pathology, University of
Dundee, Ninewells Hospital, Dundee, UK
Alan K Foulis BSc MD FRCP(Ed) FRCPath
Consultant Pathologist and Professor of Pathology,
Department of Pathology, Southern General Hospital,
Glasgow, UK
C Simon Herrington MA DPhil FRCP(Lond) FRCP(Ed) FRCPath
Professor of Pathology, University of Dundee and Consultant
Pathologist, Ninewells Hospital and Medical School,

Dundee, UK

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Andrew HS Lee MA MD MRCP FRCPath

Consultant Histopathologist, Nottingham University
Hospitals, City Hospital Campus, Nottingham, UK
Sebastian Lucas FRCP FRCPath
Professor of Pathology, Department of Histopathology,
King’s College London School of Medicine, St Thomas’
Hospital, London, UK
Elaine MacDuff BSc MBChB FRCPath
Consultant Pathologist, Department of Pathology, Southern
General Hospital, Glasgow, UK
Anne Marie McNicol BSc MD FRCP(Glas) FRCPath

Molecular and Cellular Pathology, University of Queensland
Centre for Clinical Research, The University of Queensland,
Australia
Sarju Mehta BSc FRCP
Consultant in Clinical Genetics, Department of Clinical
Genetics, Addenbrooke’s Hospital, Cambridge, UK
Wolter J Mooi MD PhD

Professor of Pathology, Department of Pathology, Vrije
Universiteit Medical Centre, Amsterdam, The Netherlands
James AR Nicoll BSc MD FRCPath
Professor of Neuropathology, Clinical Neurosciences,
University
of
Southampton
and

Consultant
Neuropathologist, University Hospital Southampton NHS
Foundation Trust, Southampton, UK
Sarah E Pinder FRCPath

Professor of Breast Pathology, Research Oncology, Division
of Cancer Studies, King’s College London, Guy’s Hospital,
London, UK
Alexandra Rice FRCPath
Consultant Histopathologist and Senior Lecturer in
Pathology, Imperial College, Department of Histopathology,
Royal Brompton Hospital, London, UK
Fiona Roberts BSc MD FRCPath

Consultant Ophthalmic Pathologist, Department
Pathology, Southern General Hospital, Glasgow, UK

of

Mary N. Sheppard BSc MD FRCPath
Professor of Cardiovascular Pathology, Cardiovascular
Sciences, St George’s Medical School, London, UK

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contributors to 15th edition

viii

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Dina Tiniakos MD PhD
Clinical Senior Lecturer in Cellular Pathology Institute of
Cellular Medicine, Faculty of Medical Sciences, Newcastle
University and Consultant Histopathologist, Department
of Cellular Pathology, Royal Victoria Infirmary, Newcastle
upon Tyne, UK

Paul Van der Valk MD PhD

Professor of Pathology, Department of Pathology, Vrije
Universiteit Medical Centre, Amsterdam, The Netherlands.
Sharon White BMSc BDS MFDS RCPSGlasg PhD FRCPath
Clinical Senior Lecturer and Consultant in Oral Pathology,
Department of Pathology, Ninewells Hospital and Medical
School, Dundee, UK

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PREFACE

It is a great privilege to edit this, the Fifteenth Edition of
Muir’s Textbook of Pathology. Muir’s Textbook (or just
‘Muir’s’) was first published in 1924 and has been the
stalwart of pathology education for several generations.
This Edition is in many ways an update of the Fourteenth
Edition, which, as recorded by the Editors in their Preface,
differed in a number of ways from previous editions. The
structure of the book remains the same and the highly
successful case studies and special study topics have been
retained, and updated where appropriate. The move to a

more integrated approach has been highly successful and
the presentation of core knowledge, with development of
a more in-depth discussion of specific areas that illustrate
recent advances, allows both breadth and depth of coverage. The last Edition saw the involvement of more Editors
and authors from outside Glasgow. This trend has continued
in this Edition, but many, if not most, of us who did not
train or have not worked in Glasgow have been influenced
by Glasgow Pathology through use of ‘Muir’s’ during our

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own training, or our training of others. I hope that this has
allowed us to preserve the unique feel of the book.
I am extremely grateful to the other contributors for
their efficient and timely engagement with the publishing
process. I would also like to thank those who contributed
images and other figures: they are acknowledged specifically
at the appropriate point in the book. Thanks go also to
the publishers, particularly Jo Koster who galvanized the
project in the beginning and Julie Bennett who managed
the publishing process. Finally, I am particularly indebted
to the Editors of the 14th Edition, Professors Levison, Reid,
Burt, Harrison and Fleming, for their transformation of
‘Muir’s’ into what it is today; and for allowing the use of
their material in this Edition.
C Simon Herrington
2014

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PREFACE TO
14TH EDITION

This is the Fourteenth Edition of Muir’s Textbook of
Pathology, building upon the work of previous editions. It
is different in a number of ways from previous editions, but
we think it is similar enough to retain the traditional values of its predecessors. We trust we have produced a text
that will be useful both to undergraduate medical students
and to postgraduates who are interested in having a better
understanding of disease upon which to base either their
clinical practice or their research, or both.
This edition differs in the balance between general and
systematic pathology from most earlier editions, with the
general section being relatively shorter. This is deliberate; it
is not meant to suggest that we think an understanding of the
basic sciences is any less important to clinical practice than
it used to be – quite the contrary. What we have tried to do
is to focus on the most clinically relevant basic science and
we have included some of that in the systematic chapters
where its relevance is hopefully easier to appreciate.
We have also introduced into almost every chapter one
or two special study topics where the information provided
is rather more than most medical educators would include
in the core curriculum of a medical undergraduate course.

This is intended to interest and stimulate the best students
to appreciate that undergraduate education is just the
beginning – a window on the exciting and challenging world
of disease. We have also included in most chapters, several
case histories which illustrate and add to the information

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provided in the main text, in an attempt to emphasize the
fundamental relevance of pathology to clinical medicine. By
adopting this format of special study topics and case studies
integrated into, but clearly distinguished from, the core text,
we are adopting the approach taken to medical education
in many medical schools. We strongly support the move
in the UK to more integrated teaching of the disciplines
in medicine. We, not unexpectedly, believe that the best
doctors are knowledgeable about disease processes, and we
hope that this belief is reflected in the level at which we
have pitched the text.
It will be noted for this edition of the book that for the
first time ever the majority of the editors are not based in
Glasgow. However, three of us are Glasgow graduates, and
we all acknowledge our debt to, and the inspiration we
have drawn from, our predecessors in Glasgow Pathology.
We are honoured to have had the opportunity to edit this
latest edition of ‘Muir’ and hope that we have done justice
to the task.
David A Levison
Robin Reid
Alastair D Burt

David J Harrison
Stewart Fleming
2008

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N
O
I
T
SEC

1

CELLULAR AND MOLECULAR
MECHANISMS OF DISEASE

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1
APPLICATIONS OF PATHOLOGY
C Simon Herrington

• What is Pathology?
• Diagnostic Histopathology and Cytopathology:
Images of Diseases
• How Relevant is Pathology?

3
4
6

WHAT IS PATHOLOGY?
Pathology is the study of disease. It is central to the whole
practice of evidence-based medicine. Arguably, anyone who
studies the mechanisms of a disease can be described as a
pathologist, but traditionally the term is restricted to those
who have a day-to-day involvement in providing a diagnostic service to a hospital or undertake research in a pathology department. Within the discipline there are numerous
subspecialities:
●●

●●

●●

●●

●●

Cellular pathology, including histopathology (the study
of tissues) and cytopathology (the branch in which
diagnoses are made from the study of separated cells).
Morbid anatomy is an old term that refers to postmortem dissection, and forensic pathology is the related
branch concerned with medicolegal postmortem examinations. These are carried out under the aegis of a legal
officer, for example the Coroner in England and Wales,
the Procurator Fiscal in Scotland, and the Medical
Examiner in the USA.
Microbiology is the study of infectious diseases and
their causes. This can be subdivided into bacteriology,
virology, mycology (the study of fungi), and protozoology (the study of infections by protozoa).
Haematology is the laboratory study of diseases of the
blood. This is also a clinical discipline, its practitioners
dealing with patients with these disorders. Most haematologists work in both clinical and laboratory arenas.
Chemical pathology or clinical biochemistry is the
study of body chemistry, usually by assaying the levels
of substances – electrolytes, enzymes, lipids, trace elements – in the blood or urine. Increasing sophistication
of analytical requirements often means that this discipline is at the cutting edge of new technology.

Chapter_01.indd 3

• Summary9
• Acknowledgements9
• Further Reading
9

●●

●●

Immunology is the study of host defences against
external threats. Many of these are microbiological,
but some are chemical, e.g. foodstuffs. In addition,
this is also  the  study of autoimmunity, when the
body’s defence  systems are turned on themselves (see
Chapter 2, pp. 25–26).
Genetics is the study of inheritance of characteristics
and diseases, or a predisposition to diseases. Clinical
geneticists, similar to haematologists, are directly
involved with patients, whereas laboratory-based geneticists apply the traditional techniques of karyotyping, the microscopic examination of chromosomes in
cells in mitosis, and the whole spectrum of modern
molecular techniques, such as polymerase chain reaction (PCR), fluorescence in situ hybridization (FISH),
gene-­expression profiling, and DNA sequencing.

Historically, these subjects emerged from the single discipline of ‘pathology’ which exploded in the mid-nineteenth
century, especially in Germany where Rudolf Virchow
introduced the term ‘cellular pathology’. The divergence of
specialities was largely on the basis of the different techniques used in each area. Today, the boundaries between
these subspecialities are increasingly becoming blurred as
modern techniques, especially those resulting from molecular biology, are applied to all. Cellular pathology remains
a critical part of the clinical evaluation of a patient before
definitive treatment is offered. Increasingly, some of the
roles are also delivered by scientists who are not medically qualified, bringing new opportunities and challenges to
building effective multidisciplinary teams.
The editor and almost all of the contributors to this book
are primarily histopathologists and it is on this area that the
book focuses.

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applications of pathology

4

DIAGNOSTIC HISTOPATHOLOGY
AND CYTOPATHOLOGY: IMAGES OF
DISEASES
Key Points
●●
●●

●●

Pathology is the study of disease.
Naked eye examination and the light microscope are
the traditional tools of the pathologist.
Increasingly, molecular biological techniques are
applied across the whole spectrum of study of
diseases to explore underlying mechanisms.

Cellular pathology, i.e. both histopathology and cytopath­
ology, are essentially imaging disciplines. Its practitioners
interpret an image, usually obtained by microscopy, and
from it deduce information about diagnosis and possible
cause of disease, recommend treatment and predict likely
outcome.

Fig. 1.1 Haematoxylin and eosin (H&E)-stained section of the parotid
gland allowing the serous cells (top right), mucinous cells (left), and
salivary duct (lower right) to be readily distinguished.

Preparing the Image
Tissues or cells are removed from a patient. The fairly simple technique of light microscopy is the bedrock of preparing images. A very thin slice of a tissue, usually about 3 µm
thick, is prepared and stained so that the characteristics of
the tissue, i.e. the types of cells and their relationships to
each other, can be examined. To prevent the tissue digesting
itself through the release of proteolytic enzymes, the tissue
is immersed in a fixative, usually formaldehyde, which crosslinks the proteins and inactivates any enzymatic activity. It
is impossible to cut very thin sections of even thickness
without supporting the tissue in some medium. Usually the
tissue is embedded in paraffin wax, which has the appropriate melting and solidifying characteristics, but freezing
the tissue (the principle of the frozen section) and embedding hard tissue in synthetic epoxy resins, such as Araldite,
are also done. To stain the tissue section, the vegetable dyes
haematoxylin and eosin are traditionally used to distinguish
between the nucleus and cytoplasm, and to identify some of
the intracellular organelles. It is from examination of sections
stained by these simple tinctorial techniques that normal
histology and the basic disease processes of inflammation,
repair, degeneration, and neoplasia were defined (Figs. 1.1
and 1.2). In the past century numerous chemical stains have
been developed to demonstrate, for example, carbohydrates,
mucins, lipids, and pigments such as melanin and the ironcontaining pigment haemosiderin.

Refining the Image
Electron Microscopy
Pathological applications of this technique emerged in the

1960s as the technology of ‘viewing’ tissues by beams of electrons rather than visible light became available. This greatly

Chapter_01.indd 4

Fig. 1.2 A section of renal glomerulus stained by haematoxylin and
eosin. The nuclei have affinity for the basic dye haematoxylin and are
blue. The cytoplasm has more affinity for the acidic dye eosin and is
pink. This technique has not changed significantly in well over a century.

increased the limits of resolution so that cellular organelles
could be identified, and indeed their substructure defined.
This allowed more precise diagnosis of tumour  types and
allowed the structure of proteins such as amyloid to be
determined. Ultrastructural pathology now has only a limited place in tumour diagnosis, but still has a central role in
the diagnosis of renal disease, especially glomerular diseases
(Fig. 1.3) (see Chapter 13).

Immunohistochemistry
This technique evolved in the 1980s and gained a major boost
from the development of monoclonal antibodies  by  the

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5

Primary antibody directed
against antigen A

Cells (separate or

in a section)

Slide
Type 2
cell bearing
antigen B

Fig. 1.3 Electron micrograph showing the ultrastructure of a glomerulus.
The increased detail is apparent even at this low power.

late Professor Cesar Milstein. It depends on the property
of antibodies to bind specifically to cell-associated antigens.
Of course one must beware cross-reactive binding to other
unrelated proteins. Tagging such an antibody with a fluorescent, radioactive, or enzymatic label allows specific substances to be identified and localized in tissue sections or
cytological preparations. This has proved particularly useful
in the diagnosis of tumours, in which it is important to classify the tumour on the basis of the differentiation that it
shows to allow the most appropriate treatment to be given.
The technique is outlined in Fig. 1.4.

Molecular Pathology
Molecular techniques were the logical next step: rather than
attempt to identify proteins within a cell, expression of the
genes responsible could be identified if appropriate mRNA
could be extracted from the cells or localized to them by
in situ hybridization techniques. In addition, expression of
abnormal genes could be detected, e.g. in several forms of
non-Hodgkin lymphoma, specific genetic rearrangements
appear to be responsible for the proliferation of the tumour
(see Chapter 8, pp. 206–212); their identification allows
precise subtyping (Fig. 1.5).

Future Imaging in Pathology
Histopathology sets great store on making the correct diagnosis and gleaning information that is going to be useful
in determining treatment options and the probable clinical outcome. In parallel, oncologists are now increasingly
aware of how a patient’s disease is unique to that patient

Chapter_01.indd 5

Type 1
cell bearing
antigen A

Fig. 1.4 The principles of immunohistochemistry: the aim of the
technique is to identify any cell bearing a specific antigen. The cell in the
centre has antigens on its surface which are recognized by antibodies,
often raised in mice, directed against that antigen. These are the primary
antibodies. To demonstrate where these antibodies have bound, a
secondary antibody is applied to the section. This antibody is raised in
another species, e.g. rabbit. It is directed against the Fc component of
the primary antibody and therefore binds to it. An enzyme or fluorescent
label is bound to the secondary antibody so that a coloured signal is
produced. The cells on the left and right bear different surface antigens,
which are not recognized by the primary antibody, and so no signal is
produced in relation to them.

(A)

diagnostic histopathology and cytopathology: images of diseases

Secondary antibody
directed against Fc

component of primary
antibody

Coloured reagent
bound to secondary
antibody

(B)

Fig. 1.5 Interphase fluorescence in situ hybridization (FISH) on a
lymphoma using the IGH/CCND1 dual fusion probe (Vysis). (A) Normal
pattern showing two green signals representing IGH on chromosome
14 and two red signals representing CCND1 on chromosome 11.
(B) Abnormal pattern in a mantle cell lymphoma showing a single
green IGH signal, a single red CCND1 signal, and two fused signals
representing the two derived chromosomes involved in the t(11;14)
translocation. (For more information on the probe used see www.
abbottmolecular.com/products/oncology/fish/vysis-ighccnd1-df-fishprobe-kit.html.)

and treatment must be ‘individualized’. The image that a
pathologist sees down a microscope reflects the underlying
differentiation of the cells and the processes that are taking place. The use of antibodies or RNA detection to identify
different cell types and processes adds to this basic knowledge. In recent years the techniques of genomics, transcriptomics, proteomics, and metabolomics have been developed.

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applications of pathology

6

In these, the entire DNA profile, gene-expression profile, or
protein or metabolic composition of a diseased tissue can
be established in comparison to the corresponding normal
tissue (Fig.  1.6). Many of these approaches employ high-­
throughput array-based methods that can generate large
amounts of information about normal and diseased tissues: analysis of this information presents a challenge that
requires close collaboration with bioinformaticians. The
recent development of massively parallel sequencing techniques (next generation sequencing) (see Chapter 3, p. 35)
allows the whole (or part) of the genome to be sequenced
quantitatively, rapidly, and cheaply, and has the potential to
transform the way in which tissue can be interrogated on
an individual basis. However, these high-throughput technologies can provide meaningful information only if the tissues being analysed are carefully selected and characterized.

Pathology thus has a key role in translational research and
should remain at the forefront of medical advances.

HOW RELEVANT IS PATHOLOGY?
Is Histopathology Necessary?
It might be argued that with advances in radiological imaging
and other laboratory techniques the role of the histopathologist has decreased. This misses the key point that
pathology directly addresses the question of what disease
process is occurring and is complemented by many other
diagnostic modalities. This role is especially important in
the management of patients suspected of having a tumour
(see Case History 1.1), but almost all tissues removed from
a patient should be submitted for histopathological analysis.

What Can Cytopathology Achieve?
Unlike histopathology, where assessment of the tissue architecture is of prime importance, in cytopathology it is the

characteristics of the individual cells that are of most value.
Essentially, in diagnostic practice the cytopathologist looks
for the cytological features of malignancy (see Fig. 5.3D,
p. 80). Admittedly, the relationships between adjacent cells
can be appreciated to some extent: e.g. in an aspirate from
a breast lump, loss of cohesion between cells is suggestive
of malignancy, as is a high nucleus:cytoplasm ratio of the
cells (Fig. 1.7). In screening practice, e.g. in cervical cancer
programmes, the cytopathologist seeks to identify the same
changes but at an earlier stage and thus give a warning of
incipient cancerous changes. The biological basis and efficacy of screening programmes continue to be hotly debated.

Fig. 1.6 Gene expression microarrays were developed in the mid-1990s
and have become a powerful tool to study global gene expression.
Real-time polymerase chain reaction (RT-PCR) is used to generate
complementary DNA (cDNA) from mRNA extracted from test and control
samples. The test and reference cDNAs are labelled with different
fluorochromes, in this case represented by the red and green circles.
These samples are then competitively hybridized to an array platform that
comprises representations of known genes or expressed sequence tags
(ESTs), which have been spotted on to a solid support, usually glass or
nylon. The presence of specific cDNA sequences in each sample can then
be determined by scanning the array at the excitation wavelength for each
fluorochrome, with the ratio of the two signals providing an indication of
the relative abundance of the mRNA species in the two original samples.
Although spotted microarrays are still in use today, the market is now
dominated by one-colour platforms such as the Affymetrix GeneChip,
in which a single sample is hybridized to each array. Gene expression
microarrays have been used in numerous applications including
identifying novel pathways of genes associated with certain cancers,

classifying tumours, and predicting patient outcome.

Chapter_01.indd 6

Fig. 1.7 This breast aspirate shows cells with a high nucleus:cytoplasm
ratio and loss of cohesion indicating malignancy.

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7

1.1

CASE HISTORY

The popular image of a pathologist, perhaps fostered by television programmes, is of an individual who determines the
cause of death, especially when foul play is suspected. From
the early days of pathology, the postmortem examination
has been of importance in understanding disease mechanisms, and in explaining the nature of the individual’s final illness. However, advances in imaging and a cultural move not
to accept postmortem examinations in many countries have
significantly reduced the number performed, other than
those carried out for legal reasons. Enormous advances in
imaging techniques, especially computed tomography (CT)
and magnetic resonance imaging (MRI), when coupled with
targeted needle biopsies have to some extent d
­ iminished

The patient, a man of 55, presents with altered bowel habit.
Both barium enema and colonoscopy show a stricture at the

rectosigmoid junction. A biopsy is taken from this site.

the need for postmortem examinations, but publications
­continue to show that they uncover hitherto unsuspected
­conditions.
Establishment of a robust, updated, scientific evidence
base for postmortem pathology remains a challenge. Recent
events, including the disclosure of widespread practices
of retention of tissue and organs for research purposes,
have provoked a sea change in public attitudes to postmortem examinations. In some countries specific new
legislation is attempting to find the balance of investigation versus prohibition and to provide a platform for education of the public and support of families. Nevertheless,
the postmortem examination remains the final arbiter of
the cause of death in many cases, the key investigation in
the ­forensic ­investigation of unexplained deaths, and potentially an essential part of medical audit. This can be so

Once again, what information do the clinician
and patient require?
●●

First, confirmation of the diagnosis.
Second, any information that would predict the likely
prognosis of the patient and indicate whether any
additional therapy should be given.

What does the clinician (and of course the
patient) want to know?

●●

Is this a benign stricture, perhaps due to diverticular disease

or even Crohn’s disease? Or is this a tumour and, if so, is it
benign or malignant? Fig. 1.8 shows infiltration of the normal
tissues by malignant cells arranged in glandular structures,
indicating an adenocarcinoma (see Chapter 5, p. 82).
In the light of this diagnosis, the patient proceeds to have
a resection of the rectum and sigmoid colon with anastomosis
of the cut ends to restore bowel continuity. The specimen is
submitted for pathology.

This information would include an indication of the type of
tumour and an estimate of its biological potential – how
malignant it is (its grade), how far it has spread (its stage),
e.g. how far through the bowel wall the tumour has spread,
and whether the tumour has been completely excised or is
present in lymph nodes (Fig. 1.9). To improve the collection
of such information in a standard form, the concept of a
‘minimum data set’ has evolved. The data set recommended
by the Royal College of Pathologists is shown in Fig. 1.10.

Fig. 1.8 Adenocarcinoma of the colon. Malignant glandular
structures (arrows) have invaded the wall of the bowel and have
almost reached the peritoneal surface (arrowheads).

Fig. 1.9 Secondary (metastatic) adenocarcinoma of the colon in a
lymph node. Two malignant glands can be seen, with the surviving
node to the right. A tumour that has reached the lymph nodes by
the time of diagnosis has a worse prognosis.

Chapter_01.indd 7

how relevant is pathology?

Is the Postmortem Examination a Useful
Investigation?

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CASE HISTORY continued

APPENDIX C

PROFORMA FOR COLORECTAL CANCER RESECTIONS

Surname: ………………………………… Forenames: ………………………………

Date of birth: …………….………………

Hospital………………… …………….….. Hospital no: ………………….……………

NHS no: ………………………..…..…..

Date of receipt: ……………….…………. Date of reporting: ………………………..

Report no: ………………………………

Pathologist: …………….……………

Sex: ……………………………….…….

Surgeon: …………………………….…….

Specimen type: Total colectomy / Right hemicolectomy / Left hemicolectomy / Sigmoid colectomy / Anterior resection /
Abdominoperineal excision / Other (state) …………………………………………………………………………………..

Gross description

Site of tumour ………………………………………….
Maximum tumour diameter: …………………..…..mm
Distance of tumour to nearer cut end …………….mm
Tumour perforation (pT4)
Yes †
No †
If yes, perforation is serosal † retro/infra peritoneal †
For rectal tumours:
Relation of tumour to peritoneal reflection (tick one):
Above †
Astride †
Below †
Plane of surgical excision (tick one):
Mesorectal fascia †
Intramesorectal
†
Muscularis propria †
For abdominoperineal resection specimens:
Distance of tumour from dentate line .................mm

1.1

applications of pathology

8

N/A
Yes
No
Doughnuts
†
†
†
Margin (cut end)
†
†
†
Non-peritonealised
†††
‘circumferential’ margin
Histological measurement from
tumour to non-peritonealised margin ................. mm

Metastatic spread

No of lymph nodes present ................................................
No of involved lymph nodes ...............................................
(pN1 1–3 nodes, pN2 4+ nodes involved)
Highest node involved (Dukes C2) Yes †
No †
Extramural venous invasion
Yes †
No †

Histologically confirmed distant metastases (pM1):
Yes †

Histology
Type
Adenocarcinoma

Tumour involvement of margins

Yes

†

No

†

If No, other type ...........................................................
Differentiation by predominant area
Well / moderate†

Poor†

Local invasion
†
No carcinoma identified (pT0)
Submucosa (pT1)
†
Muscularis propria (pT2)
†

Beyond muscularis propria (pT3)
†
Tumour invades adjacent organs (pT4a)
†
AND/OR
Tumour cells have breached the serosa (pT4b)†
Maximum distance of spread
beyond muscularis propria
……………………..mm
Response to neoadjuvant therapy
Neoadjuvant therapy given Yes †
No † NK †
If yes:
No residual tumour cells / mucus lakes only
†
Minimal residual tumour
†
No marked regression
†

No † If yes, site: ………………………..….

Background abnormalities: Yes †

No

†

If yes, type: (delete as appropriate)
Adenoma(s) (state number ………………..….)

Familial adenomatous polyposis / Ulcerative colitis /
Crohn’s disease / Diverticulosis / Synchronous carcinoma(s)
(complete a separate form for each cancer)
Other ................................................................ ……….

Pathological staging

Complete resection at all surgical margins
Yes (R0) †
No (R1 or R2) †
TNM (5th edition)
(y) pT ……..
Dukes
Dukes A
Dukes B
Dukes C1
Dukes C2

†
†
†
†

(y) pN ……..(y) pM ……..

(Tumour limited to wall, nodes negative)
(Tumour beyond M. propria, nodes negative)
(Nodes positive and apical node negative)
(Apical node involved)

Signature: ……………………………………….
Date …../…../……….
SNOMED Codes T…….. / M……
Fig. 1.10 National Minimum Data Set for Colorectal Cancer. (Reproduced with permission from the Royal College of Pathologists.)

Chapter_01.indd 8

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9

The Postmortem Examination Itself
The aim of a full postmortem examination is the examination first of the external aspects of the body, to look for injuries, haemorrhage, jaundice, or other stigmata of disease. The
body is then opened and the body cavities inspected, and the
organs are removed so that each in turn can be weighed and
examined both externally and on the cut surface. Ideally, if
appropriate permission has been granted, small pieces of the
major organs and any diseased tissues are taken for fixation
and histological assessment, so that the impression gained
on naked eye inspection may be confirmed (or refuted). For
a detailed analysis of some organs, especially the brain, it is
essential that the organ is retained intact, preserved in formaldehyde, and then cut into thin slices followed by histology, a process that usually takes at least 3–4 weeks.
Where is Pathology Going?
The past 20 years have seen major advances in our understanding of the underlying molecular mechanisms of disease.
The completion of the human genome project, molecular
genetics, and cell biology, and more importantly the use of
this information to allow construction of a functional framework of tissues in health and disease, will inevitably lead to
new approaches to basic research, and also to the day-to-day
investigation of disease. Proteomic and functional genomic

analysis of a few cells aspirated from a mass may give far

Chapter_01.indd 9

more information on the nature of a tumour than conventional histopathological assessment of the entire specimen,
which at present remains the gold standard, although the
issue of tumour heterogeneity (i.e. variation in tumour characteristics from one place to another) is likely to limit this.
Virchow might be familiar with the workings of a twentiethcentury pathology department. It is doubtful if he would be
as familiar with the evolving pathology department of the
twenty-first century.

further reading

only if it is carried out thoroughly and appropriately, realizing that no single investigation is the gold standard and
that the postmortem examination is a much less effective way to examine death caused by metabolic ‘failure’
than that due to a structural abnormality. The examples
of new variant Creutzfeldt–Jakob disease (see Chapter 11,
p. 323), acquired immune deficiency syndrome (AIDS) (see
Chapter 19, p. 540), and severe acute respiratory syndrome
(SARS) (see Chapter 7, p. 176) emphasize that new diseases
are still emerging. Meticulous postmortem examinations
can help clarify the disease mechanisms.

SUMMARY
●●

●●

●●

Pathology is the study of disease. Subspecialities include
histopathology, cytopathology, postmortem pathology,
forensic pathology, haematology, microbiology, chemical pathology, immunology, and genetics.
Techniques in pathology include light microscopy, electron microscopy, immunohistochemistry, and molecular
pathology.
Genomics, proteomics, and tests of metabolic function
are entering practice.

ACKNOWLEDGEMENTS
The contributions of Robin Reid and David J Harrison to this
chapter in the 14th edition are gratefully acknowledged.

FURTHER READING
Dabbs D. Diagnostic Immunohistochemistry, 2nd edn.
Philadelphia, PA: Churchill Livingstone, 2006.
Killeen AA. Principles of Molecular Pathology. Totowa, NJ:
Humana Press, 2004.
Rosai J. Rosai and Ackerman’s Surgical Pathology, 10th edn.
London: Mosby, 2011: Chapters 1–3.

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Chapter_01.indd 10

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2
NORMAL CELLULAR FUNCTIONS, DISEASE,

AND IMMUNOLOGY
C Simon Herrington

•
•
•
•
•
•
•

Introduction11
Components of the Cell: Structure
11
Cellular Biochemistry: Function
12
Intercellular Communication
13
Stem Cells and Differentiation
13
Morphogenesis and Differentiation
14
Cell Proliferation and Growth
16

•
•
•
•
•

•
•

Cell Death by Accident and Design
17
Disorders of Growth
18
Ageing19
Immunology21
Summary28
Acknowledgements29
Further Reading
29

INTRODUCTION

COMPONENTS OF THE CELL: STRUCTURE

Disease may result from an abnormality in structure or
function within cells of a particular type, e.g. in cancer, but
more often than not it manifests itself because of the way
in which other cells and tissues are affected and take part in
the response to the original cause.
Understanding the normal function of cells and tissues
gives insight into both the cause and the effect of disease,
as well as beginning to allow rational design of therapy.
Normal cellular function is encapsulated in the reproductive cycle. The body originates from a single fertilized ovum,
which generates all body tissues including germ cells in
the gonads; these in turn contribute to a fertilized ovum
ensuring continued propagation of the species. This involves

many processes: cell proliferation, cell deletion, intercellular
communication, basic energy supply and use, oxygen delivery and combustion, protective mechanisms that may be
active or passive, and complex gene programming that can
be overridden in certain circumstances by the environment
in which a cell finds itself. For this complex organization to
function there must be many checks and balances, and ways
in which different cells and tissues can communicate with
each other. At the heart of understanding the pathogenesis
of disease is recognizing how different injuries and insults
can subvert or overwhelm these normal physiological processes and lead to an imbalance in homeostasis. This principle is well illustrated by the normal and abnormal function
of the immune system, which comprises the latter half of
this chapter.

With the exception of the red blood cells, all living cells in the
human body contain a nucleus in which resides most of the
genetic information; in addition the mitochondria ­harbour
37 genes, 13 of which code for proteins. The nucleus is not
an inert structure cut off from the rest of the cell (Fig. 2.1).

Chapter_02.indd 11

Fig. 2.1 Liver cells in which the nuclei have been stained blue and
the cytoplasm red. The nuclei communicate with the cytoplasm, and
the cells connect intimately with each other through a variety of cell
junctions (confocal fluorescence microscopy).

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normal cellular functions, disease, and immunology

12

Fig. 2.2 Mitochondria, visible as rod-like structures lying mostly around
the nucleus, are demonstrated by a fluorescence technique. (Courtesy
of Dr Rehab Al-Jemal.)

The nuclear membrane is constantly crossed by factors
which regulate the expression of genes and may repair DNA
damage as soon as it occurs. The chromatin material that is
the scaffold for the double-stranded DNA is packaged very
tightly. It is critically important that this wrapped DNA is
protected from damage, and yet can  be unravelled when
needed for gene transcription and for ­replication.
In the cytoplasm, a variety of organelles are responsible for
the remainder of the cellular function. In some cases these are
permanent features, e.g. mitochondria (Fig. 2.2), but in other
cases a particular macromolecular complex may be assembled
only when needed, e.g. the proteosome, which is involved
in protein degradation, or the ‘apoptosome’, which catalyses cell death by apoptosis. Ribosomes translate messenger
RNA (mRNA) into peptide sequences and further processing, including splicing, glycosylation, and possible packaging
for secretion, occurs in the endoplasmic reticulum. The mitochondria are the primary site of oxidative phosphorylation.
As part of this function they generate free radicals, which,
in addition to potentially causing damage to membranes,
enzymes, and DNA, are also part of the redox signalling system that indirectly regulates the expression of a number of
genes involved in protection. The mitochondria are also key
players in executing apoptosis in some ­situations.

CELLULAR BIOCHEMISTRY: FUNCTION
Perhaps as many as 10,000 genes are actively expressed in

a cell simply to maintain cell viability and function. These
genes code for a variety of protein products involved directly and indirectly in energy production, protection
against unwanted side effects of carbohydrate combustion
in the presence of oxygen, maintenance of cell structure,
and waste disposal. It is clear that these many gene products interact with each other so that cell homeostasis is a

Chapter_02.indd 12

Fig. 2.3 Lung alveolar epithelium. Nuclei are blue, flattened type 1
alveolar epithelial cells are green, and type 2 cells are pink. The green
and pink fluorescence depends on the expression of proteins specific to
the different cell types identified by particular antibodies labelled with
fluorescent dyes. (Courtesy of Dr Gareth Clegg.)

complex interactive network (Fig. 2.3). The regulation of
gene expression is therefore complex, with many genes
being expressed only when needed through the assembly
of regulatory protein complexes which include transcription factors. This gives the cell the ability to express certain
genes selectively at appropriate levels in response to particular stimuli. In addition to controlling gene (and hence protein) expression, the cell controls protein function through
a network of competing enzymes that regulate the activity, structure, and function of other proteins. Thus phosphorylases and kinases act at suitable amino acid residues to
dephosphorylate or phosphorylate their targets. These cause
pH-dependent conformational shifts that alter both structure and function. Thus enzymes can modify proteins after
they have been translated (post-translational modification)
to flick protein switches, providing a rapid response to the
changing intracellular environment.
Central to understanding many diseases is the appreciation that an oxygen-rich environment is potentially toxic
and that protection against oxidant-induced stress is key
to cell survival. The balance between oxidation and reduction is central to many processes including the reduction
of ribose acids to generate deoxyribose, which is a critical
component of DNA. Antioxidant enzymes are positioned

throughout the cell to maximize protection. Thus superoxide dismutase 2 (SOD2) is located in mitochondria
where it quickly takes reactive superoxide anions and

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