Pathological Society – 2012 Undergraduate Essay Competition
“Pathology has been called ‘the hidden science that saves lives’.
Discuss how pathology directly impacts on patients, and compare
the past, present and possible future effects of pathology on a
patient’s journey.”
Aniruddh Chhabra, University of Liverpool
Introduction
Since its emergence as a medical specialty several centuries ago, pathology has come to
occupy a unique but also a rather unfortunate position within medicine. On the one hand,
it represents a pivotal and, in my opinion, irreplaceable link between the increasingly
partitioned domains of clinical medicine and the basic medical sciences. As such, the
modern pathologist is entrusted to perform a variety of complex, multi-faceted tasks and,
subsequently, provide and interpret information crucial in the prevention, diagnosis and
management of various diseases. However, on the other hand, the very nature of
pathology has rendered it, to the unassuming patient at least, a ‘hidden’ specialty with
seemingly limited connection to everyday clinical situations. This predicament, which is
made worse by popular misconceptions about pathology (present both within the general
public and, more disappointingly, within medicine), leaves unrecognised the vital ‘behind
the scenes’ role of laboratory medicine.
“The hidden science that saves lives” is an apt description of pathology in the 21 st
century; it is also the slogan employed by The Royal College of Pathologists as part of its
proactive attempt to showcase the reality of what pathology is – a dynamic amalgam of
science and art which contributes immensely to the care of patients, most likely without
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Pathological Society – 2012 Undergraduate Essay Competition
them realising it – and to banish the ill-conceived perceptions of pathology being an
isolated and immaterial entity which deals solely with death1. This is certainly not a small
task and perhaps the best way of informing the public is to remind ourselves of how the
different aspects of pathology relate to and affect the lives of so many individuals on a
day-to-day basis. This essay intends to do just that and begins by briefly contemplating
how the remarkable evolution of pathology has influenced the structure and practice of
patient care since the days of Hippocrates.
Pathology through the years
Simply put, pathology is the study of disease; therefore, locating a specific point in history
which marked its ‘beginning’ is impossible as humans have always questioned and
enquired about their ailments, investigating the origin of disease as far as the resources at
their disposal would allow. Nevertheless, modern pathology has its roots in the pioneering
work of Morgagni in the 18th century, who developed the concept of clinicopathological
correlation through his meticulously detailed autopsy studies2. His findings and the
invention of the compound microscope provided the foundation for Virchow and others to
study disease mechanisms (e.g. inflammation, necrosis, etc) at the cellular level. This
provided the impetus for morphology based identification and classification of diseases,
and also enabled other significant advances in medicine to be made. For example,
Landsteiner proposed what is now the ABO blood group system in 1901 and drastically
improved the success rate of blood transfusions, saving countless lives since3.
Although succinct, the clichéd description of a pathologist being a “doctor’s doctor”
is incomplete as it neglects to disclose the fact that a pathologist, along with being a
scientist and an educator, is also a physician directly responsible for patient care. In the
last century, the development of new technologies (e.g. immunohistochemistry, gene
expression profiling, etc) and our improved understanding of how different organs and
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Pathological Society – 2012 Undergraduate Essay Competition
tissue types can be affected by a single disease has allowed pathology to encompass
different fields (e.g. immunology, microbiology, etc). This has benefited patients as they
can now receive care from a highly specialised, multi-disciplined team of physicians. For
example, the specialist input of chemical pathologists and toxicologists may be needed by
a rheumatologist in interpreting the biochemical and liver function tests of a seriously ill
rheumatoid arthritis patient on disease-modifying anti-rheumatic drugs. Similarly,
improvements in existing and the discovery of new staining techniques have regularly
punctuated the history of pathology, facilitating the management of many diseases. For
example, the invention of Gram staining provided inroads to the development of a
clinically meaningful classification of bacteria based on cell wall types, in turn improving
the characterisation of different antibiotics and their spectrum of action4.
Pathology and malignant neoplastic diseases
Pathology has always had an intimate focus on neoplastic diseases and, unsurprisingly,
advances in our understanding of how cancer arises have closely followed technological
advances in the field of pathology. The autopsy has remained a time-tested tool for
documenting the gross appearance of solid cancers and has been valuable in informing us
of the natural history and metastatic patterns of many cancers5. It has also allowed
pathologists to characterise tumours phenotypically and immunohistochemically, which
has facilitated their understanding at the sub-cellular level. Despite their declining usage,
post-mortems still have an important role in educating clinicians and improving their
patient care. A situation which exemplifies this is the unexpectedly high incidence of
latent cancers, lacking clinical concordance, found at autopsy and its subsequent
implications, for example on organ donation6.
Histopathological examination of biopsy tissue is the gold standard for diagnosing
most cancers. Here, the histopathologist is tasked with using their knowledge and
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Pathological Society – 2012 Undergraduate Essay Competition
expertise to judge whether individual cells (and their organelles) are abnormal and
deranged such that they are ‘cancerous’. Today, pathological observations form not only
the foundation of cancer diagnosis but, through prognostication and prediction, also
directly influence treatment decisions. Indeed, this is in quite stark contrast to the
laboratory-based physician of the 1970s, whose duties in clinical oncology seldom
extended beyond making a definite diagnosis (itself not an easy task). This is perhaps a
reflection of a recurring theme in the history of pathology – that of selective change. As a
scientific discipline, pathology has always been reliant on a variety of tools and
technologies, and the rapidity of technological advances in the last century or so would
apparently have been of great benefit to the field. It may be surprising to note then that,
historically, the uptake of new technologies has been especially slow in pathology; this
peculiar state of reluctance is affirmed, for example, by the 150 or so years which passed
between the invention of the compound microscope and its widespread use in diagnostic
pathology or by the delay in utilising the polymerase chain reaction (PCR)7. Although this
approach certainly belies the drastic transformations which have occurred in the role of
the clinical pathologist, just in the last few decades, it is better described as being prudent
rather than ignorant. This is understandable because conventional pathology, at any given
period in time, has always possessed techniques (e.g. the humble hematoxylin & eosin
[H&E] stained slide) which arguably provide the most definite, pragmatic and practical
answers to questions of clinical significance. Thus, careful and watchful appraisal of new
technologies, no matter how innovative they are claimed to be, has been an important
feature in the evolution of pathology and one which has brought significant benefits to
cancer patients.
These benefits are especially clear for breast cancer. Initially, the drawbacks of
obtaining large excised specimens and carrying out gross pathologic observations (e.g. to
ascertain tumour size, vascular invasion, etc) provided the impetus for utilising and
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Pathological Society – 2012 Undergraduate Essay Competition
improving imaging procedures (e.g. ultrasound) and minimally invasive techniques for
studying breast tumours. This allowed pathologists to obtain smaller samples of diseased
tissue (e.g. using ultrasound-guided core biopsy) and spearhead the classification of both
benign and malignant breast neoplasms through their study of various microscopic
features, such as mitotic activity, tubule formation, nuclear and cellular pleomorphism,
and microscopic lymphovascular invasion. The Scarff-Bloom-Richardson histological
grading system was developed to evaluate these pathological parameters and provide
(crude) prognostic information based on how well differentiated invasive breast
carcinoma cells were to their normal counterparts8. This was a significant step in
answering a patient’s most important questions – about survival – and in placing
pathologists at the helm when it came to making treatment decisions, especially about
adjuvant therapy, with patients and their oncologists. Subsequent refinements to this
system and the incorporation of two independent prognostic factors (nodal stage and
tumour size) paved the way for widespread use of the Nottingham Prognostic Index (NPI)
as a method of predicting survival of operable primary breast cancer9. This is a continuous
variable which reflects the growth rate, metastatic potential and genetic derangement of
invasive breast cancers, with the index defining three categories of prognosis (good,
moderate and poor) and survival probability10. A needle biopsy, used to obtain tissue
samples (or flee floating cells), has important limitations which the histopathologist must
circumvent in order to provide informative diagnostic and prognostic information. As
human malignancies tend to be spatially heterogeneous, a single sample of a suspect mass
may not reveal any abnormalities. Similarly, examining several samples may lead to the
identification of a continuum of abnormalities, giving conflicting information11.
The NPI algorithm takes into account the lymph node status, a parameter which has
been shown to possess great prognostic value and is also used in other cancer staging
systems (e.g. tumour, node, metastasis (TNM) system)12. Histopathology has always
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Pathological Society – 2012 Undergraduate Essay Competition
played an important role in this assessment and, nowadays, sections of a sentinel axillary
lymph node (obtained, for example, during lumpectomy surgery) can be examined under
the microscope to detect cancer cells indicating nodal spread of the primary cancer. This
task has gained added importance over the years as many other variables (e.g. histological
grade, morphometric nuclear factors) are now seen to be of limited long-term prognostic
value13. In the last decade or so, pathologists have been able to better identify
micrometastases (cancerous growths smaller than 0.2 mm) in lymph node tissue and have
played a key part in determining the prognostic value of this finding in patients. This has
required close co-operation between pathologists, cancer surgeons and oncologists as
conclusive evidence of the benefit of axillary lymph node dissection (ALND) in patients
with micrometastases has been lacking14. As ALND carries with it a significant risk of
lymphoedema, nerve damage and shoulder dysfunction, this situation illustrates the
immense, but seemingly ‘hidden’, impact of a pathologist’s clinical judgement in multidisciplinary decision making, which must finely balance the risk of cancer recurrence
against that of a significantly impaired quality of life for the patient.
Drug discovery and development
In the bygone decades, pathology has established itself as an indispensable component in
the discovery and development of new drugs. These are time-consuming and expensive
endeavours and pathologists play a key role in ensuring that they arise logically from our
current understanding and assumptions of disease processes. Tissue-based preclinical
research, carried out by toxicologic, human anatomy and veterinary pathologists,
continues to provide major insights into the mechanism of candidate drugs and their
efficacy and toxicity profiles. This work most resembles ‘classical’ pathology and is
primarily based around studying the morphological changes that are induced in various
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Pathological Society – 2012 Undergraduate Essay Competition
animal tissues by the compound(s) under consideration. The sequencing of the human
genome has allowed better characterisation of the activities of genes and their protein
products in the pathogenesis of various conditions. This, along with new molecular-based
approaches, now permits the identification of molecular targets which can be
therapeutically acted upon by specific compounds, selected by screening large databases
of synthetic and natural compounds. Molecular pathology can replace the traditional
empirical approaches to drug discovery and, thus, it has the potential to improve
considerably the effectiveness of new drugs (i.e. improved selectivity) and the efficiency of
their development.
Going above and beyond H&E
The molecular age we now find ourselves in has seen the future roles of conventional
pathology be questioned many a time15. While many prophecies – including “the
microscope will be in a cupboard gathering dust in a few years’ time” – can be dismissed
as harmless hyperbole, it is worth noting (and admiring) the strong foundations pathology
has laid down in its long history and how these have helped to refine the field in the face
of new challenges. In 1932, Dr Cuthbert Dukes published his staging system for colorectal
carcinoma based on his meticulous histopathological observations of tumour invasion
through the three layers of the bowel wall16. Although this has largely been superseded by
other standardised systems (e.g. the TNM system mentioned earlier), it represents a key
initiating event in the elucidation of the various pathogenetic pathways involved in the
colorectal adenoma-adenocarcinoma sequence17. This achievement would also not have
been possible without the synergistic integration of conventional pathology and
molecular-based approaches.
In the last decade or so, these approaches have been pivotal in advancing the notion
of “personalised” medicine. For continuity, I will use the example of breast cancer to
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Pathological Society – 2012 Undergraduate Essay Competition
consider how patients are, and will continue to be, affected by this “paradigm” shift in
medicine. As already discussed, pathology plays an integral role in the diagnosis of breast
cancer and also significantly influences management decisions. However, in the last few
decades, growing frustration over the limitations (narrow therapeutic indices, toxicities,
etc) of empirical chemotherapy and radiotherapy meant that there was a dire need for
more focused treatment options for this heterogeneous disease. To complement this,
more reliable means of identifying and stratifying patients who might benefit from
particular treatment regimes were also needed. A useful contribution to solving this
conundrum was provided by sensitive immunohistochemical (i.e. use of labelled
antibodies to locate an antigen of interest) techniques which have thus far helped in the
identification of dozens of prognostic biomarkers. The expression status for three such
molecular markers – oestrogen receptor (ER), progesterone receptor (PR) and human
epidermal growth factor receptor 2 (Her2) – is now routinely determined by
immunostaining to guide treatment for all invasive breast carcinomas. The importance of
oestrogen in the development and progression of breast cancer has long been recognised
and, starting with bilateral oophorectomies, many anti-oestrogen therapies have been
attempted. Tamoxifen, a selective ER modulator which prevents stimulation of oestrogensensitive tumours, has reduced breast cancer-specific mortality by 31% and has extended
disease-free survival for millions of women18,19. This, along with the success of other
hormonal therapies (e.g. aromatase inhibitors), means that ER status determination is
now part of the minimum pathology dataset for breast cancer20. Similarly, establishing
overexpression of Her2 has become essential as this indicates a poorer prognosis and is a
prerequisite
for
adjuvant
therapy
with
the
monoclonal
antibody,
Herceptin
(trastuzumab). Although quantitative immunohistochemistry is the cheapest and most
convenient method of determining their ER, PR and Her2 status, problems in achieving
standardised protocols (e.g. duration of tissue fixation prior to analysis) have limited its
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Pathological Society – 2012 Undergraduate Essay Competition
consistency and reliability. Fluorescence and silver-enhanced in situ hybridisation (FISH
and SISH) are more objective, sensitive and specific, but also more expensive alternatives
available to pathologists21. These techniques are also useful in guiding treatment for many
other diseases (e.g. anti-CD20 antibodies in B-cell lymphoma).
Immunohistochemistry has also played a prominent role in improving diagnostic
certainty in every day clinical practice, as the following breast pathology example
illustrates. Stromal invasion has long been recognised as an important feature in
distinguishing between invasive (infiltrating) carcinoma and carcinoma in situ (and other
benign lesions). In the latter case, the epithelial cells lining the ducts and acini of the
breast are separated from the surrounding connective tissue by a continuous basement
membrane and a stretch of myoepothelial cells. This is not the case for invasive carcinoma
(and one benign exception: microglandular adenosis). However, the assessment of
stromal invasion on standard H&E sections not infrequently reveals an uncertain result.
For example, patchy periductal inflammation and sclerosis may distort the appearance of
an otherwise ‘typical’ high grade ductal carcinoma in situ, leading to the lesion being
misdiagnosed as an invasive carcinoma. Antibodies to basement membrane components
(e.g. laminin) were initially utilised to manage such situations but their use waned quickly
as it emerged that the synthesis of some of these basement membrane components was
not completely absent in cancer cells22. Since then, highly sensitive markers for proteins
present in breast myoepothelial cells (e.g. calponin, p63, etc) have been in common use
and more specific markers continue to be sought23.
Breast cancer can now also be systematically classified based on gene expression
profiles (determined using microarray-based gene expression analysis)24. This molecular
approach separates breast cancer into several subtypes (triple negative/basal like, luminal
A, etc) and has the potential to provide better risk stratification and more patient-specific
prognostic information than the current methods. However, no clinically acceptable
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Pathological Society – 2012 Undergraduate Essay Competition
method currently exists to implement such an approach, although correlating and
cataloguing the morphological features of breast tumours with their gene expression
profiles may be a useful indirect way of utilising this powerful achievement in molecular
pathology in the near future25.
Conclusion
Despite its perceived invisibility, pathology permeates into all branches and is the bedrock
of modern medicine. Over time, pathologists as scientists and educators have provided
other medical disciplines with an understanding of mechanisms of various diseases and
the physiologic basis of signs and symptoms. Armed with an inquisitive mindset and a
formidable array of technologies, pathologists have for a long time complemented the
typical doctor-patient relationship and have drastically, but with some subtlety, shortened
the duration of a patient’s journey through healthcare. This is particularly true for cancer
where pathologists hold most influence, and the status quo will continue as the timetested methods of pathology become integrated with the unprecedented advances in
genomics and proteomics. This, along with digitalisation of pathology and greater
international integration and corroboration between pathologists, will be beneficial in
other areas too, especially drug development. Of course, in an age of financial austerity, it
should be remembered that pathology is not immune to external drivers of change. Thus,
as the most recent Carter review identified, pathology services must remain innovative,
modernise and become more efficient despite resource constraints26. Personally, I foresee
pathology moving forward and blending seamlessly with the new generation of
diagnostics and therapeutics, carrying on the trend for adaption and self-improvement it
has silently established for itself over centuries.
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Pathological Society – 2012 Undergraduate Essay Competition
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