ABNORMAL CERVICAL

CYTOLOGY
ANATOMICAL PATHOLOGY 2B
Course Code: ANP621S
Compiled by: S. Israel
Revised by: BR Tsauses
August 2022
 INTRODUCTION
• An understanding of the normal anatomy, physiology, histology, and
cytology of the female genital system, all already covered, provides the
foundation for what is to follow here.
• As a prelude to a description of abnormal cervical cytology we will explore
what is currently known about the epidemiology and natural history of
cervical neoplasia.
• KEYPOINTS
• Cervical neoplasia is an abnormal growth of tissue/cells in the cervix.
• It may be restricted to the epithelium, in which case we call it cervical
intraepithelial neoplasia(CIN), or it may be invasive, which means that it
invades the surrounding tissues and possibly even spreads to distant parts
of the body.
• If this happens we call the disease cervical cancer.
 CONTINUE….
• Much research on the causation and complex molecular biology
of this disease has been undertaken, so it is perhaps surprising
that simple cytological methods still lie at the heart of screening
and early detection.
• The morphological features of cellular abnormalities in the cervix
will be described in detail in this presentation.
• The importance of this description should not be underestimated;
it consumes the professional lives of all who work in cytology.
• A description of the histopathological basis of cervical
abnormalities and their benign lookalikes must form an integral
part of this chapter.
• The intention is to give you a full and well rounded appreciation
of the benefit and limitations of cervical cytology.
 CONTINUE
• Cervical screening programmes exist because early
neoplastic lesions can be treated very effectively.
• This presentation would therefore be incomplete without a
brief description of the treatment methods currently
available for cervical neoplasia, and it is on this topic that
the presentation will close.
 CERVICAL CANCER
EPIDEMIOLOGY
• The global burden of cervical cancer is enormous.
• Over 500,000 women develop the disease each year, mostly in
developing countries, and at least half of these women will die
from the disease.
• Cervical cancer is second only to breast cancer in terms of
worldwide female cancer rates.
• In the UK, the picture is very different .
• Cervical cancer incidences and mortality rates are a fraction of
those seen in countries such as China, India, and Latin America.
• In the UK, approximately 2,000 women develop cervical cancer
each year and fewer than 1,000 die from the disease.
• Cervical cancer is therefore not a major cause of death in this
country; in fact, mortality from cervical cancer is in decline.
• The main reason for these figures and trends is thought to be well-
organised cervical screening.
 CONTINUE….
• There are two main types of cervicular cancer.
• The most common is squamous cell carcinoma, accounting for over 75% of all cervical
cancer.
• Adenocarcinoma accounts for most of the remaining cases and accounts for a growing
proportion of diagnoses, particularly in women under the age of 35.

What causes cervical cancer?

• Cancer of any kind is a complex disease caused by a number of interacting factors.
• Rarely can a single factor be identified as the cause of cervical cancer, and
elucidating the complexities of the disease is part of the job of an epidemiologist.
 CONTINUE….
• So, what can we say about the cause of cervical cancer ?
• Evidence for an association with sexual activity dates back to 1842,
when Rigoni-Stern showed that mortality from cervical cancer amongst
nuns was much lower than amongst married women.
• Since then the evidence implicating a sexually transmitted agent as
the cause of cervical cancer has grown steadily.
• There is now overwhelming evidence that certain high-risk types of
human papillomavirus (are responsible).
• KEY POINTS
• In the previous presentation we discovered that human papillomavirus
(HPV) is a very common virus.
 CONTINUE…..
• There are well over one hundred different types, each with a tendency to infect
particular epithelia and cause certain types of lesion.
• Low-risk types(e.g.6,11,42,44, and others) may cause genital warts, whereas the high-
risk types(e.g.16,18,31,33, 45) are closely associated with precancerous lesions and
invasive cancer.
• Squamous cell carcinoma is associated with the more common HPV type 16, whereas
adenocarcinoma is more closely associated with type 18.
• Many of the traditionally quoted risk factors for cervical cancer (such as number of
sexual partners, age at first sexual intercourse and the sexual behaviour of the male
partner) are simply markers for infection with high-risk HPV.
 CONTINUE…..
• That is not to say that other factors are not involved in the
development of cervical cancer.
• Cofactors for cervical cancer include smoking, immunosuppression,
hormones, and host genetics.
• Briefly, the virus makes contact with the basal epithelial cells of the
cervical epithelium, presumably via a break in the overlying epithelial
layers.
• Next, the protein coat of the virus(i.e.the capsid) is shed and viral DNA
enters one or more basal cells.
• At this stage viral DNA remains in episomal form (i.e. separate from
host cell DNA) and replicates in tandem with host cell DNA.
 CONTINUE…..
• This stage of infection is known as the latent-phase no new viral particles are
produced and there are no clinical or cytological manifestations.
• Importantly, most latent infections resolve but a small proportion progress to a
productive phase, in which viral DNA replication occurs independently of host DNA.
• Virus assembly is completed in the intermediate and superficial layers of squamous
epithelium and the characteristics cytopathic effect, known as koilcytosis, is
produced.
• Some women with productive HPV infections, but by no means all, then develop
cervical intraepithelial neoplasia (CIN).
• Many cases of CIN spontaneously resolve or will remain as stable lesions for many
years, but those that do not will progress to invasive cancer if left untreated.
 CONTINUE….
• At this stage the virus is said to have induced malignant transformation in the infected
cells.
• Although much research remains to be done, the most important event in malignant
transformation appears to be the integration of HPV DNA into cellular DNA.
• The interaction disrupts important genes involved in the control of cell growth, resulting
in the loss of the normal constraints to cell proliferation.
• The end result is malignant tumour formation(cancer)
• Throughout the latent and productive phases of the HPV life cycle there is an
important but incompletely understood interaction between HPV and various
cofactors, such as host immune status, cigarette smoke, and possibly other
environmental carcinogens.
 CONTINUE….
• HPV VACCINES
• The currently available HPV vaccines, known as Cervarix and Gardasil, help protect
against cervical cancer by preventing infections with the naturally occurring virus.
• Both types of vaccines contain the harmless proteins of certain types of the virus, they
do not contain the potentially carcinogenic viral DNA and are quite safe to use.
• Like all other vaccines, the HPV vaccine is most effective when it is given before the age
at which natural infection occurs.
• Because we know that most HPV infections are acquired through sexual contact it is
important to be vaccinated before the age at which sexual activity begins.
• For this reason parents are recommended to have their daughters vaccinated at
around the age of 12.
 CONTINUE……
• The vaccine is given by injection into the arm and works by stimulating
an immune response which helps to kill the virus before it is able to infect
cervical epithelial cells.
• It is important to remember that the currently available vaccines do not
protect against all types of HPV and are therefore not guaranteed to
prevent cervical cancer.
• This is why cervical screening must continue for the foreseeable future.
• Now here is a fascinating possibility.
• Although the HPV vaccines were specifically developed for prevention
of cervical disease, they may actually help to reduce the incidence of
other HPV-related conditions such as cancer of the vulva, anus, penis,
and oral cavity.
 CONTINUE…..
• Now that the link between cervical cancer, and molecular controls of
the cell cycle is firmly established, it is perhaps not surprising that HPV-
related technology is rapidly becoming a new industry.
• HPV vaccines have been developed with the expectation that mass
vaccination programmes will reduce the global burden of HPV-related
disease, including cervical cancer.
• HPV testing, tests for altered expression of cell cycle control genes or
their associated proteins are exciting opportunities to be exploited in
the diagnostic laboratory of the near future.
• For now we will concentrate on the histology and cytology of cervical
cancer and its precursors.
SQUAMOUS NEOPLASIA OF THE
CERVIX
• The knowledge that invasive squamous cell carcinoma of the cervix is
preceded by detectable precancerous changes in cervical epithelium
is the basis for the existence of cervical screening programmes.
• Cervical intraepithelial neoplasia (CIN) is the name given to the
precancerous lesion of cervical squamous epithelium.
• It develops over several years and regular cervical screening has been
the mainstay of its early detection in the UK for over five decades.
• To understand why cervical screening can be so successful you will
need to know about the histology , and cytology of CIN.
 CONTINUE…….
• Histology of cervical intraepithelial neoplasia.
• The term cervical intraepithelial neoplasia (CIN) was introduced by
Richart in 1967 to describe a lesion which is characterized by the
replacement of normal cervical squamous epithelium with neoplastic
cells showing varying degrees of morphological abnormality.
• The neoplastic cells are limited to the epithelium and do not penetrate
the basement membrane.
• The CIN terminology has now been widely adopted in clinical practice.
 CONTINUE…..
• What are mitotic figures, what is their significance and what do they look like?
• Mitosis is the normal process by which chromosomes within cell nuclei separate out into
two identical sets, thereby producing two new nuclei.
• A mitotic figure is a snapshot of a cell undergoing mitosis and they are a fairly frequent
finding in histology sections and cytology samples.
• We need to be clear about the relevance of mitotic figure.
• Histologist and cytologists often talk about ‘normal’ and ‘abnormal’ mitoses.
• The presence of normal mitoses simply indicates that cell division is taking place; they
do not necessarily mean that the tissue is neoplastic.
• The more frequent the mitoses the greater the likelihood that we are dealing with
neoplasia.
 CONTINUE….
• The finding of ‘abnormal’ mitoses, however, is a sure sign that the tissue is neoplastic.
• So, what do normal and abnormal mitoses look like?
• The morphology of a mitotic figure depends on the stage at which the process was
halted when the tissue sample collected.
• Normal chromosome separation process: the chromosomes are being pulled to
opposite ends of the cell and the mitotic figure is described as bipolar.
• You can see that instead of separating in two directions the chromosomes are
actually being pulled in three different directions, giving rise to a tripolar mitosis.
• Quadripolar and even pentapolar mitoses can sometimes be found in neoplastic
tissues.
• Three grades of CIN are recognized and are distinguished by:
1. The proportion of epithelial thickness occupied by undifferentiated neoplastic cells.
2. The level within the epithelium at which mitotic figures(sometimes these are just called
‘mitosis’) are found.
3. The presence of abnormal mitosis.
• CIN1 is characterized by undifferentiated neoplastic cells occupying the lower one-
third of the epithelium.
• Cytoplasmic differentiation is seen in the middle and upper thirds.
• Mitotic figures are infrequent and usually normal.
 CONTINUE….
• In CIN2, undifferentiated neoplastic cells reach the middle third of the epithelium and
cytoplasmic differentiation is seen in the upper third.
• Mitoses are confined to the lower two-thirds and these may be abnormal in
appearance.
• The features of CIN3 are more exaggerated.
• The full thickness of the epithelium is occupied by undifferentiated neoplastic cells
without signs of cytoplasmic differentiation.
• Occasionally, cases with cell keratinization are found.
• Mitoses are frequently seen throughout the epithelium and are often abnormal.
• In all grades of CIN the cells contain morphologically abnormal nuclei and it is on this
basis that the cervical cytology exists as a screening test for CIN.
 REFERENCE
• Shambayati B, 2011 CytoPathology