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CERVICAL CANCER

Supervisor:
dr. Sigit P. Diptoadi, Sp.OG

Authors:
Michelle Husin (2013-061-118)
Cristofer Mayo (2014-061-118)
Aninda Krisnamurti (2014-061-122)

Clinical Clerkship, Department of Obstetric Gynecology


Faculty of Medicine, Catholic University of Atma Jaya
27th of April – 4th of July 2015

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ACKNOWLEDGEMENTS

We would like to thank our mighty God, for by His grace we are able to finish
this paper entitled “Cervical Cancer”. We thank our advisor, dr. Sigit P. Diptoadi,
Sp.OG who provided insight and expertise us. We hope this paper could give useful
information for the readers about cervical cancer. We also apologize for any mistakes
encountered. We are hoping for future critics and suggestion to help improve this
paper in the future being.

Jakarta, 21 May 2015

Writer

CONTENTS
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CHAPTER 1 : INTRODUCTION
1.1 Background………………………………………………………4
1.2 Objective…………………………………………………………5

CHAPTER 2 : LITERATURE REVIEW


2.1 Definition…………………………….………………………….6
2.2 Anatomy……………………………….………………………...7
2.3 Etiology………………………………….………………………9
2.4 Risk Factor………………………………………………………9
2.5 Pathophysiology………………………………………………..10
2.6 Histological Types…………………………………………….. 16
2.7 Staging………………………………………………………….18
2.8 Diagnosis……………………………………………………….19
2.9 Screening……………………………………………………….23
2.10 Prevention………………………………………………………28
2.11 Prognosis………………………………………………………..28
2.12 Treatment……………………………………………………….29

CHAPTER 3 : CONCLUSION………………………………………………………36

CHAPTER I

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INTRODUCTION

1.1 Background
Cancer is quite a common word nowadays. It is used by both medical
practitioner and non-medical people. Cancer is a generic term for a large group of
disease that can affect any part of the body. 1 The defining feature of cancer is its
ability to rapidly create abnormal cell that grow beyond their usual boundaries, and
after that, it may invade and spread to other part of the body. 1There are many type of
cancer, cervical cancer being one of them.Cervical cancer is a cancer that grows in the
tissue of the cervix, and it is the third most common malignancy worldwide.2 3
The development of cancer is a multi-stage process. Interaction between
genetic factor and external agents (physical carcinogen, chemical carcinogen,
biological carcinogen) can cause transformation from normal cells into tumour cells. 1
In cervical cancer this transformation could be triggered by HPV infection (human
papilloma virus).4 Cervical cancer is one of the leading cause of cancer related death
for woman In developing country.5 In 2012, there was 528.000 new cases of cervical
cancer worldwide, and about 85% of those cases happened in developing countries. It
contributed for almost 12% of all female cancers.5 In the same year, it was recorded
that there was about 266.000 deaths from cervical cancer, which accounted for 7.5%
of all female cancer deaths. About 87% of those deaths occurred in developing
countries.5
In 2007, according to Departemen Kesehatan Republik Indonesia, the
prevalence of cervical cancer was 100/100.000 people. 6 In the following year, there
were over 13700 new cases of cervical cancer and almost 7500 died because of it. 7 In
2011, the prevalence was 4.3/1000 people.6
There is a difference of prevalence in developed and developing countries. In
2008, there were 453.300 estimated new cases in developing country, while in
developed countries there were only 76.500 estimated new cases.3 Furthermore, since
the introduction of mass screening with Papanicolau (Pap) test over the past few
decades, there have been a steady decline in the incidence of cervical cancer. 4 Pap
tests make early detection become possible, and so preventive measure can be taken,
which leads to the decline of incidence.

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1.2 Objectives
 To discuss the anatomy of cervix
 To discuss the definition, epidemiology, etiology, risk factors, patophysiology,
staging, diagnosis, treatment, and prognosis abour cervical cancer

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CHAPTER 2

LITERATURE REVIEW

2.1 Definition

As it has previously been mentioned in this paper, cervical cancer is a


cancer that grows in the tissue of the cervix. 2 According to Dorland Medical
Dictionary, cancer is a neoplastic disease which, unlike benign tumor cells, show the
properties of invasion and metastasis. Neoplasm itself means any new growth and
abnormal growth, specifically a new growth of tissue in which the growth is
uncontrolled and progressive.8
Most cervical cancers begin in the cells in the transformational zone, the
place where ectocervix and endocervix are overlapping with each other. The normal
cells gradually develop pre-cancerous changes that turn into cancer. There are several
terms used to describe this pre-cancerous changes, including cervical intraepithelial
neoplasia (CIN), squamous intraepithelial lesion (SIL), and dysplasia. These changes
can be detected using Pap smear test, and treated to prevent the development of the
cancer. The main types of cervical cancer are squamous cell carcinoma and
adenocarcinoma.9

Figure 2.1 Transformation zone

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2.2 Anatomy

The female internal genital organs consists of :

 Vagina
Vagina connects external genitalia organs with the internal genitalia organs. It
is located within the pelvis, anterior to the rectum and posterior to the urinary
bladder. The vaginal walls are lined by folds called rugae. Rugae enable the
vagina to distend easily during child bearing.10

 Uterus
The uterus is a pyriform or pear-shaped organ. It consists of two major parts :
the corpus and the cervix. The fundus is the convex upper segment between
the two insertion of fallopian tubes. The corpus formed the upper triangular
portion of the uterus, and it is the location where normal implantation happen.
The cervix, on the other hand, formed the lower cylindrical portion of the
uterus.11 Cervix connects the body of the uterus to the vagina. Itis divided into
two main parts :ectocervix and endocervix.. Endocervix is the part of cervix
closest to the body of the uterus, whereas ectocervix is the part next to the
vagina. The ectocervix consists mainly of squamous cell, and the endocervix
consists of glandular cells. The place where these two cells meet are called
transformation zone.9

 Fallopian tube
Fallopian tube is a tubular extension from the uterus to the ovary. The normal
length vary from 8 to 14 cm. Each tube is divided into interstisial portion,
isthmus, ampulla , and infundibulum. Interstisial portion is embodied within
the muscular wall of uterus. Isthmus is the narrow portion of the tube that
adjoins the uterus. The wider, lateral portion after passing isthmus is called
ampulla. The infundibulum is a funnel shaped opening at the distal end of
fallopian tube.

 Ovaries
The ovary is a part of female reproductive organs in which oocytes are
formed. Ovary consists of two parts :10 11
o Cortex

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The outer layer of the ovary. On its surface there is a single layer of
cuboidal epithelium. The cortex contains oocytes and developing
follicles.
o Medulla
Medulla is the inner layer of the ovary. It is composed by loose
connective tissue, there are large numbers of arteries and veins, and a
small number of smooth muscle fibers in the medulla.

Figure 2.2 The female internal genital organs

2.3 Etiology

Cervical cancer, like any other cancer, is caused by interaction between


genetic factor and external agents called carcinogen. There are three types of
carcinogen: 1

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 Physical carcinogens, such as ultraviolet and ionizing radiation
 Chemical carcinogens, such as tobacco smoke components, asbestos, arseninc
 Biological carcinogens, such as infections from virus, bacteria, or parasites

After years of researching the etiological factor of cervical cancer, scientists


finally found human papilloma virus (HPV) plays a predominant role in the initiation
of cancer. HPV is a virus that is sexually transmitted. However, penetrative sex is not
required for transmission. Skin to skin genital contact may also transmit this disease.
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HPV, according to its malignancy, canbe divided into two groups:13
 Low risk type
 High risk type

2.4 Risk factors

Although HPV plays a major role in the development of cervical cancer, not
every HPV infection ends up as a cancer, nor was it found in every cervical cancer
patient. This suggest the involvement of another factor, if not some.9 14 15 16 17

This others factors include:

 Tar exposure
Harry W. Haverkos (2005), in his paper, suggested that tar exposure can also
cause cervical cancer. The most common example of tar exposure is cigarette
smoking. Tobacco smoke delivers over 4000 compunds, and some of them are
carcinogenic, one of these compound is NNK otherwise known as 4-
(methylnitrosamino)-1-(3-pyridyl) -1- butanone. A study showed that the
cervical mucus of a smoking woman contains 3 times the level of NNK
compared to non-smoking woman.

 Low or middle income countries


Wide difference in cervical cancer incidence and mortality have been observed
around the world, with around 85% occurring in low or middle-income
countries. The difference of cervical cancer occurrence is associated with the
deployment of Pap test and screening test. Low or middle income countries
have more incidence of cervical cancer is because of a lower coverage of Pap
test compared to developed countries. Low income may also be associated
with poverty. Many low income women do not have access to adequate health
service, including Pap test.
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 Long term use of oral contraceptive
There is evidence that taking oral contraceptives for a long time increases the
risk of cervical cancer. A study conducted by Margaret Urban et al (2012) in
South Africa showed that women that have been taking oral contraceptives for
more than 10 years have a risk to develop cervical cancer 1.38 times greater
than women that don’t consume oral contraceptive. However, the risk goes
back down after the oral contraceptives are stopped.
 Immunosuppression
Human immunodeficiency virus (HIV) can damage the immune system,
resulting in a higher risk of HPV infection. This might explain why women
with AIDS have a higher risk of cervical cancer.
 Having family history of cervical cancer
Cervical cancer may run in the family. Having a mother or sister with cervical
cancer may increase the chance of developing the disease 2 to 3 times.

2.5 Pathophysiology

Human Papillomavirus (HPV)


 Virology
Papillomaviruses are members of the Papovaviridae family.
The virus contains a double stranded, circular DNA genome containing
7800-7900 base pairs. HPV is a small, nonenveloped virus, with a
diameter of 55 cm. It has an icosahedral capsid that composed of 72
capsomers. It contains at least two capsid protein, L1 (major) and L2
(minor). 17
The HPV genome can be divided into three regions. The first is
a noncoding upstream regulatory region (URR). This region contains
the p97 core promoter along with enhancer and silencer sequences
that regulate DNA replication by controlling the transcription of the
“early” and “late” regions. The URR region also contains the highest
degree of variation in the viral genome. The second is the “early”
region, which include the genes E1, E2, E3, E4, E5, E6, E7 and E8.
This region is involved in viral replication and oncogenesis.
Expression of the early gene products determines whether an HPV
infection is active or latent, or leads to malignant transformation. The

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third is the “late” region, which encodes the L1 and L2 structural
proteins for the viral capsid.17 18
Gene Category Gene Function

Early Gene E1 Viral replication

E2 Modulation of
transcription and
replication

E3 Unknown

E4 Productive viral
infections

E5 Transforming
properties

E6 Oncoprotein;
interaction with p53
protein

E7 Oncoprotein;
interaction with pRb
protein

E8 Unknown

Late genes L1 Major capsid protein

L2 Minor capsid protein

HPV classified phylogenetically within the alpha, beta, gamma,


delta, and mu genera based on differences in the nucleotide sequences.
Alpha genus HPV infect the genital and oropharyngeal mucosa
exclusively and include the oncogenic HPV types associated with
cervical cancer.17
HPV types are classified as low-risk and high-risk with regard
to their clinical ‘oncogenic potential’. The ‘oncogenic potential’ is a
function of the propensity of the respective HPV associated lesions to
progress to cervical cancer over time. High-risk HPV types can be
distinguished from low-risk HPV types by the structure and function of

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the E6 and E7 products. The E6 and E7 gene products deregulate the
host cell growth cycle by binding and inactivating two tumor
suppressor proteins, the tumor suppressor protein (p53) and the
retinoblastoma gene product (pRb). The HPV E6 gene product binds to
p53 and targets it for rapid degradation. As a consequence, the normal
activities of p53 which govern G1 arrest, apoptosis, and DNA repair
are abrogated. Low-risk HPV E6 proteins do not bind p53 at detectable
levels and have no effect on p53 stability in vitro. 17 18
HPV classification into high- and low- types17
Low-risk types 6,11,40,42-44,54,61,72,81

High-risk types 16,18,31,35,39,45,51,52,56,58,59,68,82

The HPV E7 gene product binds to pRb and this binding


disrupts the complex between pRb and the cellular transcription factor
E2F-1, resulting in the liberation of E2F-1, which allows the
transcription of genes whose products are required for the cell to enter
the S phase of the cell cycle. The E7 gene product can also associate
with other mitotically interactive cellular proteins such as cyclin E.
The outcome is stimulation of cellular DNA synthesis and cell
proliferation. The E7 protein from low-risk HPV types binds pRb with
decreased affinity.18
E5 gene product induces an increase in mitogen-activated
protein kinase activity, thereby enhancing cellular responses to growth
and differentiation factors. This results in continuous proliferation and
delayed differentiation of the host cell. The inactivation of p53 and
pRb proteins can give rise to an increased proliferation rate and
genomic instability. As a consequence, the host cell accumulates more
and more damage DNA that cannot be repaired, leading to transformed
cancerous cells. 18
In benign lesions caused by HPV, viral DNA is located
extrachromosomally in the nucleus. In high grade intraepithelial
neoplasia and invasive cancer, HPV-DNA generally is integrated into
host genome. The integration of HPV-DNA disrupt the E2 regions,
resulting in loss of its expression. This interferes with the function of

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E2, which normally down-regulates the transcription of the E6 and E7
genes, cause increasing expression of E6 and E7 genes.

 Life cycle
HPV are host-specific and also show distinct tropism for
squamous epithelial cells. HPV can infect basal epithelial cells of the
skin or the inner lining of the tissues and are frequently found in low
and high grade squamous intraepithelial lesions. Initial HPV infection
requires access to cells in the basal layer be infectious particles, which
some types are thought to require a mild abrasion or micro trauma in
stratified epithelium. For high-risk mucosal viruses, such as HPV 16,
the formation of cervical lesions may be facilitated by the infection of
the columnar cell, which can subsequently form a basal layer of
transformed stratified epithelium. The nature of the cell surface
receptor used for viral attachment is no known, although heparin
sulphate and proteoglycans have been suggested to be epithelial cell
receptors for HPV.23
In a host cell, the life cycle of HPV can be separated into two
stages, nonproductive and productive. In the nonproductive stage, the
virus maintain its genome as a low copy number episome by using the
host’s DNA replication machinery to synthesize its DNA in basal layer
of the epithelium. The viral E1 and E2 proteins are expressed in order
to maintain the viral DNA as an episome and to facilitate the correct
segregation of genomes during cell division. The productive stage of
the viral life cycle occurs in the terminally differentiating suprabasal
layers of the epithelium. In these cells, virus switches to a rollinh-
circle mode od DNA replication and amplifies its genome to higher
copy number, express late genes encoding capsid proteins, and
produces viral progeny.23
HPV infections with high-risk viral types, persistence of HPV
infection and the presence of squamous intraepithelial lesions are more
common within the immunocompromised group than in
immunocompetent. The host cellular immune response is mediated by
cytotoxic T cells and requires the interaction of viral epitopes with
histocompatibility class I molecules. A humoral immune response also

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develops, but local levels of HPV-specific immunoglobulin G (IgG)
and IgA in tissue do not correlate with clearance of virus. Systemic
levels of HPV-specific IgA have been correlated with virus clearance.
In contrast, systemic levels of HPV-specific IgG have been detected
more frequently in patients with persistent HPV infection.17
The cervical cancer is a continuous disease process that
progress gradually from mild cervical intraepithelial neoplasia (CIN)
to more severe degrees of neoplasia (CIN 2 or CIN 3) and finally to
invasive cancer. It is plausible that high-risk HPV infection occurs
early in life, may persist, and in association with other factors
promoting cell transformation, may lead to a gradual progression to
more severe disease. 18
Mild and moderate dysplasias are associated with continued
viral replication and virus shedding, and most of these lesions
spontaneously regress. Progression to high-grade lesions (CIN 2/3) and
ultimately invasive cancer is usually associated with conversion of the
viral genome from an episomal form to an integrated form, along with
inactivation or deletion of the E2 region and expression of the E6/E7
product genes. Some investigators have correlated HPV type with
different degrees of CIN and have suggested that CIN 1 and CIN 2/3
are distinct processes, with CIN 1 indicating a self-limited sexually
transmitted HPV infection and CIN 2 or CIN 3 being the only true
cervical cancer precursor. Progression to cancer generally takes place
over a period of 10 to 20 years. Some lesions become cancerous more
rapidly, sometimes within two years.18

Tumor spread

Lymphatic spread

The cervix has a rich network of lymphatics, which follow the uterine artery.
These channels drain into the paracervical and parametrial lymph nodes. The pattern
of tumor spread typically follows cervical lymphatic drainage. Thus, lymphatics
involving the cardinal ligaments and anterior and posterior parametria are commonly
involved. As primary lesions enlarge and lymphatic involvement progresses, local
invasion increases and will eventually become extensive.14
14
Lymphovascular space involvement

As tumor invades deeper into the stroma, it enters blood capillaries and
lymphatic channels. Termed lymphovascular space involvement (LVSI), this type of
invasive growth is not included in the clinical staging of cervical cancer. However, its
presence is regarded as a poor prognostic indicator, especially in early-stage cervical
cancers. Thus, the presence of LVSI often requires appropriate surgical procedure and
adjuvant radiation treatment.14

Local and distant tumor extension

With extension through the parametria to the pelvic sidewall, ureteral blockage
frequently develops, that result in hydronephrosis. Additionally, the bladder may be
invaded by direct tumor extension through the vesicouterine ligaments. The rectum is
invaded less often because it is anatomically separated from cervix by the posterior
cul-de-sac. Distant metastasis results from hematogenous dissemination, and the
lungs, ovaries, liver, and bone are the most frequently affected organs.14

2.6 Histologic Types

Squamous Cell Carcinoma

Squamous cell carcinomas can be subdivided into keratinizing and


nonkeratinizing carcinomas. Keratinizing carcinomas have keratin pearls and nests of
neoplastic squamous epithelium. Nonkeratinizing carcinomas have rounded nests of
neoplastic squamous cells with individual cell keratinization, but lack keratin pearls.

Adenocarcinomas

As this origin within the endocervix, adenocarcinomas may be advanced


before becoming clinically evident. They often give the cervix a palpable barrel shape
during pelvic examination. Adenocarcinomas exhibit a variety of histologic patterns
composed of diverse cell types. Mucinous adenocarcinomas are the most common and
can be subdivided into endocervical, intestinal, minimal deviation, or villoglandular
types The mucinous endocervical type retains resemblance to normal endocervical

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tissue, whereas the intestinal type resembles intestinal cells and may include goblet
cells.
Minimal deviation adenocarcinoma, also known as adenoma malignum, is
characterized by cytologically bland glands that are abnormal in size and shape. These
tumors contain an increased number of glands positioned at a deeper level than
normal endocervical
glands. Villoglandular adenocarcinomas are comprised of surface papillae. The
superficial portion often resembles a villous adenoma, while the deeper part is made
up of branching glands and an absence of desmoplasia. Endometrioid
adenocarcinomas are the second most frequently identified and display glands
resembling those of the endometrium. Serous carcinoma is identical to serous
carcinomas of the ovaries or uterus and is rare.

2.7 Staging

Staging is the process of finding out how far the cancer has spread. The
cervical cancer Federation Internationale de Gynecologie et d’obstetrique (FIGO)
classification is based on tumor size, vaginal or parametrial involvement,
bladder/rectum extension, and distant metastases. It requires radiological imaging
modality. This is an important process because the key factor in choosing the right
treatment plan is staging. The staging system widely used for cervical cancer is that
developed by FIGO.

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Source: Williams Gynecology

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This picture illustrate the FIGO cervical cancer staging

2.8 Diagnosis

Symptoms

Women with early cervical cancer and pre-cancer usually have no symptoms.
Symptoms often do not begin until the cancer becomes invasive and grows into
nearby tissue. When this happens, the symptoms are:
 Abnormal vaginal bleeding, such as bleeding after vaginal intercourse,
bleeding after menopause, bleeding and spotting between periods.
 Having (menstrual) periods that are longer or heavier than usual. Bleeding
after douching or after a pelvic exam may also occur.
 An unsual discharge from the vagina. The discharge may contain some blood
and may occur between your periods or after menopause.
 Pain during intercourse
 Lower extremity edema and low back pain that radiating down the posterior
leg, that may reflect compression of the sciatic nerve root, lymphatic, veins.
 Hematuria, that may resulting from tumor invasion into the bladder.

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Medical history and physical exam

Women that show the symptoms, should be asses further. The patient’s and
their family’s medical history should be seek to get information related to risk factor.
Most women with cervical cancer have normal general physical examination
findings. Enlarged supraclavicular or inguinal lymphadenopathy, lower extremity
edema, ascites or decrease breath sounds with lung auscultation may indicate
metastases in advancing disease.
Those with suspected cervical cancer, a through external genital and vaginal
examination should be performed for looking concominant lesions. With speculum
examination, the cervix may appear grossly normal if the cancer is microinvasive.
Lesions may appear as exophytic or endophytic growth. The lesions may develop into
a polypoid mass, papillary tissue or barrel-shaped cervix. The lesions also can be form
as a cervical ulceration or as a necrotic tissue. Enlarged uterus resulting from tumor
invasion and growth may be palpated on bimanual examination.

Colposcopy

If the patient have certain symptoms that suggest cancer or if the Pap test
shows abnormal cells, colposcopy needed to perform. Patient will lie on the exam
table and a speculum will be placed in the vagina to see the cervix. Colposcope will
be used to examine the cervix. Colposcope is an instrument that has magnifying
lenses. This instrument can help to see the surface of the cervix closely and clearly.
Acetic acid will applied to cervix to make any abnormal areas easier to see. If an
abnormal area is seen on the cervix, a biopsy will be done. A biopsy is a way to make
sure whether an abnormal area is a pre-cancer, a true cancer, or neither.

Cervical biopsy

Some types of biopsy can be used to diagnose cervical pre cancer and cancer, such as:

 Colposcopic biopsy
The cervix is examined with a colposcope to find the abnormal area
firstly. A small section of the abnormal area is removed using a biopsy forceps.
This procedure may cause mild cramping, brief pain, and some slight
bleeding. A local anesthetic is used sometimes.
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 Endocervical curettage (endocervical scraping)
Sometimes the transformation zone can’t be seen with the colposcope.
This means taking a scraping of the endocervix by inserting a narrow
instrument (curette) into the endocervical canal. The curette is used to scrape
the inside of the canal to remove some of the tissue, then it is sent to the
laboratory for examination.
 Cone biopsy
This procedure also known as conization. In this type, a cone-shaped
piece of tissue from the cervix is removed. The base of cone is formed by the
exocervix and the apex of the cone is from the endocervical canal.The tissue
removed in cone includes the transformation zone. The methods used for cone
biopsies are the loop electrosurgical excision procedure (LEEP), also called
the large loop excision of the transformation zone (LLETZ) and the cold knife
cone biopsy.
- LEEP/LLETZ : In this way, the tissue is removed with a thin wire loop
heated by electrical current and acts as a scalpel. For this procedure, a
local anesthethic is used.
- Cold knife cone biopsy: This procedure uses a surgical scalpel or a
laserinstead of a heated wire to remove tissue. Anesthesia is needed.

Imaging studies

Imaging studies may be done because it can show whether the cancer has
spread or not. It is important to choose treatment planning and prognosis. Radiologic
imaging that commonly used are computed tomography (CT) scanning and magnetic
resonance imaging (MRI).
 CT scan
This imaging is widely used for the assessment of nodal involvement
and distant metastatic disease. This modality can be used to evaluate tumor
size and bulky extension beyond the cervix. CT also can detect the enlarged
lymph nodes, uretral obstruction or distant metastasis. But, CT is not accurate
to assess parametrial invasion or deep cervical stromal invasion. This matter is
because of its poor soft tissue contrast resolution. CT is also limited by its
inability to detect small-volume metastatic involvement in normal size lymph
nodes.
 MRI
This imaging offers superior contrast resolution at soft tissue
interfaces. MRI is effective for measuring tumor size, even endocervical
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lesions, and delineating cervical tumor boundaries. MRI aids identification of
surrounding bladder, rectal or parametrial invasion. But, MRI is less accurate
to diagnose microscopic or deep cervical stromal invasion or identifying
minimal parametrial extension. MRI is superior to CT for determining cervical
carcinoma size, local tumor extension, and lymph node involvement.

Marker
Tumor markers are secreted, released, or leaked into the interstitial fluids,
lymph, and finally (or directly) into the bloodstream, where they become detectable in
serum samples. Tumor markers can be associated with patient diagnosis, prognosis,
clinical management, and follow up. The marker would enable a diagnosis for a
specific type of cancer.
The squamous cell carcinoma antigen, SCC, is the most commonly used
serum marker for squamous cell carcinoma. This marker seems the most useful
marker in squamous cell cervical cancer. Elevated serum SCC levels have been
detected in 28-88% of cervical squamous cell carcinomas. Serum concentration of
SCC have been found to correlate with tumor stage, tumor size, residual tumor after
treatment, recurrent or progressive disease, and survival in patients with squamous
cell cervical cancer.
The marker CYFRA 21-1 is also being used as serum tumor marker for
cervical cancer, especially for squamous cell carcinoma. Elevated CYFRA 21-1 levels
have been detected in 42-52% of patients with squamous cell carcinoma of uterine
cervix.
The marker such as SCC, CYFRA 21-1, CA 125, CA 19-9, and CEA can be
positive in adenocarcinomas.

2.9 Screening
Being alert to any signs and symptoms of cervical cancer can help avoid
unnecessary delays in diagnosis. Early detection greatly improves the chances of
successful treatment and prevents any early cervical cell changes from becoming
cancerous.
The latest routine cervical cancer screening guidelines are: 25
• Cervical cancer screening should start at age 21 years.
• Women aged 21–29 years should have a Pap test every 3 years.
Studies found that there is no overall advantage to having yearly Pap test

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over Pap test every 3 years. Yearly Pap test do find a slightly higher number of
cancer cases than tests performed every 3 years, however women who have
yearly screening undergo many follow-up test for what turns out not to be
cancer than women who have 3-year testing.
• Women aged 30–65 years should have a Pap test and an HPV test (co-testing)
every 5 years (preferred). It is acceptable to have a Pap test alone every 3 years.
Combination of a Pap test plus an HPV test can help predict whether dysplasia
will be diagnosed in the next few years, even if the Pap test results are normal.
If the results of both the HPV test and the Pap test are normal, the chance that
mild or moderate dysplasia will develop in the next 4–6 years is very low.
• Women should stop having cervical cancer screening after age 65 years if they
do not have a history of moderate or severe dysplasia or cancer and they have
had either three negative Pap test results in a row or two negative co-test results
in a row within the past 10 years, with the most recent test performed within the
past 5 years.
• Women who have a history of cervical cancer, are infected with human
immunodeficiency virus (HIV), have a weakened immune system, or who were
exposed to diethylstilbestrol (DES) before birth should not follow these routine
guidelines.

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Cervical Cancer Screening Guidelines from CDC

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Papanicolaou smear test
Data from many countries have shown that screening with cervical cytology
reduces the incidence and mortality from cervical cancer. The best way to find
cervical cancer is to have a regular screening with a Pap smear test. A well-proven
way to prevent cervix cancer is to have testing (screening) to find pre-cancers before
they can turn into invasive cancer. The Pap test (or Pap smear) and the human
papilloma virus (HPV) test are used for this. If a pre-cancer is found it can be treated,
stopping cervical cancer before it really starts. Most invasive cervical cancers are
found in women who have not had regular Pap tests. 24
The Pap test (or Pap smear) is a procedure used to collect cells from the cervix
so that they can be looked at under a microscope to find cancer and pre-cancer. These
cells can also be used for HPV testing. A Pap test can be done during a pelvic exam,
but not all pelvic exams include a Pap test.24
 Conventional Pap—In a conventional Pap smear, samples are smeared directly
onto a microscope slide after collection.
 Liquid based cytology—The sample of (epithelial) cells is taken from the
Transitional Zone; the squamo-columnar junction of the cervix, between the
ecto and endocervix.

Pap Tests commonly look for epithelial abnormalities/ metaplasia/ dysplasia/


borderline changes, all of which may be indicative of CIN. Nuclei will stain dark
blue, squamous cells will stain green and keratinised cells will stain pink/ orange.
Koilocytes may be observed where there is some dyskaryosis (of epithelium). The
nucleus in koilocytes is typically irregular, indicating possible cause for concern;
requiring further confirmatory screens and tests.

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Picture. How pap smear was done

HPV test
An HPV test can be done on the same sample of cells collected for the Pap
test. HPV test is no recommended for women younger than 30 years. HPV infections
is very common in younger women, but it usually goes away on its own. It is only
when HPV remains in the cervical cells for many years that it can cause cervical
cancer.26
HPV test interpretation:26
- (-) : there is no HPV type that is linked to cervical cancer found
- (+) : there is an HPV type that may be linked to cervical cancer. It doesn’t mean
there is a cancer cells.

2.10 Prevention
25
Some things you can do to prevent pre-cancers:24
- avoiding exposure to HPV
- getting an HPV vaccine
- stop smoking
- getting a regular Pap test, at least every 3 years or 5 years with HPV test

Human Papillomavirus (HPV) Vaccine


The HPV vaccine protects against the HPV types that most often cause
cervical cancer and is given in a series of 3 shots over 6 months. These vaccines are
also recommended to boys and young men.26 The vaccines are used as a prevention
but not as a treatment for cervical cancer.
There are 3 types of these vaccines: Cervarix, Gardasil, and Gardasil 9.
Gardasil and Gardasil 9 can also protect against genital warts and anal cancer in both
female and male.27
a. Cervarix
Cervarix is a vaccine against HPV 16, 18 which covered 70% of cervical
cancer.
b. Gardasil
Gardasil is a vaccine against HPV 6, 11, 16, 18. HPV 6, 11 caused 90% of
genital warts.
HPV vaccine is administered intramuscularly as three separate 0.5-mL doses.
The second dose should be administered 2 months after the first dose and the third
dose 6 months after the first dose. The vaccine is available as a sterile suspension for
injection in a single-dose vial or a prefilled syringe.27

2.11 Prognosis
The International Federation of Gynecology (FIGO) staging is the most
significant prognostic factor. Lymph node involvement is an important factor in
determining prognosis.14
To determine patient prognosis, we often use the 5-year survival rate. The 5-
year survival rate refers to the percentage of patients who live at least 5 years after
their cancer is diagnosed.
Survival rates are often based on previous outcomes of large numbers of people
who had the disease, but they cannot predict what will happen in any particular
person's case. Many other factors can affect a person's outlook, such as their general
health and how well the cancer responds to treatment.
The 5-year survival rate are based on the stage of the cancer at the time of

26
diagnosis.

Stage 5-year Observed Survival Rate


0 93%
IA 93%
IB 80%
IIA 63%
IIB 58%
IIIA 35%
IIIB 32%
IVA 16%
IVB 15%
Source: AJCC

2.12 Treatment
The treatment for cervical cancer is based on their stage of disease. Other
factors that may influence the treatment options are age, general health, individual
circumstances, and patient preferences. 24
Treatments for cervical cancer are:24
- surgery
- radiation therapy
- chemotherapy
If a cure is not possible, the goal may be to remove or destroy as much of the
cancer as possible to help you live longer and feel better. Sometimes treatment is
aimed at relieving symptoms. This is called palliative treatment.24
Surgery
a. Cryosurgery
A metal probe cooled with liquid nitrogen is placed directly on the cervix. This
kills the abnormal cells by freezing them. Cryosurgery is used to treat
carcinoma in situ of the cervix (stage 0), but not invasive cancer.
b. Laser surgery
A focused laser beam, directed through the vagina, is used to vaporize (burn
off) abnormal cells or to remove a small piece of tissue for study. It is done
under local anesthesia. Laser surgery is used to treat carcinoma in situ of the
cervix (stage 0). It is not used to treat invasive cancer.
c. Conization
A cone-shaped piece of tissue is removed from the cervix. This is done using a
27
surgical or laser knife (cold knife cone biopsy) or using a thin wire heated by
electricity (the loop electrosurgical, LEEP or LEETZ procedure). After the
procedure, the tissue removed (the cone) is examined under the microscope. If
the margins (outer edges) of the cone contain cancer (or pre-cancer) cells
(called positive margins), some cancer (or pre-cancer) may have been left
behind, so further treatment is needed. A cone biopsy may be used to diagnose
the cancer before additional treatment with surgery or radiation. It is used for
treatment in women with early (stage IA1) cancer who want to preserve their
ability to have children.
d. Hysterectomy
This is surgery to remove the uterus (both the body of the uterus and the
cervix) but not the structures next to the uterus (parametria and uterosacral
ligaments). The vagina and pelvic lymph nodes are not removed. The ovaries
and fallopian tubes are usually left in place unless there is another reason to
remove them. The methods are abdominal hysterectomy, vaginal
hysterectomy, and laparoscopic hysterectomy. It is appropriately selected for
benign gynecologic pathology, preinvasive cervical disease, and stage IA1
cervical cancer. Any type of hysterectomy results in infertility (inability to
have children). Complications are unusual but could include excessive
bleeding, wound infection, or damage to the urinary or intestinal systems.
Hysterectomy is used to treat stage 0, IA1 cervical cancers.
e. Radical hysterectomy
The uterus along with the tissues next to the uterus (the parametria and the
uterosacral ligaments) and the upper part (about 1 inch) of the vagina next to
the cervix are removed. The ovaries and fallopian tubes are not removed.
Because the uterus is removed, this surgery results in infertility. Complications
are unusual but could include excessive bleeding, wound infection, or damage
to the urinary and intestinal systems. A radical hysterectomy and pelvic lymph
node dissection are the usual treatment for stages IA2, IB, patients with
relative contraindications to radiation (diabetes, pelvic inflammatory disease,
hypertension, collagen disease, adnexal masses), and less commonly IIA
cervical cancer, especially in young women.
f. Modified radical hysterectomy

28
Modified radical hysterectomy removes the cervix, proximal vagina, and
parametrial 0 paracervical tissue. The ureters are unroofed from the
paracervical tunnel until their point of entry into the bladde. This hysterectomy
is well suited for tumors with 3- to 5-mm depths of invasion and smaller stage
IB tumors.
g. Trachelectomy
Most women with stage IA2 and stage IB cervical cancer are treated with
hysterectomy. Another procedure, known as a radical trachelectomy, allows
women be treated without losing their ability to have children. This procedure
removes the cervix and the upper part of the vagina but not the body of the
uterus. The surgeon places a "purse-string" stitch to act as an artificial opening
of the cervix inside the uterine cavity. The pregnancy rate after 5 years was
more than 50%, but the women who had this surgery had a higher risk of
miscarriage than what is seen in normal healthy women. The risk of the cancer
reccurency is low.

h. Pelvic exenteration
It is often used to treat recurrent cervical cancer. In this surgery, all of the same
organs and tissues are removed as in a radical hysterectomy with pelvic lymph
node dissection (lymph node dissection is discussed in the next section). In
addition, the bladder, vagina, rectum, and part of the colon may also be
removed, depending on where the cancer has spread.

29
Radiation
Radiation therapy uses high energy x-rays or particles to kill cancer cells.
a. External beam radiation
External beam is commonly administered in 25 fractions during 5 weeks.
b. Brachytherapy
During brachytherapy, to limit bladder and rectal doses, bowel and bladder are
packed away from intracavitary source during tandem inserion, using vaginal
packing. Potential candidates fot vaginal brachytherapy are women who are
elderly, not surgical candidates due to medical disease, or do not wish to
preserve ovarian or sexual function.

The side effects of radiation therapy are:


- fatigue
- stomachache
- diarrhea
- nausea and vomiting
- skin irritation
- anemia
- leucopenia

Chemotherapy
Drugs that are often used for chemotherapies are:
- Cisplatin
- 5-fluorouracil (5-FU)
Chemotherapy is not only kill the cancer cells but also the normal cells, which can
lead to some side effects. Common side effects of chemotherapy are:
- nausea and vomiting
- loss of appetite
- hair loss
- xerostomia
- fatigue
- changes in menstrual cycle
- infertility

30
- neuropathy
Chemotherapy is commonly used following an radiation, it is called chemoradiation.
In chemoradiation, cisplatin is given weekly for 5 weeks, administered concurrently
with radiotherapy.

Treatment based on staging (FIGO) 14


Stage IA
The term microinvasive cervical cancer identifies this subgroup of small
tumors. Microinvasive cervical cancer carries a minor risk of lymph node
involvement and excellent prognosis following treatment. Stage IA tumors are divided
to IA1 and IA2. These cancers are subdivided to reflect increasing depth and width of
invasion and increasing risks rof lymph node involvement.
Stage IA1
These tumors invade no deeper than 3 mm, spread no wider than 7 mm, and
are associated with the lowest risk for lymph involvement.
Treatment: conization, hysterectomy
Stage IA2
Cervical lesion with 3 to 5 mm of stromal invasion have a 7% risk of lymph
node metastasis and a greater than 4-percent risk of disease recurrence.
Treatment: modified radical hysterectomy, pelvic lymphadenectomy, radical
trachelectomy – lymphadenectomy for fertility preservation, intracavitary
brachytherapy.
Preoperative MRI is recommended, if the tumor has extended past the internal
cervical os, trachelectomy is contraindicated.
Stage IB to IIA
Stage IB lesions are defined as those extending past the limits of
microinvasion yet still confined to the cervix. This stage is subcategorized either as
IB1 if tumors measure ≤ 4 cm or as IB2 if they measure > 4 cm. stage II cancers
extend outside the cervix, may invade the upper vagina and the parametria but do not
reach the pelvic sidewalls. Stage IIA tumors have no parametrial involvement but
extend vaginally as far as proximal two thirds of the vagina.
Treatment: surgery or radiation therapy

31
Before choosing a treatment, the clinical factor we should assess are menopausal
status, age, concurrent medical illness, tumor histology, and cervical diameter. Radical
hysterectomy usually selected for young women with low BMIs who wish to preserve
ovarian function and have concerns about altered sexual functioning following
radiotherapy.
Stage IIB to IVA
Advanced-stage cervical cancers extend past the confines of the cervix and
often involve adjacent organs and retroperitoneal lymph nodes.
Treatment: radiotherapy, chemoradiation, pelvic exenteration for primary disease
Radiation therapy is the cornerstone of advanced-stage cervical cancer management.
It can be an external beam pelvic radiation and brachytherapy. Chemoradiation has
superior survival rates compared with pelvic and extended field para-aortic region
irradiation alone. Primary exenteration may be considered for women with stage IVA
cancer, that is, with direct tumor invasion into bladder/or bowel without distant
spread.
Stage IVB
Patient with stage IVB disease usually treated with palliative therapy. Women
with persistent nausea and vomiting from tumor-associated ileus may benefit from a
gastrotomy tube. Pelvic radiation is administered to control vaginal bleeding and pain.
Systemic chemotherapy can also be used too. The chemotherapy regimens used in
palliative therapy is similar to those with non-palliative therapy.

32
33
CHAPTER III
CONCLUSION

Cervical cancer is a cancer that grows in the tissue of the cervix. It is the most
common gynecologic cancer in women, mostly in younger population of women.
Most cervical cancers begin in the cells in the transformational zone, the place where
ectocervix and endocervix are overlapping with each other. The main types of cervical
cancer are squamous cell carcinoma and adenocarcinoma.
HPV plays a major role in the development of cervical cancer. Tumor
extension can be from lymphatic, lymphovascular space involvement, or local and
distant tumor extension.
Most early cancers are asymptomatic, in advanced stage the manifestation
include bleeding, watery discharge, and signs associated with venous, lymphatic,
neural, and ureteral compression. For the diagnosis we can do a colposcopic
examination and histololgic evaluation of cervical biopsies. Imaging using CT Scan
and MRI may be useful too. CT Scan is widely used for the assessment of nodal
involvement and distant metastatic disease. MRI is effective for measuring tumor size,
local tumor extension, nad lymph node involvement.
For the staging, there is Federation Internationale de Gynecologie et
d’obstetrique (FIGO) classification which is based on tumor size, vaginal or
parametrial involvement, bladder/rectum extension, and distant metastases. Treatment
varies and is typically dictated by this staging. The prognosis are also depend on the
staging.

34
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