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1. Introduction

1.1 Anatomy, Histology and Normal Changes in Cervical Epithelium

The cervix is the caudal part of the uterus that protrude to the vagina part. Cervical

have 2.5-3 cm in length and form a third length of the uterus. The boundary between the

uterine Cervix is a fibromuscular junction nown as internal ostium and cervical canal

associated with the vaginal opening at the esternal ostium. The cervical canal has a

maximum diameter of !-" mm# 3 cm in length# and a flat shape from anterior to

posterior.$#2

%osisition of

Cervical maintained by several

ligaments# which is

the broad ligament# the uterosacral ligament and cardinal

ligaments. &road ligament divides the pelvic cavity into the anterior and posterior. 'terosacral

ligament forming the lateral edge of the pouch of (ouglas. The structure of the ligament# mainly#

composed of fibrous tissue and mostly composed of smooth muscle tissue containing nerves#

blood vessels and lymph vessels. The ligaments maintain the normal position of the cervix and

uterus into anteflexion posisition. $#3

Figure 1. Anatomy of Cervix and terine.

Source : Crispen !"

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The arterial systems derived from decending branches of the uterus# toward the lateral wall

through the paracervical ligament. The vessels are derived from internal iliac artery. The main

braches of this artery anastomoses with vaginal artery and forming vascular bed that surrounding

the cervix. The lymph vessels in the cervical tissue lie beneath the surface epithelium and

surrounds the endocervical gland. (rainage of cervical lymph will be drained to hypogastric

lymph nodes located in the internal iliac and paraaorta branch. Cervical nerves that innervate the

system comes from the superior# middle# and inferior hypogastric plexus a cervical autonomous

systems. )erve supply was limited to the endocervical part. $#3

*t the end of the growth and development of the fetus# cylindrical epithelium lining the

mullerian duct will be cover the uterine cavity and extends to cervical canal part. The cylindrical

epithelium will join s+uamous epithelium derived from the vagina and form a s+uamocolumnar

junction ,C/.

0mbriology of vagina was coming from urogenital sinus lined by s+uamous epithelium.

The mullerian duct lining from a layer of cylindrical epithelium. ince 1th

gestational periode#

epithelial cylindric at vaginal part transform become stratified s+uamous epithelium until

childhood phase. This C located the outside of external orifice of the uterus.1#5

*t puberty# eversion was occur because of enlargement of cervix and uterine. ncreasing

of vaginal acidity will affect the C and lead into cercival canal. (uring pregnancy# eversion is

occur but it will be disappear after the first child was born.5

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Figure #. Histology of Normal cervix.

$ource % Hart &! '

The area of this transformation occurs with the physiological process called metaplasia.

+uamous metaplasia is a dynamic physiological process# which is columnar epithelium is

replaced by s+uamous epithelium and tae place within a few days or wees. The most rapid

metaplasia occurs durring puberty and pregnancy. These changes lead to instability in the region

that often develop into cervical neoplasia in the area. Cervical epithelium at puberty and

adulthood consists of three types# which is s+uamous or columnar epithelium# epithelial

s+uamous metaplasia# and epithelial atypia# some of which have a malignant potential.!

Branched

Mucus-

secreting

Non-keratinized

squamous

epithelium

Transistion

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Figure ". Histopatology of metaplasia of s(uamous cell

ource 4art ( 6

The cervical cancer occur is closely related with metaplasia process. The entry of agent or

substances that can alter the genetic properties of the cell during the active phase metaplasia can

cause potentially malignant cells and these changes usually occur in the transformation 7one.6#

1.# !alignant Changes

(ysplasia was correlated with various disruption of maturation s+uamous epithelium.

4istologically# the cell was very different from normal epithelium. (ifferences of dysplasia

degree are based thicer epithelial abnormalities and the severity of abnormalities in cells# while

Basal cell at basal

area

Squamous in

surface area

Polygonal cell form

into several layer

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cancer in situ is maturation disorder that resembles the s+uamous epithelium invasive cancer# but

the basement membrane is still normal.!

Figure ). &ifferences of Histopathological CIN 1, CIN # and CIN ".

ource 4art (6

The current classification uses C) terms ,cervical intraepithelial neoplasia/ and

pathogenesis of C) can be considered as a spectrum of disease which starts from mild

Mild dysplasia

!" of upper layers are

The third basal cells have a high

ratio of core nucleocytoplasmic

pleomorphic on this layer

Mytotic cells

The remaining of that# there is

consist immature cell $ith large

Maybe# there are one or t$o

of strati%ed epithelium on

Severe

The abnormal basal cells %ll

the bottom part

Moderatedysplasia

Some of epithel

sho$s strati%cation

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dysplasia ,C) /# dysplasia ,C) 2/# severe dysplasia and carcinoma in situ ,C) 3/# then

develop into invasive cancer. C) can experience being spontaneous regression to become

normal again at C) $ and 2 levels# however there doesn8t have specified lesions that will

develop into a progressive phase# all levels of C) considered potentially becoming

malignant and should be managed appropriately.5#!

1." Epidemiology

Cervical cancer is the fourth most common cancer in women# and the seventh overall#

with estimated 52"#999 new cases in 29$2. There were an estimated 266#999 deaths from

cervical cancer worldwide in 29$2. n outheast *sia there are $!5#999 new cases with a

mortality rate of :1#999 in 29$2."

Cervical cancer is still become a problem in developing countries# including ndonesia

because the incidence is still high. 0very year found 1!$#999 cases and 233#999 deaths

caused by cervical cancer worldwide# "9; of whom are in developing countries.:#$9

Cervical cancer is also the second cause of death in women ,after breast cancer/# with

high mortality ,5:;/ in developing countries# including ndonesia. The high incidence of

these diseases in developing countries due to a lot of ris factors and lac of effort for early

detection of cervical cancer# conse+uently patients usually arrive on advanced stage

disease.$$#$2

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Figure *. Epidemiology of cervical cancer

ource (epartment of health 35 years/# epidemiological factors such as education and labor history are also maing a

significant change. There is study conduct by 4ans and his collages# they divided the patient into

four groups. The patients were grouped according to the year of diagnosis-group ,$::6?$::"/#

group ,$:::?299$/# group ,2992?2991/# and group = ,2995?2996/. The results of these

study are tendency increasing occur in patient with secondary and higher education with p value

p @ 9.993 and number parity ,>1/ tend to increase with p value p @ 9#9$5.$3

4istology of s+uamous cell carcinoma ,CC/ covers !5-"9; of cases# while the

adenocarcinomas and adenos+uamous between $9-$5; of cases. The incidence in the age of 59

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years and above is two times higher ,$3.: A $99#999/ compared to the age below it ,6.! A

$99#999/ and the highest age group is between 15-1: years. &ut the important thing in

developing countries# as well as in ndonesia is a majority of cases ,62-"2;/ comes at an

advanced stage.$1

1.) Etiology of cervical cancer

Causes of cervical cancer is the 4uman %apillomavirus ,4%=/. 4%= viruses are obligate

intracellular parasites# including a group of viruses that have a ()* double-stranded circular

genome. (eoxyribonucleic acid ,()*/ of 4%= was founded in :9; patients with intraepithelial

neoplasia. 4%= types $6 and $" have the highest percentage in patients with cervical cancer

,1!; and 23;/.5#$5

The 4%= virus is a double stranded ()* viruses ,ds()*/# %apova virus family# has a

circular genome with a si7e of !-" base pairs ,bp/# and its genome is wrapped by icosahedral

capsid.$5-$!

n humans and animals# process of cell division is regulated by two types of protein

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* lifetime ris of 4%= genital infections around "9;# but a few of them will develop

cervical cancer. Bithin $2 months after the infection# !9; of women did not get infected again

and before 21 months only :; is still infected.$6

4igh-ris types of 4%= infection can lead to severe s+uamous dysplasia or carcinoma in

situ without going through the stages of mild dysplasia. n one study# severe dysplasia occurred

within a median of 26 months after 4%= infection is detected.$6

ost epidemiological studies have shown that more than :9; of cervical cancers

associated with infection with human papilloma virus ,4%=/. Borld 4ealth rgani7ation ,B4/

and the nternational *gency for

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much as 5-$9;. Bomen aged over 39 years with normal cervical cytology smears# but got a

high-ris types of 4%= infection# has a ris $$6 times got severe lesion.!#$"

%ersistent infection of human papilloma virus can develop into cervical intraepithelial

neoplasia ,C)/. ncoprotein 06 and 0! are the major genes of 4%= that can cause malignant

transformation. Eigure ! below illustrates the process of infection with human papilloma virus in

cervical cancer.$:

Figure +. &isease Course of H- infection in cervical cancer

ource 4ellweg F( $:

* woman with a sexually active can be infected by high ris of 4%= =irus# "9; will be

transient and will not develop into C). 4%= will disappear within 6" months. n this case# the

antibody response have a role against high ris 4%= infection. Twenty percent of them will

develop into C)# estimates "9;. *fterwards# the virus will disappears but the lesion become

,nvasivecarcinomNormal

ervical infected by

cleansi 0egressi

invasioProgressiinfectio

Normal

cervi1

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persistent. C) will persist or C) $ will develop into C) 3 and finally become an invasive

cancer. Gow ris 4%= do not develop into C) 3 or invasive cancer# but became C) $ and C)

2. 2#5

Gow-ris 4%= infection was never found in ) 3 or invasive cancer. &ased on the

results of a population-based screening program in the )etherlands# the interval between ) $

and the invasive cancer is estimated to $2.! years. f counted# from high-ris 4%= infection until

cancer is estimated to $5 years. n this time# persistent high-ris 4%= infection and

immunological factors ,4%=-specific response of T-cells# antigen presentation/# also re+uired a

change in the genome of the infected cell. n this case# the factor of oncogenes 06 and 0! of

Figure . &isease course of cervical cancer

Source & 2evine 34 5

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4%= bind suppressor p53 and