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Cervical Cancer

Cervical cancer is a malignant tumor/carcinoma that grow in cervix, which is an area in the female reproductive organs which is the entrance to the uterus which lies between the womb (uterus) with a hole intercourse (vaginal). This cancer usually occurs in women who have aged, but the statistical evidence shows that cervical cancer can also attack women aged between 20 to 30 years (Anonim, 2007).

90% of cervical cancers are from squamous cells (epithelial tissue) lining the cervix while 10% comes from the mucus-producing gland cells in the cervical canal leading into the uterus (Anonim, 2005).

INCIDENCE OF CERVICAL CANCER

In 2008, cervical cancer cases are still in the first level the incidence of cancer in Indonesia. According to sources obtained, women who have cancer is intensified by their habit to smoke (Anonim, 2007).

According to cancer experts, cervical cancer is one type of cancer the most preventable and cured of all cancer cases. Nevertheless, in the region of Western Australia, there were 85 women diagnosed positive for cervical cancer every year. And in 1993, 40 women had died a victim of this cancer malignancy (Yohanes, 2000).

CAUSE
The main cause of cervical cancer is family members Papovirida HPV (Human Papiloma Virus) which has a diameter of 55 µm and the virus is transmitted sexually. HPV has isohedral bare capsules with 72 capsomeres, and contains a circular double-stranded DNA with a length about 8000 base pairs
(La Russo, 2004;Sjamsuddin, 2001).
Based on research
Sjamsuddin (2001), concluded that there are 3 groups of HPV types in relation to cervical cancer, namely: 1) low-risk HPV, HPV types 6 and 11, 46 are rarely found in invasive carcinoma; 2) intermediate risk HPV, HPV 33, 35, 40, 43, 51, ​​56, and 58; 3) high-risk HPV, HPV types 16, 18, 31. The three types of HPV can cause abnormal cell growth, but only type 2 and 3 are causing cancer (Anonim, 2006;Yamato et al., 2006).

RISK FACTORS
Cervical cancer risk factors
(Anonim, 2008b) :
1. HPV infection (Human Papilloma Virus)
2. Sexually transmitted diseases
3. Starting sexual activity at a very young age
4. Changing sex partners
5. Use of contraception
6. Pemakaian Dietilstilbestrol (DES)
7. Often breeds
8. Diseases that suppress the immune system
9. Smoke
10. Genetic

12

Figure A. Female anatomy (www.medicinenet.com)
Figure B. The appearance of a healthy cervix and cervical cancer (www.ehealthmd.com)

STADIUM

To grow into cervical cancer takes several years from the cells of the cervix undergo changes. Cervical cells are abnormal cells that are not cancerous but can develop into cancer called cervical intra-epithelial neoplasia (CIN). CIN is also referred to as precancerous cells which if left untreated would further potential to grow into cancer. However, not all women who have CIN will suffer cancer. The existence of CIN identical with dysplasia (Anonim, 2003c).

The developments of cervical cancer include light dysplasia (5 years), medium dysplasia (3 years), and heavy dysplasia (1 year) to become cancerous stadium 0. These pre-cancers stadium often does not cause symptoms (92%), the next entry in the form of invasive cancer stage cancer stadium I to stadium IV (Anonim, 2003).

According to International Federation of Gynecologists and Obstetricians, cervical cancer growth is divided by 5 stadiums based on tumor size, depth of penetration of the cervix and cancer spread inside and outside of the cervix. The stadiums are as follows (Canavan dan Doshi, 2000) :

Stadium

0

Occurs cancer growth (carcinoma) in the epithelial tissue of the cervix

Stadium

I

The growth of the cancer is still confined to the cervix

Ia

Microscopically, the cancer has invaded tissue (penetration). Size cancer cell invasion: depth <5 mm, while the width is <7 mm

Ia1

Size has a depth of invasion <3 mm and a width of <7 mm

Ia2

The depth of invasion> 3 mm and <5 mm, width of <7 mm

Ib

Lesions were larger than lesions that occur on stadium Ia

Ib1

Tumor size < 4 cm

Ib2

Tumor > 4 cm

Stadium

II

Carcinoma extends out until the cervix but not to the pelvic wall; carcinoma invading the vagina but has not yet reached 1/3 lower vagina

IIa

There are no clear parameters

IIb

Parameter clear

Stadium

III

Carcinoma extends to the pelvic wall; on rectal examination, not seen any empty space between the tumor and the pelvic wall; tumor attacking 1/3 lower vagina; in all cases also found the hydronephrosis or renal function not

IIIa

Cancer does not spread to the pelvic wall, but the attacking 1/3 lower vagina

IIIb

Spread to the pelvic wall, occurs hydronephrosis or renal function failure, or both

Stadium

IV

Carcinoma extends beyond the pelvis or bladder or rectal mucosa

IVa

Spread to adjacent organs

IVb

Spread to distant organs

MOLECULLAR MECHANISM
Cervical cancer is caused by certain types of human papillomavirus (HPV) have a high risk like HPV16 and HPV18 have oncogenes E6 and E7 where both of that gene expression become a requirement for the cancer growth and malignant phenotype defense. Extermination of both oncogenes are considered to be applied in the treatment of cervical cancer molecular(Yamato et al., 2006).
E6 and E7 proteins of HPV modulate cellular proteins that regulate the cell cycle.
1.

a. Binds to a cellular protein called E6-associated protein (E6-AP) form a ubiquitin E3 ligase targets the tumor suppressor p53 degradation(Gewin et al., 2004). Degradation of p53 resulted in cells not undergoing apoptosis orentering cell cycle arrestin G1/S.
b.
Induces c-myc protein that can stimulate telomerase enzyme that causes cells are immortal. Stimulates the expression of exogenous hTERT gene (human telomerase reverse transcriptase) which encodes the catalytic subunit of telomerase(Horner et al., 2004)other than that induction of telomerase also occur through intermediaries E6-AP complex(Gewin et al., 2004).

2. Protein E7
a.
Bind to the hipophosphorilated active form of p105Rband members of the other retinoblastoma family(Rb) from tumor suppressor protein resulting in destabilizationand loss of complex pRb/E2F where complex pRb/E2F function suppress transcription of genes required for cell cycle progression. The p53 and pRb pathway relate each other: phosphorylation p105Rb which results in the release of Rb/E2F complex mediated by cyclin-dependent kinase (cdk) which is inhibited by p21 that include in transcriptional targets of p53. Protein E6 and E7 also show not dependent on p53 and pRb activity(DeFilippis et al., 2003).

b. Protein E7 can inhibit p21 and p27 (Fehrman, 2003). The majority of cervical cancer cells have p53 and p105Rb genesin the form of wild-type. So, growth regulatory genes are active in normal cells is also present in cervical cancer cells. But, its activity is inhibited by the expression of E6 and E7 proteins of HPV(Goodwin dan DiMaio, 2000). If the E6 and E7 oncogene expression is inhibited, the tumor suppressor proteins p53 and retinoblastoma activeand cervical cancer cells undergo senescence which then leads to apoptosis (Horner et al., 2004).

Papillomavirus genomes replicate as extrachromosomal plasmids in lesions premalignanand also integrated in most cervical carcinomas randomly.(Dalimartha, 1999; Matsukura et al., 1989). The integrated virus genome will provide a mechanism :
E6 and E7 expression is inhibited by E2. E2 can suppress the expression of E6 and E7because E2 will binds to the HVP early promoter, thus blocking the binding of two essential transcription factors, TBP and Sp1 (Desaintes et al., 1999). But, E2 is not expressed on the DNA viral integrates existing host cell genome, because E2 genes undergo splittingand become inactive. As a result, in a condition without a repressor, E6 and E7 proteins are expressed in high amountsso that causing tumor suppressor protein, namely p53 and p105Rb inactive and stimulating the growth (Hwang et al., 1993).

HOW DETECT CERVICAL CANCER
Like all cancers, the occurrence of cervical cancer is characterized by the growth of cells on the cervix which is not uncommon (abnormal). But before these cells become cancer cells, there are some changes experienced by these cells. Changes in such cells usually take up many years before the cells had been transformed into cancer cells. During these breaks, proper treatment will soon be able to stop the abnormal cellsbefore they turn into cancer cells. Abnormal cells can be detected with a test called“Pap smear test”, so the earlier the abnormal cells were detected, also the lower risk of the person to suffer cervical cancer.

Pap smear test is a test that is safe, fast and inexpensive and has been used for years to detect abnormalities that occur in the cells of the cervix. This test was first discovered by Dr. George Papanicolou, so-calledPap smear test. Pap smear test is a method of examination of cells taken from the cervixand then examined under a microscope to see the changes that occur from the cells. In a lying supine condition, an instrument called a speculum will be inserted into a hole intercourse. This tool is used to open and hold the vaginal walls to remain open, allowing independent view and cervix seen clearly. The cells of the cervix and then collected by wiping the cervix with an instrument called a spatula, a tool resembling a handle on ice cream, and smears is applied to the object-glass, and then sent to a pathology lab for a more thorough examination(Dolinsky, 2002).

Pap smear test procedures may be very unpleasant, but will not cause pain. Pap smear test is done a week or two weeks after the end of the menstrual period. For people who have not menstruating, a Pap smear test can be done anytime. But, if the bladder uterus and cervix have been removed or inoperable (hysterectomy or surgical removal of the uterus and cervix of the uterus), Pap smear test is not necessary anymore because the person is automatically freed from the risk of cervical cancer. Pap smear test is usually done every two years, and better done on a regular basis. The thing to always remember is never too late to do a Pap smear test. Pap smear test is always required even though no longer a sexual activity(Anonim, 2003b).

If there is bleeding after sexual activityor between menstrual periods occurand the discharge occursit must be done immediately to a doctor examination. The change is not a normal thing, and a thorough examination should be done even if just doing a Pap smear test.

‘Pap Smear’ results say if the abnormal cervical cells when examined under a microscope will give a different appearance to the normal cells and a thorough examination should be done even if just doing a Pap smear test.This event usually occurs 1 in 10 ‘Pap Smear’ tests(Sofyan, 2000). Some of the factors that can give indications discoverysightings ‘Pap Smear’ abnormal are:
1. Unsatisfactory ‘Pap Smear’.
In this case, means that employees in the Lab can not see the cervical cells with detailthus failing to make a comprehensive report to the doctor. Therefore, it must be done Pap smear test again(Sofyan, 2000).
2.
If there is an infection or inflammation. Sometimes the ‘Pap Smear’ test, give the appearance of inflammation. This means that the cells in the cervix that are experiencing a mild irritation. Indeed, sometimes the inflammation can be detected through a ‘Pap Smear’, even if we do not feel the complaints because it does not feel clinical symptoms. Various cause, may have occurred due to infection by bacteria, or because of fungal. Therefore Pap Smear test should be done after an infection or inflammation healed(Sofyan, 2000).
3. Atypia or Minor Atypia.
The meaning of this situation is if the ‘Pap Smear’ detectable change in cervical cells, but it is very minor and the cause is not clear. In this case, the results are usually reported as ‘atypia’.Usually a change in the appearance of these cells due to inflammation, but not infrequently due to virus infection. Because to make a definitive diagnosis is not possible at this stage, so it must be inspected again within six months.In general, these cells will go back to normal again. So it is very important to do ‘Pap Smear’ again to ensure that the abnormalities that appear on first inspection it is not a serious disorder.If the test showed the same results it is advisable to undergo colposcopy(Sofyan, 2000).
Colposcopy is a procedure in cervical and vaginal examination by a physician experienced in the that field. By examining the surface of the cervix, the doctor will determine the cause of the abnormality of cervical cells rahimsas stated in the ‘Pap Smear’. How to colposcopy examination is as follows: the doctor will insert liquid into the vagina and cervical canal color with a liquid that makes the surface of the cervix containing the abnormal cells stained. Then the doctor will look into the cervical canal through an instrument called a colposcope. Colposcope is a binocular microscope sort of tool that uses a powerful light with high magnification(Anonim, 2003b).

If the abnormal area was localized, doctor will take samples of the tissue (a biopsy) to be sent to a lab for a detailed examinationand accurate. Treatment will depend on the results of colposcopy(Yohanes, 2000).

PREVENTION
What should be done to prevent cervical cancer is the first, if you ever had sexual intercourse then have to do a Pap smear test regularly every two years and this is done by the age of 70 years. In some cases doctors may recommend to do a Pap smear test more often. The second thing is to report symptoms such as abnormal bleeding, especially after coitus (intercourse). The third thing is not to smoke. Statistical data reported that the risk of cervical cancer would be higher if women smoke. By doing some actions that can minimize these risks, the incidence of cervical cancer is avoidable(Zhao, 2004).

TREATMENT
Therapy for cervical cancer is different for each stadium of cancer. In the early stages surgery may be done to the network containing cancer cells. In the next stadium, the therapy with radiotherapy, chemotherapy, or chemo-radiotherapy. This type of therapy can affect normal cells(La Russo, 2004).

If the initial changes of cervical cells is well known, the general treatment is given by:
1.
Heating, diathermy or laser.
2.
Cone biopsy, namely by taking a bit of cervical cells, including cells undergoing changes.This allows a more thorough examination to ensure that the cells undergo changes.This examination can be carried out by a gynecologist (Anonim, 2007).
If the course of the disease has reached the stage of pre-cancer and cervical cancer have been identified,it is for healing, some things that can be done are:
1.
Operation, namely by taking the cancerous area, usually the uterus and cervix.
2.
Radiotherapy is the use of high-powered X-rays that can be done internally and externally (Tyagi, 2000).

REFERENCES

Anonim, 2008b, What Are The Risk Factor for Cervical Cancer, http://www.cancer.org, diakses November 2008.

Anonim, 2007, Kanker : Pertumbuhan, Terapi dan Nanomedis, http://www.nano.lipi.go.id/utama.cgi?artikel&1187593839, diakses 25 Juli 2008.

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Hwang, E.S., Riese, D.J., Settleman, J., Nilson, L.A., Honig, J., Fyynn, S., and DiMaio, D., 1993, Inhibition of Cervical Carcinoma Cell Line Proliferation by the Introduction of a Bovine Papillomavirus Regulatory Gene, J. Virology, 67 (7): 3720-3729.

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CONTRIBUTORS

Sendy Junedi, Rosana Anna Ashari, Fany Muthia C, Titi Ratna Wijayanti, Esti widayanti, Nur Latifah Sri Wijayanti, Andrrea Thea Rhosita dan Agus Setiawan.