Introduction of Cervical Cancer

Cervical cancer is defined as carcinoma in cervix where it is located at the lower, narrow portion of the uterus and it joins with the top end of vagina. The major causative agent of cervical cancer is human papillomavirus, HPV (Schlecht et al. 2001). More than 100 different strains of HPV are known to exist. However, persistent infection of high risk-HPV(HPV 16 and 18) may only leads to invasive cervical cancer while low risk-HPV (HPV6 and 11) might cause genital warts (papillomas) or condylomas. The virus is spread by contact with skin and membranes but not body fluids.

There are some risk factors which contribute to the development of cervical cancer. Women who are having sex at an early age, having multiple sexual partners and multiparity are seems to more likely to be infected by HPV. Irregular or never have Pap smears examination might cause 1 in 90 women to develop cervical cancer and 1 in 200 women die of cervical cancer. Those who did not getting HPV vaccine will have higher chance to get cancer-causing HPV compared to those who accepted HPV vaccination. Cervical cancer are found to be quite common cancer in developing countries. This may due to the poor economic status which will unable to obtain adequate and effective screening system (Rostad et al. 2002). Taking oral contraceptive, smoking and weak immune system are possible risk factors which leads to cervical cancer.

Early cervical cancer might not give any significant symptoms. However, several symptoms may occur if there is no proper treatment given to the patient. The symptoms are abnormal vaginal bleeding or spotting between periods, after sexual intercourse or after menopause and continuous vaginal discharge (pale, watery, pink, brown, bloody or foul-smelling). Some patients complain that they experienced pain during sex. At advanced stage, cancerous cells might spread to other parts in the pelvic cavity or even distant organs such as bone, lung, intestine, liver and extremities. The symptoms of metastasis cervical cancer include back pain, bone pain or fractures, fatigue/loss of appetite/ weight loss, swollen lymph nodes, urine/feces leaking from vagina, pelvic pain, leg pain and swollen leg.

The development of cervical cancer is gradual and begins as a precancerous condition called dysplasia. Two major types of cervical cancer are squamous cell cancer and adenocarcinoma (glandular cell cancer). In addition, squamous cell cancer is the most common type of cervical cancer. After the cervix infected by high risk-HPV, the cervix will progress to a squamous precancerous lesions which are known as cervical intraepithelial neoplasia (CIN). CIN is categorized as low-grade squamous intraepithelial neoplasia (LSIL) and high-grade squamous intraepithelial neoplasia (HSIL). Low-risk HPV types, such as HPV 6 and 11, usually result in condyloma and low-grade dysplasia (CIN 1) and the high-risk HPV types, most commonly HPV 16 and 18, usually result in the full range of dysplasias (CIN 2 and CIN 3/ Carcinoma In Situ). Squamous dysplasia is characterized by abnormal parabasal cell proliferation, loss of polarity, overlapping nuclei, high nuclear and cytoplasmic ratio,increased mitosis, dyskeratosis and apoptosis, and significant nuclear atypia.

High risk subtypes of HPV virus integrate with host DNA, disrupting the E2 region and causing loss of transcriptional control of viral sequences E6 and E7. Overexpression of E6 and E7 accelerates proteolytic degradation of p53, blocks function of p21, and E7 binds the RB gene, eventually displacing sequestered transcription factors. Loss of the retinoblastoma gene productE2F complex results in overexpression of p16. Loss of p53 and RB gene functions, which causes the dysfunction of cell proliferation control, is the key step in the development of cervical dysplasia.

Human papillomavirus (HPV) life cycle differs from all other virus families. The infection requires the availability of epidermal or mucosal epithelial cells that are still able to proliferate (basal layer cells). In these cells, viral gene expression is largely suppressed even though the limited expression of specific early viral genes (such as E5, E6 and E7) results in enhanced proliferation of the infected cells and their lateral expansion. Following entry into the suprabasal layers, late viral gene expression is initiated. The circular viral genome is then replicated and structural proteins form. In the upper layers of the epidermis or

mucosa, complete viral particles are assembled and released. Three genes possess proliferation-stimulating activity: E5, E6 and E7. E5 seems to be important in the early course of infection. It stimulates cell growth by forming a complex with the epidermal growth-factor receptor, the platelet-derived growth factor- receptor and the colony-stimulating factor-1 receptor (Hausen 2002).

Recently, E5 has also been shown to prevent apoptosis following DNA damage. However, as HPV-infected lesions progress to cervical cancer, the episomal viral DNA frequently becomes integrated into host-cell DNA and a substantial part of thegenome, commonly including the E5 coding sequence, is deleted. So, E5 is not obligatory in late events of HPV-mediated carcinogenesis. A more significant role for malignant transformation can be assigned to the E6 and E7 genes and their respective proteins. They are consistently expressed in malignant tissue, and inhibiting their expression blocks the malignant phenotype of cervical cancer cells. They are independently able to immortalize various human cell types in tissue culture, but efficiency is increased when they are expressed together (Hausen 2002).

Several functions have been described for E6 and E7. Initial observations revealed that E6 interacts with p53, and E7 interacts with RB to block the activity of these tumour suppressors. Indeed, some of the prominent functions of the E6 protein originate from its interaction with, followed by degradation of, p53 and the pro-apoptotic protein BAK, which results in resistance to apoptosis and an increase in chromosomal instability. In addition, the activation of telomerase and the postulated inhibition of degradation of SRC-family kinases by the E6 oncoprotein seem to fulfil important functions in growth stimulation. It has been speculated that the stabilization of the activated forms of specific members of the SRC family of kinases could contribute to the HPV-transformed phenotype. The cyclin-dependent kinase inhibitor INK4A (also known as p16) seems to counteract these functions. E7, however, interacts with and degrades RB, which releases the transcription factor E2F from RB inhibition and upregulates INK4A. The resulting high E2F activity might lead to apoptosis in E7- expressing cells. Moreover, E7 stimulates the S-phase genes cyclin A and cyclin E, and seems to block the function of the cyclin-dependent kinase inhibitors WAF1 (also known as CIP1 and p21) and KIP1 (also known as p27). By inducing centriole amplification, E7 also induces aneuploidy of the E7-expressing cells, which contributes to tumorigenesis. . As mentioned previously, E6 seems to be impaired by INK4A, whereas E7 bypasses this inhibition by directly activating cyclins A and E. E6, in turn, prevents E7-induced apoptosis by degrading the apoptosis-inducing proteins p53 and BAK (Hausen 2002).

CERVICAL INTRAEPITHELIAL NEOPLASIA (CIN)

(A) CIN 1: dysplastic squamous cells in the lower one-third of the epithelium with HPV changes in the rest of the superficial epithelium.

(B) CIN 2: dysplastic squamous cells in the basal two-thirds of the epithelium and the upper half of the epithelium shows HPV changes

(C) CIN 3: dysplastic squamous cells marked throughout the full thickness of the epithelium. HPV changes are confined to the superficial layer.

FIGO: Clinical Staging of Cervical Cancer

Stage

Definition

I

Carcinoma strictly confined to the cervix (extension to the corpus should be disregarded).

IA

Invasive cancer identified only microscopically; invasion limited to measured stromal invasion with maximum depth of 5 mm and no wider than 7 mm (the depth of invasion should not be more than 5 mm taken from the base of the epithelium, either surface or glandular, from which it originates; vascular space involvement, either venous or lymphatic, should not alter the staging).

IA1

Measured invasion of stroma no greater than 3 mm in depth and no wider than 7 mm.

IA2

Measured invasion of stroma greater than 3 mm and no greater than 5 mm and no wider than 7 mm.

IB

Clinical lesions confined to the cervix or preclinical lesions greater than stage IA.

IB1

Clinical lesions no greater than 4 cm in size.

IB2

Clinical lesions greater than 4 cm in size.

II

The carcinoma extends beyond the cervix but has not extended to the pelvic wall; the carcinoma involves the vagina but not as far as the lower third.

IIA

No obvious parametrial involvement, the cancer may have grown into the upper part of the vagina .

IIA1

Tumor size of less than or equal to 4cm with involvement of less than the upper two-thirds of the vagina.

IIA2

Tumor size of more than 4cm with involvement of less than the upper two-thirds of the vagina.

IIB

Obvious parametrial involvement.

IIB1

Unilateral parametrial invasion.

IIB2

Bilateral parametrial invasion.

III

The carcinoma has extended to the pelvic wall; on rectal examination, there is no cancer-free space between the tumor and the pelvic wall; the tumor involves the lower third of the vagina; all cases with a hydronephrosis or nonfunctioning kidney are included unless they are known to be due to other causes.

IIIA

The cancer has spread to the lower third of the vagina but not to the pelvic wall.

IIIB

The cancer has grown into the pelvic wall. If the tumor has blocked the ureters (a condition called hydronephrosis) it is also a stage IIIB.

IV

The carcinoma has extended beyond the true pelvis or has clinically involved the mucosa of the bladder or rectum; a bullous edema as such does not permit a case to be allotted to stage IV.

IVA

Spread of the growth to adjacent organs.

IVB

Spread to distant organs.

(Adapted from New gynecologic cancer staging: FIGO Cancer Committee. Int J Gynecol Obstet 2009; 105:107)

Epidermiology Of Cervical Cancer

The report of GLOBOCAN 2008 International Agency for Research on Cancer (IARC) has shown the global epidemiology of different cancer in the world. The study shows that cervix uteri cancer is the fifth most common cancer in the world. The number of incidence of cervical cancer in global is 530,232 cases and the age standardized rate (ASR) is 15.2 per 100,000 population. The number of mortality caused by cervical cancer is 275,008 in 2008 and ASR of mortality is almost 7.8 per 100,000 population.

Kent and his collegues (2010) reported that approximately 80% cervical cancer occurs in developing countries.This may due to inadequate and insufficient screening system to identify precancerous and high risk cervical cancer at the early stage and not given appropriate treatment. 5-year prevalence of cervical cancer in the world is 63.2 per 100,000 women per year while the mortality rate is 9 per 100,000 per year.

In Malaysia, cervical cancer becomes the third most common cancer among women after breast and colorectal cancer. According to Report of Malaysian Cancer Statistics in Peninsular Malaysia (2006), there are 1,074 cases of cervical cancer registered with NCR. The overall ASR of cervical cancer in Peninsular Malaysia is 12.2 per 100,000 population and crude incidence rate (CR) is roughly 10.9 per 100,000 population. The report also mentioned that the incidence rate of cervical cancer increased after 30 years and has its peak at ages of 60-69 years. The Chinese population (15.6 incidence per 100,000 population) shows the highest incidence rate of cervical cancer, following by Indian (9.5 incidence per 100,000 population) and Malay population (5.8 incidence per 100,000 population).

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