I. Introduction

Cervical cancer continues to be a significant public health problem. It is the second leading gynecologic malignancy affecting women in the world (Platz and Benda, 1995; Rohan et al, 2003). Cervical cancers are predominately squamous cell carcinomas, with approximately 20% of the cases are accounted for by adenocarcinoma which appears to be increasing in frequency. Human papillomavirus (HPV) is acknowledged as the causative infectious agent in the vast majority of cases of cervical cancer (Stoler, 2003). HPV infections leads to precursor lesions, progressing to dysplasias and frank carcinoma over time. There is often an orderly progression to invasive cancer, and can occur asymptomatically over a course of 10-20 years.

II. HPV biology

HPV is a DNA virus which is the causative agent of cervical cancer (Stoler, 2003). This virus is sexually transmitted. More than 80 types of HPV have been identified. The majority of cervical cancers are associated with types 16, 18, 31, 33, and 35. These are often referred to as high risk HPV types, in contrast to others which are more associated with warts, condyloma and low grade cervical intraepithelial neoplasia (CIN). Of these HPV 16 is associated with about 50% of cases of cervical cancer. HPV can infect and cause a acute transient infection, but these frequently may clear and the patient would not be at risk for neoplastic transformation (Baseman and Koutsky, 2005). It is widely accepted that with persistant infection, and integration of the HPV genome into the host DNA is the background in which carcinogenesis occurs (Ferenczy and Franco, 2002). HPV proteins encoded by E6 and E7 genes interact with cellular proteins including p53 and Rb gene, respectively, which regulate cell cycle, and presumably this pathway is involved in cervical carcinogenesis (Munger et al, 1992; Giarre et al, 2001).

III. Cervical cancer epidemiology and screening

Cervical cancer screening using the Papanicolaou smear has effected marked impact on this disease, reducing both the incidence and mortality of cervical cancer (Foulks, 1998). In the United States for the period 1996 to 2000, the average annual age adjusted incidence rate for cervical cancer was 8.7 per 100,000 women. This incidence reaches a peak in white women at ages 45-49; while it continues to increase beyond that age in black women. Women older than 50 years of age have a higher incidence than those younger (6.7 versus 13.9 per 100,000), with mortality rates also increasing with age, being more than four fold higher in women over 50 years of age. The age adjusted mortality rate from cervix cancer in the United States was 3.0 per 100,000 women in the period between 1996 and 2000. This is a significant reduction compared to data from 1975 when mass screening was first widely adopted, at which time the age adjusted incidence and mortality rate were 14.8 and 5.6 per 100,000 women respectively.

Socioeconomic status impacts on incidence, and mortality in patients with cervical cancer (Singh et al, 2004; Wang et al, 2004). Lower social economic status confers a 1.6 fold increase risk for developing carcinoma in situ (CIS) when compared with those with higher socioeconomic status. A two fold increase risk for cancer was also correlated with limited accessibility to the healthcare system. Social and economic pressures can also indirectly affect the incidence of cervix cancer through lifestyle and cultural factors, such as sexual behavior, smoking and diet which are known risk factors. Parity, oral contraceptive use, smoking and other concomitant sexually transmitted disease appear to play a role in cervical carcinogenesis (Castellsague et al, 2002). Dietary factors as vitamin A, vitamin C, vitamin E, folic acid, as well as the immune status are also linked to the disease progression.

IV. Diagnosis

Abnormal bleeding presenting as post-coital bleeding, intermenstrual or post-menopausal bleeding remains the most common presenting symptoms of cervical carcinoma (ACOG, 2002). Less than 10% of cases are asymptomatic when detected by cervical screening. Other presenting symptoms, such as urinary dysfunction, pelvic pressure or pain, sciatic pain in advanced disease may be present. Biopsies, whether colposcopically directed or a visible gross lesion will provide the tissue for histologic diagnosis. Endocervical curettage, cervical conization and endometrial biopsy may contribute to the diagnosis, especially in the absence of an obvious lesion.

The extent of the disease at presentation remains the most important prognostic factor (Pecorelli and Odicino, 2003). Clinical staging as defined by the 1994 FIGO staging system for cervical carcinoma is useful (Table 1). Cervical cancer continues to be a clinically staged disease, as opposed to the surgical staging used in defining other gynecologic malignancies. Survival is related to stage, with 5-year survivals ranging from 99% (for early stage IA) to 15% stage IV disease. The earliest of stage I disease are based on histologic examination and microscopic measurements of the depth of tumor invasion.

Other prognostic indicators used for treatment planning include radiologic findings from computed tomography (CT) and magnetic resonance imaging (MRI) (Chiang and Quek, 2003). Because clinical staging remains subjective, lesions may be understaged in up to 20-30% of cases, and these may correspond to nodal involvement or parametrial spread. On the other hand, overstaging can result from pelvic inflammatory disease

Table 1. The 1994 FIGO staging system for cervical carcinoma

Stage 0	Carcinoma in situ, cervical intraepithelial neoplasia grade III
Stage I	Carcinoma strictly confined to the cervix (extension to the corpus is disregarded)
	IA	Invasive carcinoma that can be diagnosed only by microscopy. All macroscopically visible lesions – even with superficial invasion –are allotted to be stage IB carcinomas. Invasion is limited to a measured stromal invasion with a maximal depth of 5.0 mm and a horizontal extension of not more than 7.0 mm. Depth of invasion should be not more than 5.0 mm taken from the base of the epithelium of the original tissue-superficial or glandular. The involvement of vascular spaces-venous or lymphatic-should not change the stage allotment.
		IA1	Measured stromal invasion of not more than 3.0 mm in depth and extension of not more than 7.0 mm.
		IA2	Measured stromal invasion of greater than 3.0 mm and not more than 5.0 mm with an extension of not more than 7.0 mm.
	IB	Clinically visible lesions limited to the cervix uteri or preclinical cancers greater than Stage IA
		IB1	Clinically visible lesions not more than 4.0 cm
		IB2	Clinically visible lesions greater than 4.0 cm
Stage II	Cervical carcinoma that invades beyond the uterus, but not to the pelvic wall or to the lower third of the vagina
	IIA	No obvious parametrial involvement
	IIB	Obvious parametrial involvement
Stage 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 hydronephrosis or nonfunctioning kidney are included, unless they are known to be due to other causes.
	IIIA	Tumor that involves the lower third of the vagina, with no extension to the pelvic wall
	IIIB	Extension to the pelvic wall and/or hydronephrosis or nonfunctioning kidney
Stage IV	The carcinoma has extended beyond the true pelvis, or biopsy proven involvement of 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

and other non-neoplastic pathology, which is estimated to be as high as 20% in stage IIIB disease. The use of positron emission tomography-CT (PET-CT) has been shown in some studies to have a high specificity and sensitivity in cervix cancer staging, approaching a positive predicted value of 100% and a negative predicted value of 96% in patients with early stage disease (Kumar and Alavi, 2004). This may be used more frequently in the future for accurate staging in cases with equivocal clinical findings especially in advanced disease to assess disease extension.

V. Treatment and management

Superficially invasive cervix cancer carries an excellent prognosis. Both depth of tumor invasion, and degree of superficial tumor spread are related to the probability of nodal metastases. The presence of lymphovascular space involvement (LVI), although not in the FIGO staging schema, also appears to imparts a more significant risk of metastatic tumor spread (Graflun et al, 2004). In IA2 lesions, the risk of tumor recurrence is less than 1% if there is no LVI. This risk increases to 17% when LVI is noted by pathologic examination. Stromal response, histologic grade and tumor histology have been implicated as prognostic factors but the data pertaining to these remain weak.

Microinvasive cervical carcinoma is often treated with a simple extrafascial hysterectomy (Mota, 2003). Early stage cancer, usually referring to stage IB1 (equal to or less than 4 cm) and early stage IIA cancers can potentially be cured with surgery (Lu and Burke, 2000). Traditionally, the treatment of choice has been radical hysterectomy or with radiation therapy, with comparable cure rates (Greven et al, 1999). Prospective randomized studies directly comparing surgery versus chemoradiation have not been forthcoming. Chemoradiation is utilized in conjunction with surgery for the treatment of bulky tumors (greater than 4 cm) Radiation is utilized after radical hysterectomy in high-risk patients with positive lymph nodes, positive surgical margins of resection, or tumor involving parametria (Kim et al, 2005). The role and benefit for adjuvant chemotherapy after hysterectomy is not yet defined.

Locally advanced cervical carcinoma (stage IIB-IVA) is treated with chemoradiation for the most part utilizing a platinum-based chemotherapy (Greven et al, 1999; ACOG 2002). External beam radiation and brachytherapy provide tumoricidal management for advanced cervical carcinoma. Neither surgery nor chemoradiation are without their inherent risk of a major complication. Perioperative complications associated with surgery are rare; and late complications possibly include lymphocyst formation, lymphedema, bowel and bladder dysfunction. Although the risk of major complications related to radiation therapy is low, the incidence increases with time, and include fistulization, involving either bowel or bladder, and small bowel obstruction. Thin body habitus, a history of smoking, pre-radiation surgery and pelvic infection are factors correlated with increased risk of major complications.

VI. Pathology of cervical cancer

The vast majority of cervical cancers are epithelial tumors with squamous cell carcinomas accounting for about 80% of the primary tumors in the cervix (Figure 1, Platz and Benda, 1999).

Rarely tumors of glandular origin and small cell carcinomas are seen (Han et al, 2000; Zarka et al, 2003). Squamous carcinomas may have varying degrees of differentiation and amounts of keratin formation. In addition to HPV infection, cervical cancers frequently harbor other genetic alterations that herald other steps in oncogenesis (Carico 2001; Klaes et al, 2001) These most frequently include p16 and p53 (Keating et al, 2001; Finegan et al, 2004). p16 has been shown to be expressed in a large proportion of cervical squamous carcinomas (approximately 70% or more). The regulation of this tumor suppressor protein, presumably involves an HPV dependent pathway (Sano et al, 1998, 2002). Current studies are underway to examine the utility of p16 as an adjunctive marker for cervical cancer screening (Lin et al, 2000; Bibbo et al, 2002; Klaes et al, 2002).

In addition our group has been interested in examining the role of adhesion protein expression in cancers of the cervix. We have seen the cell-cell adhesion marker P-cadherin as a good marker for glandular tumors of the cervix (Han et al, 2000), and often seen in increasing frequency in dysplastic to frankly neoplastic glandular tumors. In small cell cancers of the cervix, we have shown that the neural adhesion protein N-cadherin may be a tumor suppressor protein that is operative in the development of these tumors (Zarka et al, 2003) Recent studies on the oncogenetic profiles of cervical squamous carcinoma has uncovered tumor heterogeneity, suggesting that these tumors are not static, but undergo additional mutations and expression or loss of oncogenes, probably as a result of tumor clonal selection or tumor evolution (manuscript in preparation)

VII. Summary

The last thirty years has seen dramatic change in the incidence and mortality of cervical cancer in the United States. This has been most dramatically affected by the effective screening program associated with the pap smear. Cervical cancer continues to be a significant disease worldwide, and we are understanding more and more of the tumor biology involved, and optimizing current treatment approaches to the disease. Future studies will hopefully uncover best practices for screening strategies for developed and developing countries, as well as preventative options (Lorincz, 1996; Cronje, 2004; Lee et al, 2004; Suba, 2004) Since HPV is the cause of cervical cancer in the majority of cases, research looking at eradicating HPV infection, specifically through vaccine trials is an area of significant interest, and holds much promise (Wolf et al, 2003; Sterlinko and Banks, 2004).

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Review Article

Received: 31 March 2005; Revised: 11 April 2005

Accepted: 12 April 2005; electronically published: April 2005

I. Introduction

II. HPV biology

III. Cervical cancer epidemiology and screening

VII. Summary

References