2.1.1. Cervical intraepithelial neoplasia

The incidence of noninvasive intraepithelial neoplasia (CIN I, II and III or cervical dysplasia and carcinoma in situ) is not known but it is estimated that approximately 10% of the Papanicolaou tests performed annually in the United States will show some type of abnormality (Kurman et al. 1994).

The epithelium covering the cervix contain two cell types: squamous and columnar. The squamous epithelium covers the ectocervix and is continuous with the vaginal epithelium. It is stratified, non-keratinizing epithelium, which is separated from the underlying stroma by basal lamina. Stratification refers to the way in which the epithelium is divided into layers of progressively more mature and flattened cells as the surface is reached. Basal layer cells have a large nuclear cytoplasmic ratio and this is attached to the basal lamina. The parabasal cells form the next few layers. Further maturation and differentiation produces the intermediate cells in which the cytoplasm is more abundant, and the superficial layer of epithelium which is composed of markedly flattened cells. The fully mature and differentiated cell of the squamous epithelium is very flat (Anderson et al. 1992).

It is believed that CIN represents stages of morphologic continuum towards invasive carcinoma of the cervix. These changes begin with minimal atypia and progress through stages of more marked abnormalities to invasive squamous cell carcinoma (Johnson et al. 1968). CIN or dysplasia are divided into three grades. The squamous epithelium undergoes changes leading to mild abnormalities, i.e. nuclear abnormalities confined to the deeper layers of the epithelium (CIN I). In CIN II the nuclear abnormalities are more marked and extend higher in the epithelium than in CIN I. In CIN III or carcinoma in situ nuclear abnormalities may extend through the entire thickness of the epithelium.

It has been shown that a large proportion of low-grade lesions in cervical cytology will regress spontaneously (Kurman et al. 1994, Matsuura et al. 1998, Holowaty et al. 1999). Holowaty et al. (1999) found that at 10 years, over half of the women with mild or moderate dysplasia had not progressed to a more severe lesion. Progression from moderate to severe dysplasia or from mild to moderate dysplasia was highest in the first two years. High-grade CIN lesions are less likely to regress to normal and are more likely to progress to invasive carcinoma (Koss 1989, Melnikow et al. 1998). At least 20% of the CIN III cases progress to invasive carcinoma within 10 years. Long-term follow-up studies show that invasive recurrences continue to appear for at least 8 years after treatment for CIN, and the risk remains 4 to 5 times greater than in the background population (Soutter 1998). Some studies have expressed that less aggressive treatment will result in increased rates of invasive cervical carcinoma (Ferenczy 1993, Flanelly G & Kitchener 1995).

In CIN lesions colposcopical examination is important in order to delineate the extent of the lesions to indicate the areas to be biopsied. The majority of the CIN I-III changes are treated with LEEP (the large loop excision of the transformation zone) and also cryotherapy, laservaporization or cone biopsy are used. The choice of treatment is based on the severity and location of the lesion as well as on the availability of different treatment modalities in spesific hospitals.

2.1.2. Cervical carcinoma

Squamous cell cervical carcinoma is often associated with chronic cervicitis, severe dysplasia and carcinoma in situ, usually progressing over 10-20 years (Barron & Richart 1970, Kashigarian & Dunn 1970). Several risk factors for cervical carcinoma have been identified, such as HPV infection (Kadish et al. 1986, zur Hausen 1996, Gomousa-Michael et al. 1997, Lombard et al. 1998, Kjellberg et al. 1999), early age at first intercourse, large number of lifetime sexual partners (Brinton 1992), sexually transmitted diseases (Paavonen et al. 1998), and low socioeconomic status (Herrero 1996).

Moleculobiological studies have demonstrated a strong relationship between human papillomavirus (HPV), CIN and invasive cervical carcinoma (Kadish et al. 1986, Smotkin & Wettstein 1986, Park et al. 1995). HPV DNA (deoxyribonucleic acid) sequences are found in approximately 90% of the cervical carcinomas (Iwasawa et al. 1996). HPV types 16 and 18 were declared to be human carcinogens by the International Agency for Research on Cancer (IARC 1995). They are the most important single etiological causes of cervical squamous cell carcinomas (zur Hausen 1996). Types 16, 18, 31, and 33 have been associated with high grade CIN lesions and invasive carcinomas (Crum et al. 1985, zur Hausen 1991, Lorincz et al. 1992, Ho et al. 1998, Roteli-Martins et al. 1998, Kjellberg et al. 1999), whereas types 6 and 11 usually cause benign warts, but are occasionally associated with invasive lesions. Also other viruses, like the Herpes simplex virus (HSV) and the Ebstein-Barr virus (EBV) are linked as cofactors to CIN (Landers et al. 1993, van den Brule et al. 1995, Payne et al. 1995).

In the earliest stage at which invasion can be recognized a small group of cells is seen to penetrate the basement membrane and push into the underlying stroma. Cervical carcinoma grows by direct invasion to surrounding structures and through lymphatic vessels, and only rarely by the hematogenous route. Squamous cell cervical carcinoma has been found to extend into the lower uterine segment and endometrial cavity in 10% to 30% of the patients (Perez et al. 1981). Local extension into surrounding tissues results in ureteral compression as well as bladder and rectal involvement. Metastases to regional lymph nodes involve the paracervical, hypogastric and external iliac nodes. As invasion becomes more advanced, the cells become better differentiated than the overlying CIN. (Anderson et al. 1992).

The International Federation of Gynecology and Obstetrics (FIGO) has accepted a staging system for cervical carcinomas (Table 1). The Figo stage is based on careful clinical examination and the results of specific radiologic studies.

The standard treatment for patients with early stage I cervical carcinoma is radical hysterectomy and bilateral pelvic lymph node dissection. In more advanced diseases preoperative radio-, chemo- or chemoradiotherapy before operation can be used. Postoperative external radiation therapy is offered to high risk patients. There are several studies in which adding concurrent chemoradiotherapy (cisplatin or cisplatin and fluorouracil) to radiotherapy significantly improved survival and recurrence free survival among women with stage IB (Keys et al. 1999) and with locally advanced cervical carcinoma (Morris et al. 1999, Rose et al. 1999).

The 5-year overall survival rate in cervical carcinoma is approximately 65-70% (FIGO Annual Report 1998, Suris & Dexeus 1998). Early stage cervical carcinoma has a relatively favorable prognosis, with a 5-year survival rate of 80-95% (FIGO Annual Report 1998). When the pelvic lymph nodes are involved, the 5- year survival rate decreases to 40-50% (Sevin et al. 1995, Lin et al. 1996).

The prognosis of cervical carcinoma is dependent on the presence or absence of pelvic lymph node metastasis (Sevin et al. 1995, Lin et al. 1996), which is the most powerful prognostic factor. Also other prognostic factors such as the size of the primary tumor, tumor grade, depth of invasion, lymphvascular space involvement and tumor extension over the cervix appear to be related to survival. As invasion progresses other histological features need to be taken into account, such as tumor dimension, lymphatic channel involvement and pattern of growth (Anderson et al. 1992).