Invasive squamous cell carcinoma accounts for 80% of cervical malig- nancies. Unlike the remainder of the reproductive tract cancers, which are more prevalent in industrialized countries, cervical cancer ranks second in cancer mortality in developing nations. Virtually all cervical cancers are associated with the human papillomavirus (HPV), which is the most common sexually transmitted infection. Squamous cancer of the cervix is unique in that it is a preventable disease when vaccina- tion, proper screening and treatment are available and employed.
Like prostatic cancer in men (Chapter 41), cervical cancer typically arises from a precursor lesion, cervical intraepithelial neoplasia (CIN). CIN is asymptomatic and appears to precede invasive carcinoma of the cervix by 5–15 years. Almost all cervical cancer arises in the transformation zone (squamocolumnar junction) of the cervix. Here, the columnar, glandular epithelium of the endocervix meets the squamous epithelium of the ectocervix. The anatomic location of the squa- mocolumnar junction changes in response to a variety of factors and is different in young postpubertal girls when compared with postmeno- pausal women (Fig. 44.1). In older women, the transformation zone may be high in the endocervical canal. This makes the early diagnosis of cervical neoplasia more difficult.
Cervical carcinomas can spread in any one of four ways: (i) directly into the vaginal mucosa; (ii) directly into the myometrium of the lower uterine segment; (iii) into the paracervical lymphatics and from there to the obturator, hypogastric and external iliac lymph nodes; and (iv) directly into adjacent structures such as the bladder anteriorly, the rectum posteriorly, or the parametrial tissues and pelvic sidewalls laterally. Lymphatic invasion can occur even when cervical tumors are still small. Hematogenous spread and distant metastases are usually very late manifestations of the disease.
Surgical treatment is used for early-stage cervical cancers. A combination of radiation and chemotherapy is used for patients with advanced disease and in those who are poor surgical candidates.
Epidemiology of cervical cancer
The association of sexual activity with cervical cancer was first identified over 150 years ago when it was noted that the disease was rare in nuns and frequent in prostitutes. Subsequent epidemiologic data have identified the onset of sexual activity in adolescence and multiple sexual partners as high-risk characteristics for cervical cancer. Its incidence is higher in low-income women but this effect is not inde- pendent of early sexual activity and multiple sex partners. Smoking is an independent risk factor for the development of cervical cancer. Characteristics of a “high-risk” male partner include men whose previ- ous partner developed cervical cancer, who themselves develop penile cancer or who have not had a circumcision.
Epidemiologic data suggesting that cervical cancer behaves like a sexually transmitted disease led to identification of HPV as the causative agent. Although it has been identified in over 99% of all cervical cancers, HPV infection of the cervix appears necessary but not sufficient for the development of cervical cancer. This distinction is important as cervical infection with HPV is very common; however, the majority of these infections are transient. Persistent infection with an oncogenic type of HPV confers an increased risk of developing cervical cancer.
Pathogenesis of squamous cell neoplasia of the cervix
Because the cervix is so physically accessible, the pathogenesis of cervical neoplasia has been studied extensively. Pathogenesis clearly involves exposure of a vulnerable tissue (the transformation zone) to carcinogens.
The squamocolumnar junction is one of six epithelial boundaries present within the lower genital tract. The position of the squamoco- lumnar junction is affected by the hormonal and anatomical changes of puberty, pregnancy and menopause (Fig. 44.1). Prior to puberty, the squamocolumnar junction is at the level of the external cervical os (Chapter 9). With puberty, estrogen-induced changes in the shape and volume of the cervix carry the squamocolumnar junction out onto the anatomic ectocervix. This repositioning exposes tissues previously found in the lower endocervical canal to the vaginal environment. The exposure of the simple mucin-secreting epithelium to the acidic vaginal milieu induces a chemical denaturation of the villus tips of the columnar epithelium. The reparative process that follows eventually produces a mature squamous epithelium. After menopause, the squamocolumnar junction retreats to a position high within the endocervical canal.
HPV is a DNA virus that causes epithelial lesions in the skin, cervix, vagina, vulva (Chapter 47), anus and oropharynx. More than 100 types of HPV have been identified to date. The HPV infections affecting the genital tract are classified according to their oncogenic potential. The highest risk HPV genotypes are 16 and 18, which have been detected in 65% of cervical cancers.
Cervical infection with HPV is very common – 80% of all sexually active women will have at least one infection with HPV; however, the majority of these infections are transient. The average duration of infection is 8 months, and 90% of HPV infections in young women will clear within 2 years. It is thought that the local immune response of the host is primarily responsible for HPV clearance; only persistent (greater than 6–12 months’ duration) HPV infection puts the cervix at risk for changes that could develop into cancer. Typically, HPV infection persists for greater than 10 years before causing carcinogenesis. Women with an impaired immune system, such as HIV-infected women, have high rates of persistent cervical HPV infections and cervical neoplasia.
Cervical intraepithelial neoplasia (CIN) is the term used to encompass all premalignant epithelial abnormalities of the cervix. It has replaced an older terminology that used the terms “dysplasia” and “carcinoma in situ” of the cervix. CIN, although divided into grades, is actually a single neoplastic continuum. The designations CIN1, 2 and 3 reflect the extent of the cellular aberrations within the cervical epithelium (Fig. 44.2). For instance, in CIN1, the lower one-third of the epithelial cells (closest to the basement membrane) lack evidence of differentiation or maturation. This exit from the normal differentia- tion pathway signals neoplastic transformation.
Screening tests for cervical cancer
The cervical smear or Pap test (named after Dr. George Papanicolaou who developed the test) was designed as a screening test to detect squamous cell abnormalities. Its success is based on the fact that the nuclear abnormalities of neoplastic cervical cells are present in samples that are scraped or exfoliated from the surface of the cervix. In countries where cervical cancer screening with Pap testing is routinely performed, the incidence and mortality rates of cervical cancer have both decreased by 70%. It is likely that the treatment of premalignant lesions and the finding of earlier stage cervical cancers have contributed to the decreased incidence and mortality of cervical cancer. HPV tests of the cervix can be used as an adjunct to cervical cytol- ogy screening for women aged 30 years and over. HPV testing for primary screening of younger women is not recommended because of the high rates of transient HPV infections that would be detected. The benefits of adding HPV testing include: (i) a reliable, readily reproducible measure of the risk of disease; (ii) a high negative predictive value with a single test that allows prolongation of the screening interval; and (iii) increased sensitivity (although lower specificity) compared with cervical cytology in the detection of CIN2–3.
Prophylactic HPV vaccination
Two prophylactic HPV vaccines based on virus-like particles (VLPs) have been developed. Both provide protection against HPV types 16 and 18 – the causative agent for approximately 65% of cervical cancers worldwide. HPV vaccines prevent the development of HPV 16 and 18 infections, HPV 16 and 18 associated CIN2 or 3, adenocarcinoma in situ and invasive cervical cancer, with 98% efficacy in young women without prior HPV 16 or 18 infection. Vaccination is recommended for girls who are not yet sexually active as HPV infections rates are very high among adolescents. Interestingly, the mechanism of action of these vaccines is not well understood as the primary mode of natural immunity to HPV is a local immune response and not a systemic response.
Adenocarcinoma of the cervix is much rarer than squamous cell lesions. It occurs most often in women during the reproductive years and is frequently associated with HPV type 16 or 18. Although adeno- carcinoma in situ is thought to be the precursor lesion of invasive cervical adenocarcinoma, the timing of progression from precursor to invasion is not well-defined. Cervical cytology does not reliably detect adenocarcinomas but may detect concomitantly present cervical squamous neoplasia; HPV testing should have improved sensitivity for the detection of adenocarcinomas.