16: Cervical cancer

Cervical cancer

Jovana Y. Martin1Britt K. Erickson2 and Warner K. Huh2

Department of Obstetrics and Gynecology, University of Alabama at Birmingham, Birmingham, AL, USA

Division of Gynecologic Oncology, University of Alabama at Birmingham, Birmingham, AL, USA


Cervical cancer is the second most common cancer among females worldwide, with an incidence of almost 500 000 new cases per year [1]. Cervical cancer typically presents in the fourth to fifth decade of life [1] with a variable clinical presentation ranging from no symptoms to abnormal vaginal bleeding, vaginal discharge, or pelvic pain. On physical exam an exophytic mass, ulcerative mass, or grossly normal appearing cervix can be seen. Cervical cancer is clinically staged and treatment options and outcomes are dependent on the stage at diagnosis.

Infection with the Human Papillomavirus (HPV) is necessary for the development of both pre‐invasive disease of the cervix, known as cervical intraepithelial neoplasia (CIN), and cervical cancer [2, 3]. HPV infection can be divided into high‐risk and low‐risk types. It is the high‐risk types that cause high grade CIN and invasive disease.

Squamous cell carcinoma is the most common histological type of cervical cancer, accounting for 80% of cervical cancers [4, 5] followed by adenocarcinoma and adenosquamous carcinoma, which account for 15% of cervical cancers [4]. The remaining 5% of cervical cancers consist of rare histological types [4]. Recent trends have shown a significant decline in both the incidence and mortality of cervical cancer in many developed and some developing countries [6, 7]. These trends are related to large population based screening programs that have been implemented to detect pre‐invasive disease of the cervix.

Table 16.1 Cervical cancer risk factors

Risk factor Mechanism
Infection with high‐risk HPV types Established high‐risk HPV types: 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66
Probably high‐risk HPV types: 26, 53, 67, 68, 70, 73, 82
Overexpression of oncoproteins E6 and E7 affect tumor suppressors p53 and pRB leading to loss of control of the cell cycle
HPV acquisition Age at first intercourse Age related susceptibility of the transformation zone to HPV
Increasing number of sexual partners Increased exposure to HPV
Co‐infection with chlamydia, genital herpes simplex virus Pro‐inflammatory state; allows HPV access to basal epithelium
HPV persistence Tobacco use Impaired immunity; disruption of normal cell division
Immunosuppression Impaired immunity

Clinical questions

  1. In women (population), are there environmental, genetic, or behavioral risk factors (exposure) that increase their risk of developing cervical cancer (outcome)?

    • Search Strategy: Cervical Neoplasm; Risk factors; Sexually Transmitted Disease STD; Tobacco use; Immune suppression; Oral contraception; Meta‐analysis; Clinical trial; Randomized controlled trial.
    • Databases: EMBASE, CINAHL, PubMed, Medline, Cochrane Database.
    • Manual Search of references

While high‐risk HPV infection is necessary for the development of cervical cancer [2], there are other environmental and behavioral factors that alter the course of CIN and affect progression to invasive cancer (Table 16.1). These risk factors can largely be grouped into those that increase the rate of HPV acquisition and those that affect HPV persistence. Age of sexual debut, number of sexual partners, and history of infection with other STDs have been shown in the literature to increase HPV acquisition, whereas tobacco use and immunosuppression affect HPV persistence.

A number of epidemiological studies have shown a strong correlation between early age of first sexual intercourse and HPV prevalence [8, 9]. In addition to increasing the risk of HPV infection, early age of sexual intercourse also increases the risk for cervical cancer [5, 10]. This age related susceptibility is secondary to cellular changes within the transformation zone which begin during menarche [11]. Specifically, cells transform from columnar to squamous epithelium, a process known as metaplasia. Metaplastic cells in the transformation zone are especially susceptible to HPV infection, and thus HPV exposure at an early age corresponds to increasing rates of HPV infection [12].

Another component of sexual history that increases the risk of HPV infection is number of sexual partners. There has been a clear association with an increasing number of sexual partners and HPV infection [5, 9, 10, 1315]. Herrero et al., in a large case‐control study, reported a 1.7 times greater risk for cervical cancer with six or more lifetime partners compared to women with one lifetime partner [10]. More recently, a prospective cohort study examined risk factors for newly acquired HPV infections and found that risk of HPV infection increased 10‐fold for each new sexual partner per month [14].

Previously it was thought that co‐infection with other STDs increased the rate of HPV infection and cervical cancer risk, [10] however most studies were confounded by other elements of the sexual history making a causative relationship difficult to establish [10]. Despite this, there have been data showing an association between Herpes Simplex Virus type 2 (HSV 2) and Chlamydia trachomatis (C. trachomatis) and HPV infection. Smith et al. performed a pooled analysis and adjusted for sexual behavior confounders and found an association between HSV 2 seropositivity and cervical cancer suggesting a carcinogenic mechanism exists between these two viruses [14, 16].

Epidemiologic and case‐control studies have shown that co‐infection with chlamydia is associated with an increased risk for cervical cancer [1720]. Co‐infection with chlamydia may affect HPV persistence secondary to a chronic inflammatory state [21] or by micro‐abrasions, which allow HPV access to the basal epithelium [22]. A nested case‐control study of 182 women with invasive cervical cancer found that serum antibodies to C. trachomatis was associated with a twofold increase risk of invasive squamous cell carcinoma [17].

Historically, oral contraceptive use was thought to contribute to cervical cancer risk through various hormonal pathways [23, 24]. A recent meta‐analysis supported this view and also suggested that increased duration of use was proportional to increasing cervical cancer risk [25]. In addition, this study noted that cessation of hormonal contraceptive use was associated with a return to baseline risk for cervical cancer [25]. Follow‐up studies have failed to show hormonal contraceptive use as an independent risk factor for cervical cancer and have suggested that differences in sexual behavioral patterns likely account for the previously observed differences in cervical cancer risk [26, 27].

Most infected females will clear their HPV infection within two years [14]. However, factors that affect persistence, such as tobacco use and immunodeficiency, alter this clearance rate and thus put women at risk for CIN and cervical cancer. Carcinogens from tobacco use have been found in cervical tissue and are thought to impair immunity and disrupt normal cell division [28, 29]. Several studies have shown that tobacco use increases cervical cancer risk and that this risk is correlated to the number of pack‐years smoked [2932]. Increased risk exists even in former smokers [30]. The data correlating tobacco use and cervical cancer risk has been so convincing that The International Agency for Research on Cancer (IARC), an agency that performs global investigations using evidence based medicine regarding potential human carcinogens, declared tobacco use as a human carcinogen and risk factor for cervical cancer [33].

Because cervical cancer is caused by a viral infection, a competent immune system plays an important role in preventing the progression of HPV infection to CIN and cervical cancer. Conversely, population based trials have shown that patients who are immunocompromised, such as women with Human Immunodeficiency Virus (HIV), have high rates of HPV persistence [34, 35]. Higher HIV viral loads and lower CD4 counts are correlated with persistence [36]. Moreover, rates of CIN are higher in HIV positive women, independent of other risk factors [37]. Although data is conflicting regarding the risk of cervical cancer in women with well‐controlled HIV, retrospective case‐control studies have shown that the degree of immunosuppression correlates with an increased risk of invasive disease [38].

  1. 2. In women with HPV infections (population) are there certain HPV types (exposure) which are more likely to cause cervical cancer (outcome) than other HPV types (comparison)?

    • Search Strategy: HPV; Cervical cancer; CIN; Meta‐analysis; Clinical trial, Randomized controlled trial.
    • Databases: EMBASE, CINAHL, PubMed, Medline, Cochrane Database.
    • Manual Search of references.

Forty types of HPV can affect the anogenital tract [39]. Thirteen HPV types have been established as oncogenic [40] while an additional seven types are probably oncogenic [41] (Table 16.1). With the advent of more sensitive HPV DNA detection methods, it is now recognized that high‐risk HPV DNA is detected in almost 100% of cervical cancers [2, 42]. HPV types 16, 18, 45, 31 have consistently been shown to be the most common high‐risk oncogenic types in cervical cancer [3]. Specifically, HPV 16 and HPV 18 are detected in 60–70% of cervical cancers [43]. This may be due, in part, to their slower clearance rates compared to other HPV types [44]. Oncoproteins E6 and E7 are overexpressed in cells infected with HPV 16 and 18. These proteins in turn affect tumor suppressor proteins pRB and p53, leading to loss of control of the cell cycle and consequently increase the risk of developing malignancy [11, 39, 45].

The implications of identifying the HPV types with the most oncogenic potential have been widespread. In order to decrease the burden of HPV disease globally, prophylactic vaccines against HPV 16 and 18 have been developed. A meta‐analysis of 13 randomized controlled trials found that prophylactic HPV vaccines have been effective in reducing both vaccine‐targeted HPV infections and pre‐invasive cervical disease [46]. Data regarding the effects of vaccination on morbidity and mortality due to cervical cancer is limited due to the recent introduction of large scale vaccination programs.

  1. 3. For women in the general population, what is the sensitivity and specificity of cervical cytology compared to primary HPV testing (diagnostic test) for the detection of CIN and cervical cancer (outcomes)?

    • Search Strategy: Cervical neoplasm; Screening; HPV; Pap smear; Cytology; Sensitivity; Specificity; Meta‐analysis; Clinical trial; Randomized controlled trial.
    • Databases: EMBASE, CINAHL, PubMed, Medline, Cochrane Database.
    • Manual Search of references.

In the 1940s, George Papanicolaou and his colleague Herbert Traut reported that malignant cervical cells could be detected with vaginal cytological evaluation [47]. This method of cytological testing became known as the Papanicolaou, or “Pap” smear. In the decades that followed, population based studies described the utility of the Pap smear in screening programs to prevent morbidity and mortality from cervical cancer [4850]. Public health efforts throughout the world have led to the widespread implementation of cervical cancer screening with the Pap smear.

A Pap smear is performed by gently sampling the transformation zone with a brush and/or a spatula to collect cervical epithelial cells. These cells may either be immediately transfixed to a slide (conventional cytology) or suspended in a preservation solution for delayed fixation (liquid based cytology). The slide is then evaluated by a clinician or cytopathologist. The spectrum of epithelial cell changes in a Pap smear range from a normal appearance to koilocytosis (clearing of cytoplasm around the nucleus typical of HPV infection), cellular dysplasia, and features suggestive of carcinoma. Dysplastic changes are then characterized as low‐grade or high‐grade, guiding the evaluation for underlying CIN.

While Pap smears have historically been the basis of cervical cancer screening, they are not without limitations. The specificity of a Pap smear is high (i.e. low number of false‐positive test results). However, the sensitivity of Pap smears is only moderate (i.e. high number of false‐negative test results) leading to missed CIN and cervical cancer diagnoses. More specifically, a systematic review reported the mean sensitivity and specificity of Pap smears to be 47% (range 30–87%) and 95% (range 86–100%), respectively [51]. This moderate sensitivity is further supported by a recent meta‐analysis which reported that 30% of women with invasive cervical cancer had at least one normal Pap smear in the six years prior to being diagnosed with cervical cancer [52].

In addition to its moderate sensitivity, the Pap smears have other limitations. Pap smears have considerable interobserver and intraobserver variability [5355

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Jul 19, 2020 | Posted by in GYNECOLOGY | Comments Off on 16: Cervical cancer
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