Cervical Cancer

lowest point in 2004–2006, and have since remained stable. The largest decreases have been in females aged 50–64 and 65–79, with European age-standardized incidence rates decreasing by 62% and 64%, respectively, between 1985–1987 and 2011–2013. This decline is attributable to the availability of cytological screening, which has led to the identification and therapy of precursor lesions, thus preventing their progression to invasive cervical cancer (Gustafsson et al. 1997; Womack and Warren 1998; Plaxe and Saltzstein 1999). The overall mortality from cervical cancer has declined by over 50% since 1970 and the figures continue to decrease slightly. The annual mortality rate today is 2.4 per 100,000 women in the USA and ranges between 0.7 (Iceland) and 14.2 (Romania) in Europe. In addition, there has been a change in therapeutic strategies as it has been shown, for instance, that certain subgroups of patients benefit from the combination of surgery and radiochemotherapy. Novel and minimally invasive operative techniques primarily aim to improve the patient’s postoperative quality of life. Despite these advances, there has been only slight change in the prognosis of invasive cervical cancer over the last decades. The average relative 5-year survival rate in the USA raised from 69% in 1975 to 70% in 2010 (Siegel et al. 2015).

1.2\ Pathogenesis

The main cause of cervical cancer is infection of the cervical epithelium by one of the oncogenic human papilloma virus (HPV) types. The highrisk types of HPV are 16 and 18, which have been shown to have a high oncogenic potential (Castle et al. 2002; Lorincz et al. 2002; Walboomers et al. 1999; Yamada et al. 1997; Bosch et al. 1995; Munoz et al. 2002). HPV16/18 account for at least two-thirds of cervical carcinomas in all continents. The overall prevalence of cervical HPV infections is 5–20%, with a peak between 20 and 25 years of age. Spontaneous regression and clearance of HPV infection with complete eradication of the virus by cell-mediated immunity within 1–2 years of exposure are common (Walboomers et al. 1999). Persistence of the virus is only associated with the risk of epithelial changes of the cervical

mucosa. Especially women with cofactors such as multiple sexual partners, poor genital hygiene, or immunosuppression as in women with AIDS are at risk of developing invasive cancer (Smith et al. 2002a, b). Cervical cancer of the squamous cell type develops in several stages from local epithelial proliferation, through definitive epithelial changes and dysplasia, to a truly precancerous lesion. The precancerous stages are referred to as cervical intraepithelial neoplasia (CIN) (Richart 1973) or squamous intraepithelial lesion (SIL) and first progress to carcinoma in situ before they become invasive cancers. About 3–5% of sexually mature women have CIN. The incidence of advanced precancerous conditions (CIN II, III) is about 100 times higher than the incidence of cervical cancer. CIN often resolves spontaneously but may also progress to carcinoma in situ—typically between 25 and 35 years of age—and finally to invasive cervical cancer at around age 40. Cervical cancer usually arises from the cervical transformation zone, a ring of mucosa at the junction between the squamous epithelium of the portio and the columnar epithelium of the cervical canal (Schiffman et al. 2007).

1.3\ Screening

The ultimate goal of cervical screening tests is to decrease the incidence and the subsequent mortality from invasive cervical cancer through the identification of precursor lesions. In fact since the introduction of the conventional cytology test (commonly referred to as the Pap smear) in the mid-twentieth century cervical cancer incidence and mortality rates have declined significantly (Smith et al. 2015). For the period from 2002 to 2011, cervical cancer incidence rates decreased at an average annual rate of 1.2% per year in women younger than 50 years and by 1.5% per year in women aged 50 years and older (Smith et al. 2015). Following the indications of current guidelines, cervical screening should begin at age 21 years and should be discontinued after the age of 65 years in case of three consecutive negative cytology tests (Smith et al. 2015). While women of 21–29 years should receive cytology screening every 3 years, for women of 30–65 years, the preferred approach

is the combination of cytology and human papillomavirus (HPV) testing every 5 years (Smith et al. 2015). Thanks to these efforts, today over 80% of cervical carcinomas are detected at stage I when the tumor is still locally confined.

unilateral leg edema, peritoneal seeding, and increased body circumference. General symptoms of advanced cervical cancer are a decline of physical performance and weight loss. Late complications include respiratory disturbance and cough in patients with metastatic spread to the lungs.

1.4\ HPV Vaccination

Due to the etiologic role of HPV in the pathogenesis of cervical neoplasia, immunization against HPV infection offers a primary prevention strategy. In the past 10 years, most industrialized countries have introduced national HPV vaccination­ programs targeting adolescent girls (Kahn 2009). Ten years ago, in 2006, the first vaccine targeting HPV was approved by the US Food and Drug Administration. This quadrivalent vaccine using a late protein L1 construct to induce antibody-mediated immunity is active against HPV genotypes 6, 11, 16, and 18, which are responsible for approximately 66% of cervical cancers and 90% of genital warts. In 2009, a bivalent (HPV-16, -18) vaccine was approved, with similar efficacy profile against cervical cancers caused by these HPV genotypes. More recently, in 2014 a vaccine targeting nine HPV types was approved and demonstrated over 95% efficacy against the additional HPV genotypes in Phase III trials (Castle and Maza 2016). Current guidelines indorse routine HPV vaccination principally for females aged 11–12 years; all forms of HPV vaccine are currently recommended as a three-dose schedule across a 6-month period.

1.5\ Clinical Presentation

Early forms of cervical cancer do not present any symptoms. Clinical symptoms occur fairly late, typically when the tumor has reached the stage of invasive ulcerating cancer. The symptoms include vaginal bleeding after intercourse, vaginal discharge, and dyspareunia. Diffuse pelvic and back pain radiating into the legs may indicate advanced cervical cancer with infiltration of adjacent structures. Large cervical cancers may cause pain or bleeding with urination or passage of stools. Tumorinduced disturbance of lymphatic drainage causes

1.6\ Histopathology

Histologically, approximately 80% of all cervical cancers are of the keratinizing or nonkeratinizing squamous cell type. Adenocarcinoma is the second­ most common histologic type, accounting for about 15% of all cervical cancers (Vizcaino et al. 2000). Although infection with a carcinogenic HPV is a necessary cause of both squamous cell carcinoma and adenocarcinoma, the latter has been found to correlate with recurrent or chronic cervicitis and the intake of estrogen-containing drugs. Stage II and III adenocarcinomas have a slightly more unfavorable prognosis than squamous cell carcinoma (Davidson et al. 1989). A small proportion (about 3%) of adenocarcinomas is of the histologic subtype of highly differentiated mucinous adenocarcinoma. This so-called adenoma malignum has a very poor prognosis because of its early spread into the abdominal cavity and poorer response to chemotherapy or radiotherapy (Kaminski and Norris 1983; Fu et al. 1982). At the same time, its well-differentiated morphology may lead to misinterpretation of its malignancy. MRI depicts a solid tumor containing multiple cysts arising from the endocervical glands and invading the cervical stroma (Doi et al. 1997). This malignant tumor is difficult to differentiate from cystic cervical lesions, which have a similar appearance. The solid tumor portions provide the key to the diagnosis (Li et al. 1999). Adenoma malignum is often seen in patients with Peutz-Jeghers syndrome, which is characterized by pigmentation of the skin and mucous membranes, multiple hamartomas of the gastrointestinal tract, and ovarian tumors (Chen 1986). Among the rarer histologic types of cervical cancer is adenosquamous carcinoma with a proportion of 3% and a poorer prognosis than squamous cell carcinoma and adenocarcinoma (Sheridan et al. 1996). Other types of cervical tumors are

neuroendocrine­ tumors, small-cell tumors, and rhabdomyosarcoma. Small-cell cervical cancer has a poor prognosis due to early metastatic spread. Neuroendocrine tumors account for 0.3% of cervical cancers and show aggressive growth. Accompanying carcinoid syndrome is rare and the clinical symptoms do not differ from those of squamous cell carcinoma (Lea et al. 2002; Koch et al. 1999; Ueda and Yamasaki 1992; Sheridan et al. 1996).

1.7\ Staging

The most widely used staging system for patients with cervical cancer is the Féderation Internationale de Gynécologie et d’Obstétrique (FIGO) classification, introduced before the advent of modern imaging modalities and hence based on solely clinical parameters including physical examination under anesthesia, colposcopy, endocervical curettage, hysteroscopy, cystoscopy, proctoscopy, intravenous urography, barium enema, and radiography of the lungs and skeleton (Pecorelli and Odicino 2003) (Table 1). Findings obtained with MRI, CT, ultrasound, and scintigraphy are not taken into consideration in determining the FIGO stage, which is regarded as a drawback of this staging system. In fact, while the vaginal extent of cervical cancer can be determined with a high degree of accuracy by means of rectovaginal examination and colposcopy, clinical examination has proved to be less accurate in evaluating tumor size (especially in primary endocervical tumors), parametrial and pelvic sidewall invasion, and metastatic spread including nodal status. The concordance between the clinical FIGO staging and surgical staging has been reported to be 85.4%, 77.4%, 35.3%, and 20.5% for stage IB, IB2, IIA, and IIB, respectively (Qin et al. 2009). In addition to the inaccuracies of clinical staging, the evaluation of nodal status, which is a crucial prognostic factor and a determinant in treatment planning, is not considered in the FIGO staging system (Lagasse et al. 1980; LaPolla et al. 1986). Despite these limitations, while the use of modern imaging modalities is expressly encouraged in a revised version of the FIGO staging system implemented in 2009, cross-

Table 1  FIGO staging of cervical cancer (Wiebe et al. 2012)

FIGO

stage Description

ICervical carcinoma strictly confined to the cervix

IICarcinoma extending beyond the uterus but not involving the pelvic wall or lower third of vagina

IIITumor involves the lower third of the vagina and/or extends to the pelvic sidewall and/or causes hydronephrosis/nonfunctioning kidney

sectional imaging techniques such as ultrasound, CT, and MRI remain excluded from the FIGO staging system due to their high cost and lack of availability in the underdeveloped regions of the world, where invasive cervical cancer is most prevalent (Pecorelli et al. 2009).

Important factors for staging according to the FIGO classification comprise tumor size, vaginal