Cancer of the uterine cervix

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CHAPTER 39 Cancer of the uterine cervix

Kavita Singh, Janos Balega

Epidemiology

Cervical cancer is the most common gynaecological malignancy in the world with an estimated 493,000 new cases diagnosed each year (Ferlay et al 2004). It accounts for nearly 10% of all cancers in women. Although the incidence of cervical cancer has decreased in industrialized countries in the past 20 years, it still remains a major problem in the developing world. In most parts of Africa, South-Central Asia and Central America, cervical cancer accounts for 7–13% of all newly diagnosed cancers, with an incidence of 30–40 new cases per 100,000 population (Cancer Research UK, 2005).

In the UK, 2800 patients are diagnosed with cervical cancer per year, which accounts for approximately 2% of all female cancer cases, and 950 patients die from the disease (Cancer Research UK, 2005). With the introduction of the cervical screening programme in the UK, the incidence of cervical cancer has decreased from 16/100,000 in 1985 to 8/100,000 in 2005, while the incidence of carcinoma in situ has risen because of early detection with screening (Cancer Research UK, 2005). Carcinoma in situ is most common in women aged 35–39 years, while the incidence of cervical cancer is highest in women aged 30–34 years (17/100,000). The distribution of cervical cancer is bimodal, with a second peak reached in women aged over 85 years (14/100,000) (Cancer Research UK, 2005). Only 30% of cervical cancers are detected by screening, and the majority of cases occur in women who have never had a smear test or who have not been regular participants in the screening programme.

Aetiology

Epidemiological studies have long indicated a positive correlation between sexual activity and cervical cancer (Schiffman and Brinton 1995). Promiscuity, a sexual partner with promiscuous sexual behaviour and early age at first sexual intercourse have all been associated with a high risk of cervical cancer. It has been well demonstrated that human papilloma virus (HPV) infection is the major and probably a necessary causal factor, enhanced by several cofactors for both squamous cell carcinoma and adenocarcinoma of the cervix (Muñoz et al 1992, Schiffman et al 1993, Bosch et al 2002). HPV viral particles have been detected in almost all cases of cervical cancer (99.7%) (Walboomers and Meijer 1997, Franco et al 1999, Walboomers et al 1999).

Human papilloma virus

HPV is a double-stranded DNA virus that contains eight genes: six early (E1, E2, E4, E5, E6, E7) and two late (L1, L2). The early genes are expressed when the virus enters the host cell and encodes those proteins that regulate viral replication and the interaction with the host cell. The late genes code for capsid proteins.

E6 and E7 encode oncoproteins. After the virus enters the host cell, E6 and E7 integrate into the host DNA and encode for oncoproteins. The E6 oncoprotein binds to and destabilizes the host’s p53 tumour suppressor gene, resulting in a shorter half-life and inactivation. The E7 oncoprotein binds to tumour suppressor genes pRB, p21 and p27, resulting in increased cell proliferation.

To date, more than 200 subtypes of HPV have been identified. According to oncogenic potential, HPVs can be classified as low-risk or high-risk types (Table 39.1) (Duenas-Gonzalez et al 2005, Smith et al 2007). Approximately 75% of cervical cancers are related to HPV 16 and 18 in Europe, and 90% of genital warts are caused by HPV 6 and 11 (Smith 2003). However, the distribution of HPV subtypes varies in other parts of the world (Smith et al 2007).

Table 39.1 Risk groups of human papilloma virus (HPV)

High-risk HPV	16, 18, 31, 33, 35, 45, 51, 52, 58, 59, 68, 73, 82
Low-risk HPV	6, 11, 40, 42, 43, 44, 54, 61, 70, 72, 81

It is estimated that nearly 80% of sexually active women will acquire an HPV infection during their lifetime, while oncogenic subtypes are identified in 15% of the population (Brown et al 2005, Dunne et al 2007). Ninety percent of HPV infections will be eradicated by the host immune system, and only a minority of women will develop preinvasive disease or cancer (Pagliusi and Teresa Aguado 2004). The prevalence of HPV infection decreases with age, from approximately 20% in women aged 20–25 years to approximately 5% in women aged 50 years (Woodman et al 2001).

Cofactors

Cigarette smoking

Cigarette smoking has been linked with a higher risk of cervical cancer and has been demonstrated to be an independent risk factor (Winkelstein 1990, Kapeu et al 2009). High concentrations of nicotine metabolites have been detected in cervical mucus, and their molecular interaction with fragile histidine triad (FHIT) tumour suppressor gene has been investigated (Schiffman et al 1987, Holschneider et al 2005). The loss of function of FHIT plays an important role in early carcinogenesis (Pichiorri et al 2008). In comparison with non-smokers, smokers have impaired immune responses in the cervical epithelium and produce reduced levels of HPV 16/18 antibodies (Simen-Kapeu et al 2008).

A recent meta-analysis confirmed that smoking is an independent risk factor for squamous cell cervical cancer, but failed to demonstrate the same for adenocarcinoma (Berrington de González et al 2004).

Oral contraceptives

The association between long-term oral contraceptive (OC) use and cervical cancer is unclear. Recent analyses have shown an increased risk (relative risk 1.3–1.9) of cervical cancer amongst OC users (Smith 2003, Appleby et al 2007, Hannaford et al 2007). In contrast, others have reported that sexual behaviour differs between OC users and non-users, and that OC use is not an independent risk factor (Miller et al 2004, Syrjänen et al 2006).

Immunodeficiency

It has been observed that patients with immunodeficiency disorders, those on immunosuppressive therapy and those with human immunodeficiency virus (HIV) infection are at higher risk of developing anogenital HPV-related premalignant changes and cancers. Cervical cancer is an acquired-immunodeficiency-syndrome-defining disease. One meta-analysis estimated a six-fold increased risk of developing cervical cancer for patients with HIV infection, and a two-fold increased risk for those with previous transplant surgery (Grulich et al 2007).

HPV vaccination

Cervical cytology

Cervical cytology is an effective secondary preventive measure. Since the identification of HPV as a causative factor for cervical cancer, laboratory research has focused on developing a primary preventive method, i.e. a vaccine against HPV.

HPV-virus-like particles have been developed that have similar antigenic properties to the virus itself, and therefore provoke a host immune response.

Two types of HPV vaccine have been developed: the bivalent Cervarix targeting HPV 16 and 18, and the quadrivalent Gardasil for HPV 6, 11, 16 and 18. The efficacy of Gardasil and Cervarix has been demonstrated in large, prospective, randomized trials (FUTURE II and PATRICIA) (FUTURE II Study Group 2007, Paavonen et al 2007). The vaccines are prophylactic and are not effective in patients with existing HPV infection. There is some cross-protection against other high-risk types of HPV.

Vaccination programme in the UK

The routine vaccination of 12–13-year-old girls with Cervarix has been introduced in the UK, and catch-up vaccination is available until 18 years of age. Three 0.5 ml injections are given at 0, 2 and 6 months. Immunity has been demonstrated for at least 5 years and long-term follow-up studies are ongoing.

Natural History and Spreading Pattern of Cervical Cancer

Cervical cancers can arise from the ectocervix or endocervix. Most ectocervical cancers are squamous in histology, and endocervical cancers arise from squamous and columnar epithelium. All cervical cancers are preceded by a preneoplastic stage (cervical intraepithelial neoplasia and cervical glandular intraepithelial neoplasia). Cervical cancers may present as an exophytic growth or an endophytic expansion without any visible tumour on the surface of the cervix.

The pattern of spread may be direct, lymphatic or haematogenous. The cancer can spread directly to the parametria, vagina, corpus, bladder and rectum. Primary sites of lymphatic spread are the external and internal iliac and obturator lymph nodes, while secondary sites are the presacral, common iliac and para-aortic lymph nodes. The most common sites of haematogenous metastases are lungs and liver.

Clinical Presentation

Patients with cervical cancer may be symptomatic or asymptomatic. Symptoms associated with cervical cancer are often non-specific, such as postcoital bleeding, intermenstrual bleeding, postmenopausal bleeding, excessive foul-smelling vaginal discharge and pelvic pain. Patients with locally advanced cancer can present with loin pain secondary to obstructive uropathy; sciatic pain due to compression of pelvic nerves; and fistula formation between the rectum, vagina and bladder. Renal failure is regarded as the most common cause of death by cervical cancer.

The positive predictive value of postcoital and intermenstrual bleeding for the diagnosis of cervical cancer in younger women is very low (Shapley et al 2006). Only 2% of patients with postcoital bleeding will be diagnosed with cervical cancer (Shapley et al 2006).

Asymptomatic patients are usually referred with either abnormal appearance of the cervix, a suspicious smear or an incidental discovery of cervical cancer on loop biopsy performed for treatment of intraepithelial neoplasia.

Diagnosis and Staging

Clinical examination

Apart from the routine medical history, special emphasis must be placed on the patient’s desire for future fertility. Detailed examination is essential, including physical examination to exclude any obvious peripheral lymphadenopathy, speculum examination to assess the size of tumour and vaginal extension, and a rectovaginal examination to assess the size of cervical tumour and its extension to the parametria, vaginal vault and rectal mucosa. In cases of suspected bladder and bowel involvement, an examination under anaesthesia with cystoscopy and rectosigmoidoscopy is required, and biopsies are obtained for histological confirmation.

Pathology review

All patients referred with cervical cancer need to have their histology reviewed by a gynaecological oncopathologist. Information is obtained regarding the tumour histological type, differentiation, size (breadth × horizontal width × depth of invasion), pattern of invasion (uni- or multifocal, pushing or spreading), and presence or absence of lymphovascular space invasion.

Imaging in cervical cancer

Although cancer of the uterine cervix is staged clinically worldwide, a more precise assessment of the extent of cancer by cross-sectional imaging results in more tailored management. Magnetic resonance imaging (MRI) of the abdomen and pelvis is performed to assess the size and volume of tumour, the presence of parametrial invasion by analysing the integrity of the high-intensity stromal ring around the tumour, and to exclude bladder or rectum involvement. MRI is more accurate than computed tomography (CT) for assessment of local spread, and both modalities are superior to clinical examination.

Positron emission tomography (PET) is a functional scan that assesses the increased uptake of fluorodeoxyglucose (FDG). Organs with high metabolic activity (liver, brain, neoplastic tissue) have high FDG uptake. Addition of CT to PET (PET–CT) provides improved assessment of tumour localization. PET–CT has been used to assess para-aortic nodal status to facilitate planning of radiotherapy fields (Figure 39.1F) (Grigsby et al 2001). A further role of PET–CT is to assess the response to primary chemoradiotherapy, as well as early detection of cancer recurrences (Figure 39.2D).

Figure 39.1 Assessment of cervical cancer with magnetic resonance imaging. (A) Stage IB1 cervical cancer in the posterior lip of cervix (arrow). (B) Stage IB2 cervical cancer with bulky tumour replacing the cervix (arrow). (C) Stage IIB cervical cancer with right parametrial invasion. Note the interruption of the high-signal-intensity ring around the cervix on the right side (arrow). (D) Stage IIIB cervical cancer causing right hydronephrosis (arrow). (E) Stage IVA cervical cancer with fistula formation between the bladder and vagina (arrow). (F) Stage IVB cervical cancer with mediastinal lymphadenopathy (star). Note the increased uptake of left common iliac lymph nodes (arrow).

Figure 39.2 Imaging follow-up after primary chemoradiotherapy for stage IIB cervical cancer. (A) Pretreatment magnetic resonance imaging (MRI) scan. (B) Three months post chemoradiation. (C) Six months post treatment MRI scan. (D) Six months post treatment positron emission tomography–computed tomography scan with no uptake of fluorodeoxyglucose in the cervix. Note the increased uptake in the bladder.

Laparoscopic para-aortic lymph node sampling

Laparoscopic para-aortic lymph node sampling has been performed to assess the para-aortic lymph nodes; however, the only prospective randomized study failed to confirm therapeutic benefit (Lai et al 2003). The detection of micrometastasis in the para-aortic nodes has been used to modify radiation treatment fields (Leblanc et al 2007). Superiority of lymphadenectomy over PET–CT in assessment of the para-aortic nodes has not been established.

Staging

The International Federation of Obstetricians and Gynecologists (FIGO) staging of cervical cancer is based on clinical findings and, in the early stages, on the microscopic extent of the disease, and is not changed by intraoperative findings or the postoperative histological result (Table 39.2). When doubt exists regarding the stage of a particular cancer, the earlier stage should be chosen.

Table 39.2 Revised FIGO staging of cervical cancer (2009)

Stage I	The carcinoma is strictly confined to the cervix (extension to the corpus would be disregarded)
IA	Invasive carcinoma which can be diagnosed only by microscopy, with deepest invasion ≤5.0 mm and largest extension ≤7.0 mm
IA1	Measured stromal invasion of ≤3.0 mm in depth and horizontal extension of ≤7.0 mm
IA2	Measured stromal invasion of >3.0 mm and not >5.0 mm with an extension of not >7.0 mm
IB	Clinically visible lesions limited to the cervix uteri or preclinical cancers greater than stage IA*
IB1	Clinically visible lesion ≤4.0 cm in greatest dimension
IB2	Clinically visible lesion >4.0 cm in greatest dimension
Stage II	Cervical carcinoma invades beyond the uterus, but not to the pelvic wall or to the lower third of the vagina
IIA	Without parametrial invasion
IIAl	Clinically visible lesion ≤4.0 cm in greatest dimension
IIA2	Clinically visible lesion >4.0 cm in greatest dimension
IIB	With obvious parametrial invasion
Stage III	The tumour extends to the pelvic wall and/or involves lower third of the vagina and/or causes hydronephrosis or non-functioning kidney^§
IIIA	Tumour involves lower third of the vagina, with no extension to the pelvic wall
IIIB	Extension to the pelvic wall and/or hydronephrosis or non-functioning kidney
Stage IV	The carcinoma has extended beyond the true pelvis or has involved (biopsy proven) the mucosa of the bladder or rectum. A bullous oedema, 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

* All macroscopically visible lesions, even with superficial invasion, are allotted to 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 >7.0 mm. Depth of invasion should not be >5.0 mm taken from the base of the epithelium of the original tissue — superficial or glandular. The depth of invasion should always be reported in mm, even in those cases with ‘early (minimal) stromal invasion’ (∼1.0 mm). The involvement of vascular/lymphatic spaces should not change the stage allotment.

^§ On rectal examination, there is no cancer-free space between the tumour and the pelvic wall. All cases with hydronephrosis or non-functioning kidney are included, unless they are known to be due to another cause.

Surgical staging in cervical cancer is an issue that continues to generate discussion. Should lymph node status influence the staging? Should further substages be included? Should the histological findings and cross-sectional imaging influence the process of staging? A consensus statement from the International Gynecological Cancer Society meeting in 2006 reported as follows (Odicino et al 2007).

• Surgical staging is not practical, feasible or beneficial in the majority of cervical cancer patients, hence it is not recommended for staging. Nearly 80% of cervical cancer patients are diagnosed in the developing world, and the majority are diagnosed in late stages and are not suitable for surgical staging. Therefore, cervical cancer should remain a clinically staged disease.

• Pathological extent and other pathological findings such as lymphovascular space invasion (LVSI) should be reported but not included in the staging of cervical cancer.

• Use of imaging techniques such as MRI, if available, is encouraged but not mandatory.

• Clinical investigations, including examination under anaesthesia, cystoscopy or sigmoidoscopy, which were previously mandatory for staging purposes are now optional and adopted for selected cases.

• The following modifications in cervical cancer staging would be adopted at the next FIGO meeting in 2009:

Stage 0 will be erased, as it is not an invasive disease.

Stage IIA: should be subgrouped similar to stage IB based on tumour size as stage IIA1 with tumour size less than 4 cm with involvement of up to two-thirds of the upper vagina, and stage IIA2 with tumour size greater than 4 cm with involvement of up to two-thirds of the upper vagina.

Stage IIB and IIIB: inclusion of unilateral or bilateral parametrial involvement. Stage IIB1 and IIIB1 indicate unilateral parametrial involvement, and stage IIB2 and IIIB2 indicate bilateral parametrial involvement.

Histology

The vast majority of cervical cancers (75%) are squamous cell carcinomas. The clinical appearance is usually exophytic, but it is not uncommon to have an endophytic tumour with a normal ectocervix. Histologically, three types of squamous cell carcinoma can be distinguished: large cell keratinizing, large cell non-keratinizing and small cell squamous carcinoma.

Adenocarcinoma is the second most common histological type and represents 20% of cervical cancers. The proportion of adenocarcinomas compared with squamous cell carcinomas has increased significantly over the past three decades. The cause of this change is two-fold: relative, due to the gradual decrease in incidence of squamous cell carcinoma following the introduction of the cervical screening programme; and absolute, probably due to factors such as increased use of OCs (Ursin et al 1994, Smith et al 2000, Sasieni and Adams 2001). The gross appearance of adenocarcinomas is similar to squamous lesions; however, nearly 15% of patients present with clinically non-apparent lesions due to the endophytic expansion of the cancer (barrel-shaped cervix).

Microscopically, several subtypes are distinguished. The most common types are the endocervical (mucinous), intestinal and endometrioid variants.

It is a common clinical dilemma to distinguish between endocervical cancer with extension to the uterus and endometrial cancer of isthmic origin involving the cervical stroma. Clinical impression, cross-sectional imaging (MRI scan) and immunohistochemistry studies using p16 antibody can be of help to determine the origin of the cancer. The p16 protein is mainly expressed by HPV-related cancer cells.

Adenosquamous carcinomas consist of both squamous and glandular elements. A dedifferentiated form of adenosquamous carcinoma is the glassy cell carcinoma, which tends to occur in young patients and has a particularly aggressive clinical behaviour with poor outcome. Microscopically, it is characterized by large cells with glassy cytoplasm.

Neuroendocrine cervical carcinomas are rare histological subtypes, accounting for less than 5% of cervical cancers. They are characterized by highly aggressive clinical behaviour, manifesting as early nodal and distant diseases in more than half of patients. This results in poor survival despite multimodal treatment. Neuroendocrine cervical carcinomas are similar to the neuroendocrine cancers of the lung, both clinically and histologically. There are four subgroups: classical carcinoid, atypical carcinoid tumour, neuroendocrine large cell carcinoma and neuroendocrine small cell (oat cell) carcinoma (Albores-Saavedra et al 1997).

Clear cell carcinomas of the cervix are rare and have been linked with diethylstilboestrol exposure in utero. They usually present with large, exophytic tumours and are chemoradioresistant. Surgery is therefore the cornerstone of management, followed by chemoradiotherapy.

Treatment of Cervical Cancer

Surgical management

The method of surgical treatment of cervical cancer depends on the stage of disease, tumour volume, histological features, patient’s desire for future fertility and performance status. Treatment options for different stages of cervical cancer are shown in Table 39.3. The Wertheim-Meigs radical hysterectomy with pelvic lymphadenectomy has been the standard treatment for over a century in patients with stage IA2–IIA cervical cancer. Critical analysis of the data on the role of parametrectomy and pelvic lymphadenectomy has changed the practice significantly, and narrowed the indication for the radical operation. In stage IA2 and low-volume stage IB1 (<500 m³) cervical cancer, the risk of parametrial involvement is low (<2%); therefore, simple hysterectomy is recommended (Stegeman et al 2007). Novel developments in surgical technique, such as fertility-sparing surgery (trachelectomy), laparoscopic radical hysterectomy, pelvic lymphadenectomy and para-aortic lymphadenectomy, have been developed and are practised increasingly. Sentinel node biopsy in cervical cancer is also being explored (Levenback et al 2002).

Table 39.3 Management of cervical cancer

Stage	Treatment	LND
IA1	Cone biopsy/simple trachelectomy/simple hysterectomy	No
IA2	Cone biopsy/simple trachelectomy/simple hysterectomy	+/− (variable practice)
IA1/IA2 + LVSI	Cone biopsy/simple trachelectomy/simple hysterectomy	+
IB1: low volume (<500 mm³)	Simple trachelectomy/simple hysterectomy	+
IB1: <2 cm diameter	Radical trachelectomy/radical hysterectomy	+
IB1: 2–4 cm diameter	Radical hysterectomy	+
IB2/IIA	Chemoradiation/radical hysterectomy	+
IIB–IVA	Chemoradiation/palliative surgery
IVB	Chemotherapy +/− palliative radiotherapy