Chapter 25 Cervical Cancer

Harmeet Kaur, M.D. , Claire F. Verschraegen, M.D.

Introduction

Cervical cancer is the third most common gynecologic malignancy in the United States. In 2011, 12,710 new cases and 4290 deaths ¹ are expected in the United States. However, in the underdeveloped world where screening remains underutilized, cervical cancer is the second most common cancer in women, with 275,000 deaths worldwide in 2002.²

In the past 50 years, there has been a steep decline in mortality from cervical cancer that can be attributed to the use of the Papanicolaou (Pap) smear, one of the most effective and widely used screening tests. However, exfoliative cytology obtained with the Pap smear permits early detection of only early squamous cell carcinoma; this has led to a relative increase in the incidence of cervical adenocarcinoma.³

Epidemiology and Risk Factors

In the early half of the 20th century, cervical cancer was the leading cause of cancer-related mortality in women. In the developed world, this has declined significantly to its current position as the eighth leading cause of cancer-related deaths. This success has partly been due to the development of an effective screening test but also to the nature of cervical cancer in which the development of invasive cervical cancer is preceded by a long precancerous phase and the fact that these lesions, once detected, are then accessible and amenable to treatment.

There are numerous predisposing factors in the development of cervical cancer; however, early epidemiologic studies implicated an infectious agent as the most important factor. In 1983, this was identified as human papillomavirus (HPV). Although HPV infection is widespread, the majority of infections are cleared by cell-mediated immunity within 2 years and less than 10% of individuals will develop persistent infection. It is this persistent infection with HPV that plays a central role in the development of cervical cancer and can be identified in almost all cases. There are numerous HPV genotypes, of which HPV-16 and -18 have been determined as the most potent carcinogens. HPV-16 alone accounts for almost 60% of cervical cancers.³ In addition to its causative role in the development of squamous cell carcinoma of the cervix, HPV has also been implicated in the development of cervical adenocarcinoma and neuroendocrine carcinoma.

HPV targets the immature basal cells of the cervical epithelium; mature squamous cells, in contrast, are resistant to infection. In the cervix, there is a significant area of immature squamous metaplastic cells at the squamocolumnar junction. This is also called the transformation zone and anatomically is located where the squamous lining of the ectocervix meets the columnar cells of the endocervix at the level of the external os. This ring of metaplastic tissue is most susceptible to the carcinogenic effects of HPV infection.

In addition, numerous factors function in concert with exposure to high–oncogenic risk HPV infection and an inefficient immune response to increase the risk of developing cervical cancer, including

1. Multiple sexual partners and high-risk sexual partners.

2. History of sexually transmitted diseases (e.g., chlamydia or herpes simplex).

3. Prolonged use of oral contraceptives.

4. Smoking.

5. High parity.

6. Young age at first intercourse.

7. Low socioeconomic status.

8. Immunosuppression.

9. Exposure to diethylstilbestrol.

However, all these risk factors are linked to sexual behavior and infection with HPV and none, except for smoking, has been shown to be an independent risk factor. Smoking, even passive smoking, is associated with an increased risk of squamous carcinoma but not adenocarcinoma. The presence of cigarette carcinogens in the cervical mucus may be the explanation for this observation.

Anatomy and Pathology

Cervix

The female genital tract arises from the müllerian ducts, which are formed by an invagination of the coelomic epithelium. The müllerian ducts give rise to the fallopian tubes, the corpus or body of the uterus, the cervix, and the vagina. This common embryologic origin accounts for the commonality of tumors arising in different parts of the genital system and with tumors arising from the peritoneum.

The uterus has three distinct anatomic parts: the corpus or body, the lower uterine segment, and the cervix. The cervix is divided into suprvaginal and vaginal portions. The vaginal portion, or portio vaginalis, is covered by stratified nonkeratinized squamous epithelium, which also lines the vagina. This meets the columnar epithelium of the endocervix at the external os. This is the squamocolumnar junction, or transformation zone, described previously. In this area, a gradual transformation of columnar to squamous epithelium proceeds through life, leading to a gradual migration of this zone from the level of the external os in young women to a position within the endocervical canal in older women. This has consequences on the location of squamous tumors, which may present as endocervical masses in older women.

Squamous cell carcinoma is by far the most common malignancy of the cervix and accounts for 85% of all tumors in this region. This is followed by adenocarcinoma, which arises from the columner epithelium of the endocervical canal and accounts for 10% of cervical tumors. The remaining 5% is composed of uncommon pathologies such as neuroendocrine and adenosquamous tumors.

The gross morphologic appearance of invasive squamous tumors is as either infiltrative or fungating masses that generally arise at the level of the external os. Adenocarcinomas, in contrast, arise within the lumen of the cervical canal; consequently, they are difficult to evaluate on physical examination. This makes magnetic resonance imaging (MRI) particularly important in the assessment of these tumors.

As previously mentioned, squamous carcinoma is preceded by a long premalignant phase of epithelial dysplasia originating in the squamocolumnar junction. Cervical dysplasia is classified depending upon severity as cervical intraepithelial dysplasia I to III (CIN I-III). This classification has been recently simplified into a two-tiered system because this reflects clinical management. CIN I is now called low-grade squamous intraepithelial dysplasia (LSIL), and CIN II and III are high-grade squamous intraepithelial dysplasia (HSIL). The majority of LSILs will regress, with only 10% progressing to HSIL. Similarly the majority of HSILs, which most frequently arise from LSILs, will also disappear and only 10% will develop into invasive squamous carcinoma. In the United States, approximately 1 million of these precancerous lesions are detected every year, but only about 11,000 cases of invasive cancer are diagnosed. This implies that, with screening, early cancers are diagnosed and eradicated, many of which would have progressed to invasive disease.

It is important to note that, in spite of its effectiveness, Pap smears have a false-negative rate of 15% to 20%; hence, the need for repeat screening, particularly in high-risk patients. A number of techniques such as computerized screening, liquid-based sampling technique, and HPV typing are being used to improve accuracy. An additional limitation of the Pap smear is that it is ineffective in the detection of adenocarcinoma, adenosquamous, and neuroendocrine tumors. Consequently, these tumors generally present with more advanced disease.

Pelvic Anatomy

A basic overview of pelvic anatomy is important for staging cervical cancer because an understanding of pelvic ligaments, vessels, peritoneal reflections, and pelvic lymph node stations is vital in evaluating cross-sectional computed tomography (CT) and MRI.⁴

The important ligaments from the imaging perspective that are found in relation to the uterus, cervix, and ovaries include the broad ligament, round ligaments, uterosacral ligaments, cardinal ligaments, and suspensory ligament of the ovary (Figure 25-1).

Figure 25-1 Uterine anatomy.

The broad ligament is a peritoneal reflection that extends from the uterus to the pelvic sidewall. It contains the fallopian tubes along the upper margin; the cardinal ligament runs in the base of the broad ligament. It contains fat, connective tissue, the uterine and ovarian vessels, lymphatics, and the ovarian and round ligament. It is difficult to see except in the presence of ascites. The round ligament runs from the anterior wall of the uterus through the inguinal canal to the labia and is easy to see on CT. The cardinal ligament is an important structure that runs from the cervix and upper vagina to the obturator internus muscle. The uterine arteries run along the superior aspect of this ligament and help define this structure. As these arteries course from their origin from the internal iliac arteries to the edge of the uterus, they arch over the ureters creating the “arc sign,” which can frequently be seen on CT. The uterosacral ligament arises from the cervix and upper vagina to arc on either side of the rectum to the S2-S3 segments of the sacrum. This structure is thickened after radiation therapy. The suspensory ligament of the ovary carries the gonadal vessels to the ovary and is defined by the course of these vessels on cross-sectional imaging.

The main vascular supply to the uterus is the uterine arteries that arise from the internal iliac vessels, run along the superior aspect of the cardinal ligament, and then ascend on either side of the uterus to trifurcate and supply the fallopian tubes, fundus of the uterus, and ovaries (Figure 25-2). The ovarian arteries arise from the aorta below the renal arteries; the vaginal arteries arise from the internal iliac arteries.

Figure 25-2 Vascular supply to the uterus.

An important goal of imaging is to define the presence or absence of parametrial invasion. Consequently, the most important anatomic structures are those that assist in this evaluation. On CT and MRI, these structures are the ureters and the uterine vessels as they pass in the base of the broad ligament on either side of the supravaginal cervix. The ureters and uterine artery are in close proximity to either side of the supravaginal cervix, and abutment of the margins of ureters or uterine arteries is a confirmatory feature of parametrial invasion. As the extent of parametrial tumor progresses, ureters will get entrapped leading, to hydronephrosis. MRI has the added benefit of definition of the cervical stroma, which substantially increases the accuracy of this modality over CT for parametrial invasion.

Pelvic Nodal Anatomy

Disease spread to pelvic nodes is the most common pathway of tumor dissemination from the cervix. An understanding of the pathways of spread is essential for image analysis because these are the nodes that should be most closely scrutinized when evaluating cross-sectional imaging studies (Figure 25-3).

Figure 25-3 Pelvic nodes.

The nodal group most commonly first involved by tumor spread from pelvic tumors is the perivisceral nodes, which in the instance of cervical cancer are the parametrial nodes. This is followed by spread to pelvic sidewall nodes. Lymphatic spread from cervical tumors can spread to the pelvic nodes by three routes: (1) the lateral pathway of spread toward external iliac nodes, (2) the hypogastric route toward nodes along the internal iliac vessels, and (3) the posterior route, where lymphatics course along the uterosacral ligament to nodes along lateral sacral vessels and nodes anterior to the sacral promontory.⁵ The nodes along the external iliac vessels are subclassified into middle, medial, and lateral groups. The lateral chain nodes are located, as the name implies, lateral to the vessels; the middle chain nodes are between the external iliac artery and vein; and the medial chain nodes are located posterior and medial to the artery and vein. The nodes medial to the external iliac arteries are the group most commonly involved by metastatic spread from cervical cancer. These nodes are located in close proximity to nodes along the obturator vessels and are frequently grouped together with obturator nodes, although there is some controversy in this regard (Figure 25-4). All the pelvic nodal chains drain to the common iliac nodes. The common iliac nodes are also classified similar to external iliac nodes into middle, lateral, and medial subgroups. The middle subgroup is located posterior to the common iliac vein in the lumbosacral fossa, which is bordered posteriorly by the sacral vertebral body.⁶ This node is in close proximity to the L5 nerve root and can impinge on this root when enlarged, causing back pain (Figure 25-5). Spread from common iliac nodes is most commonly to the para-aortic nodes.

Figure 25-4 Bilateral obturator adenopathy (arrows) is identified on the axial T2-weighted fast spin echo magnetic resonance imaging (MRI) study. These nodes are seen to be fluoro-2-deoxy-D-glucose (FDG)-avid on the fused positron-emission tomography/computed tomography (PET/CT) images.

Figure 25-5 Common iliac adenopathy shows enlarged nodes involving the medial, middle, and lateral radial groups on the right (arrowheads). The right L5 nerve (arrow) root is in close proximity to the lateral chain nodes.

Key Points Anatomy, pathology, and epidemiology

• Persistent infection with HPV-16 and -18 is the most important risk factor in the development of cervical cancer.

• Cervical cancer has a long premalignant phase and, therefore, is accessible to early intervention and screening.

• Squamous carcinoma accounts for 85% of cervical tumors and arises from the zone located at the level of the external os and may present as exophytic or infiltrative masses.

• The uterine arteries and ureters as they course on the surface of the cardinal ligament define the level of the supravaginal cervix and site of parametrial invasion.

Clinical Presentation

In early cervical cancer, there may be no clinical symptoms as the disease progresses. Common clinical complaints are vaginal discharge, postcoital bleeding, irregular vaginal bleeding, or postmenopausal bleeding. In more advanced disease, lower abdominal or back pain or weight loss may also develop.

Patterns of Tumor Spread

The most common pathways of tumor spread in cervical cancer are direct invasion of contiguous pelvic structures and through lymphatics to lymph nodes; hematogenous spread is an uncommon pathway.

Direct spread occurs from penetration through the cervical stroma of the supracervical cervix into the parametrium, where the ureters and uterine arteries are located.

Lymph node spread in cervical cancer generally occurs in a sequential fashion with parametrial nodal involvement followed by external or internal iliac adenopathy, common iliac adenopathy, and then para-aortic adenopathy. It is very uncommon for para-aortic nodes to be involved in the absence of pelvic nodal disease.

As with all tumors, it is important to define regional and nonregional nodal groups; involvement of the latter upstages the tumor to stage IV because these nodes are viewed as M1 nodes. In the case of cervical cancer, parametrial, internal iliac, obturator, external iliac, common iliac, presacral, and lateral sacral are viewed as regional nodes, whereas inguinal, para-aortic, mediastinal, and supraclavicular are viewed as nonregional nodes, and consequently, qualify as metastatic disease.⁶

Key Points Patterns of tumor spread

• The most common pathways of tumor spread are direct invasion through the cervical stroma into the parametrium and adjacent pelvic structures and lymphatic spread.

• Nodal spread in cervical cancer occurs in a stepwise progressive manner from the parametrial to external, presacral, or internal iliac nodes followed by common iliac and para-aortic nodes.

• Para-aortic and inguinal adenopathy constitute nonregional nodes and, consequently, metastatic disease.

Staging

Unlike most other tumors, the staging of cervical cancer is primarily clinical, using the classification by the Federation of Gynecology and Obstetrics (FIGO) committee. This is because, in most countries where this disease is prevalent, elaborate cross-sectional staging techniques such as MRI, CT, and positron-emission tomography (PET)/CT are not available. Consequently, to maintain some uniformity between clinical trials across nations, the basis for initial staging is the clinical stage. The classification has undergone numerous revisions. This chapter references the most recent 2009 revision (Figure 25-6). Some important facts about the FIGO staging is that it applies only to squamous carcinoma; the clinical stage is determined prior to the start of therapy and cannot be changed because of subsequent findings once treatment is started. For evaluation of the T (tumor) stage, the following examinations are recommended: physical examination, preferably as an examination under anesthesia; colposcopy; cystoscopy; proctoscopy; intravenous urography; and chest x-ray. Suspected involvement of the rectal or bladder mucosa must be confirmed by biopsy. The tumor size plays an important prognostic role; consequently, subgroups have been created in both stages I and II for tumors less than 4 cm (T1a&b1 and T2a1) or greater than 4 cm (T1b2 and T2a2) in the tumor-node-metastasis (TNM) and FIGO classifications. It is noted that the definition of T categories corresponds to stages accepted by the FIGO classification (Table 25-1).7 A limitation of the clinical system of staging is that, compared with surgical staging, it can be erroneous in up to 32% of patients with stage IB and 65% of patients with stage III disease.^8,⁹

Figure 25-6 Stages I-IV of cervical cancer.

Table 25-1 TNM & FIGO Staging of Cervical Cancer

TNM CATEGORIES	FIGO STAGES
Primary Tumor (T)
TX		Primary tumor cannot be assessed
T0		No evidence of primary tumor
Tis^*		Carcinoma in situ (preinvasive carcinoma)
T1	I	Cervical carcinoma confined to uterus (extension to corpus should be disregarded)
T1a^†	IA	Invasive carcinoma diagnosed only by microscopy. Stromal invasion with a maximum depth of 5.0 mm measured from the base of the epithelium and a horizontal spread of 7.0 mm or less. Vascular space involvement, venous or lymphatic, does not affect classification
T1a1	IA1	Measured stromal invasion 3.0 mm or less in depth and 7.0 mm or less in horizontal spread
T1a2	IA2	Measured stromal invasion more than 3.0 mm and not more than 5.0 mm with a horizontal spread 7.0 mm or less
T1b	IB	Clinically visible lesion confined to the cervix or microscopic lesion greater than T1a/IA2
T1b1	IB1	Clinically visible lesion 4.0 cm or less in greatest dimension
T1b2	IB2	Clinically visible lesion more than 4.0 cm in greatest dimension
T2	II	Cervical carcinoma invades beyond uterus but not to pelvic wall or to lower third of vagina
T2a	IIA	Tumor without parametrial invasion
T2a1	IIA1	Clinically visible lesion 4.0 cm or less in greatest dimension
T2a2	IIA2	Clinically visible lesion more than 4.0 cm in greatest dimension
T2b	IIB	Tumor with parametrial invasion
T3	III	Tumor extends to pelvic wall and/or involves lower third of vagina, and/or causes hydronephrosis or nonfunctioning kidney
T3a	IIIA	Tumor involves lower third of vagina, no extension to pelvic wall
T3b	IIIB	Tumor extends to pelvic wall and/or causes hydronephrosis or nonfunctioning kidney
T4	IVA IV any T/any N/M1 disease	Tumor invades mucosa of bladder or rectum, and/or extends beyond true pelvis (bullous edema is not sufficient to classify a tumor as T4)