Cervical Dysplasia and Cancer

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Chapter 38 Cervical Dysplasia and Cancer

Cervical cancer kills about 250,000 women a year worldwide and is the most common cause of death from cancer in women. About 80% of new cases reported each year occur in developing countries. In developed countries, regular screening with Papanicolaou (Pap) smears has markedly decreased the incidence of the disease, and most cases now occur in women who have not had regular Pap smears. In the United States, cervical cancer now ranks only 13th among cancers in women, with 11,150 new cases expected in 2007, and 3,670 deaths.

Studies have identified persistent infection with a high-risk human papillomavirus (HPV) as the cause of virtually all cervical cancers. Recent randomized clinical trials of prophylactic HPV vaccines have demonstrated dramatic efficiency in preventing HPV 16 and 18 infections as well as precancerous cervical lesions. Although it will take several decades to demonstrate a decreased incidence of invasive cervical cancer, with widespread use, HPV vaccination has the potential to markedly decrease the incidence of cervical cancer in future generations.

Etiology and Epidemiology

There are 15 high-risk HPV types, and types 16 and 18 are responsible for 70% of cervical cancers. Types 6 and 11 have been associated with cervical condylomas and low-grade cervical intraepithelial neoplasia (CIN).

The adolescent cervix is believed to be more susceptible to carcinogenic stimuli because of the active process of squamous metaplasia, which occurs within the transformation zone during periods of endocrine change. This squamous metaplasia is normally a physiologic process, but under the influence of the HPV, cellular alterations occur that result in an atypical transformation zone. These atypical changes initiate CIN, which is the preinvasive phase of cervical cancer.

Cervical cancer and its precursors have been associated with several epidemiologic variables (Box 38-1). These risk factors basically increase the likelihood of exposure to a high-risk HPV type.

BOX 38-1 Risk Factors for Cervical Cancer

• Young age at first coitus (<20 yr)

• Multiple sexual partners

• Sexual partner with multiple sexual partners

• Young age at first pregnancy

• High parity

• Lower socioeconomic status

• Smoking

The disease is relatively rare before 20 years of age, and the mean age is about 47 years.

Primary Prevention

Two prophylactic vaccines are presently available. The quadrivalent vaccine Gardasil, which is manufactured by Merck (Whitehouse Station, NJ) and protects against HPV types 6, 11, 16, and 18, was approved by the U.S. Food and Drug Administration in June 2006 for females aged 9 to 26 years. The bivalent vaccine Cervarix, which is manufactured by GlaxoSmithKline (Philadelphia, Pa) and protects against HPV types 16 and 18, was approved by the Australian Therapeutic Goods Administration in April 2007 for use in females aged 9 to 45 years.

HPV vaccination is most effective if performed before the onset of sexual activity. Vaccination is still recommended after commencement of sexual activity, and even after prior abnormal cytology or CIN, but it is likely to be less effective after HPV exposure. Australia was the first country in the world to introduce HPV vaccination into the National Immunization Program. In 2007, vaccination with Gardasil was introduced for all schoolgirls aged 12 years.

Screening of Asymptomatic Women

The American College of Obstetricians and Gynecologists has recommended that all women undergo an annual physical examination, including a Pap smear, within 3 years of sexual intercourse, or by age 21 years. Annual screening should occur until age 30 years. If there have been three consecutive negative tests, screening may occur every 2 or 3 years at the discretion of the treating physician. Both the endocervical canal and the ectocervix should be sampled when taking the Pap smear.

The false-negative rate for conventional Pap smears for high-grade intraepithelial lesions is generally reported to be about 20%, but it is higher for glandular lesions and for invasive cancers.

New technologies have been developed to decrease the false-negative rate. ThinPrep (Cytyc, Marlborough, Mass) and SurePath (BD Diagnostics–TriPath, Franklin Lakes, NJ) are automated liquid-based slide-preparation systems. With liquid-based cytology, the spatula or brush taking the smear is placed into a fixative solution, instead of smearing the cells directly onto a glass slide. Blood, mucus, and inflammatory cells are eliminated, and a monolayer smear is then automatically prepared by a machine. BD Focal Point (BD Diagnostics–TriPath) and ThinPrep Imager (Cytyc) are computerized image processors that select the most abnormal cells on a slide. They increase the sensitivity of slide reading, while decreasing the time needed by the cytotechnician to read each slide, thereby improving the cost-effectiveness of screening.

The cost-effectiveness of HPV DNA testing as a primary screening test, either alone or in combination with cervical cytology, in women aged 30 years or older, is currently under investigation. HPV DNA testing is much more sensitive than cervical cytology, but less specific.

Women should have regular cervical screening even if they have received the HPV vaccine because the vaccine does not protect against all high-risk HPV viral types.

Cervical Topography

During early embryonic development, the cervix and upper vagina are covered with columnar epithelium. During intrauterine development, the columnar epithelium of the vagina is progressively replaced by squamous epithelium. At birth, the vagina is usually covered with squamous epithelium, and the columnar epithelium is limited to the endocervix and the central portion of the ectocervix. In about 4% of normal female infants and about 30% of those exposed to diethylstilbestrol in utero, the columnar epithelium extends onto the vaginal fornices. Macroscopically, the columnar epithelium has a red appearance because it is only a single cell layer thick, allowing blood vessels in the underlying stroma to show through it.

The embryologic squamous and columnar epithelia are designated the original and native squamous and columnar epithelia, respectively. The junction between them on the ectocervix is called the original squamocolumnar junction.

Throughout life, but particularly during adolescence and a woman’s first pregnancy, metaplastic squamous epithelium covers the columnar epithelium so that a new squamocolumnar junction is formed more proximally. This junction moves progressively closer to the external os and then up the endocervical canal. The transformation zone is the area of metaplastic squamous epithelium located between the original squamocolumnar junction and the new squamocolumnar junction (Figure 38-1).

FIGURE 38-1 Schematic representation of the transformation zone.

Classification of an Abnormal Papanicolaou Smear

In 1988, a consensus meeting was convened by the Division of Cancer Control of the National Cancer Institute to review existing terminology and to recommend effective methods of cytologic reporting. As a result of this meeting, the Bethesda system was devised and requires (1) a statement regarding the adequacy of the specimen for diagnosis, (2) a diagnostic categorization (normal or other), and (3) a descriptive diagnosis. A revised Bethesda system was developed in 2001 and is shown in Box 38-2.

BOX 38-2 Bethesda Classification of Cytologic Abnormalities (2001, Abridged)

Specimen Adequacy

Satisfactory for evaluation (note presence/absence of endocervical/transformation zone component)

Unsatisfactory for evaluation (specify reason)

Specimen rejected/not processed (specify reason)

Specimen processed and examined, but unsatisfactory for evaluation of epithelial abnormality (specify reason)

General Categorization (Optional)

Negative for intraepithelial lesion or malignancy

Epithelial cell abnormality

Other

Interpretation/Result

Negative for Intraepithelial Lesion or Malignancy

Organisms (e.g., Trichomonas vaginalis)

Reactive cellular changes associated with inflammation (includes typical repair), radiation, intrauterine contraceptive device

Atrophy

CERVICAL INTRAEPITHELIAL NEOPLASIA

CIN represents a spectrum of disease, ranging from CIN I (mild dysplasia) to CIN III (severe dysplasia and carcinoma in situ). At least 35% of patients with CIN III develop invasive cancer within 10 years, whereas lower grades of CIN often spontaneously regress. With CIN, there is abnormal epithelial proliferation and maturation above the basement membrane. Involvement of the inner one third of the epithelium represents CIN I, involvement of the inner one half to two thirds represents CIN II, and full-thickness involvement represents CIN III (Figure 38-2). The disease is asymptomatic.

FIGURE 38-2 Histologic appearance of normal cervical squamous epithelium (A) and carcinoma in situ (B) of the cervix. In the normal epithelium, note the orderly maturation from the basal layer to the parabasal cells, glycogenated intermediate cells, and flattened superficial cells. In the carcinoma in situ, the entire thickness of the epithelium is replaced by immature cells that are variable in size and shape and have irregular nuclei. Mitotic figures are seen in the lower two thirds of the epithelium.

COLPOSCOPY

The colposcope is a stereoscopic binocular microscope of low magnification, usually 10× to 40×. Illumination is centered, and the focal length is between 12 and 15 cm.

To perform a colposcopic examination, an appropriately sized speculum is inserted to expose the cervix, which is cleansed with a cotton pledget soaked in 3% acetic acid to remove adherent mucus and cellular debris. A green filter can be employed to accentuate the vascular changes that frequently accompany pathologic alterations of the cervix.

At colposcopy, the original or native squamous epithelium appears gray and homogeneous. The columnar epithelium appears red and grape-like. The transformation zone can be identified by the presence of gland openings that are not covered by the squamous metaplasia and by the paler color of the metaplastic epithelium compared with the original squamous epithelium. Nabothian follicles may also be seen in the transformation zone. Normal blood vessels branch like a tree.

Evaluation of a Patient with an Abnormal Papanicolaou Smear

An algorithm for the evaluation of patients with abnormal Pap smears is presented in Figure 38-3.

FIGURE 38-3 Algorithm for evaluation of patients with an abnormal Papanicolaou smear and a grossly normal-appearing cervix. CIN, cervical intraepithelial neoplasia; ECC, endocervical curettage; LLETZ, large loop excision of the transformation zone.

Any patient with a grossly abnormal cervix should have a punch biopsy performed, regardless of the results of the Pap smear.

Patients with atypical squamous cells of undetermined significance (ASCUS) found on their smear may have a repeat test in 6 months. Alternatively, HPV testing, such as with the Hybrid Capture assay (Digene Diagnostics, Silver Spring, Md) may be used to triage such patients. About 6% to 10% of patients with an ASCUS smear will have high-grade CIN on colposcopy, and 90% of these can be detected by HPV testing for high-risk viral types.

The colposcopic hallmark of cervical intraepithelial neoplasia is an area of sharply delineated acetowhite epithelium, that is, epithelium that appears white after the application of acetic acid. It is thought that the acetic acid dehydrates the cells and that there is increased light reflex from areas of increased nuclear density. Within the acetowhite areas, there may or may not be abnormal vascular patterns.

There are two basic changes in the vascular architecture in patients with CIN: punctation and mosaicism. Punctation is caused by single-looped capillaries lying within the subepithelial papillae, seen end-on as a “dot” as they course toward the surface of the epithelium. Mosaicism is caused by a fine network of capillaries disposed parallel to the surface in a mosaic pattern. Punctate and mosaic patterns may be seen together within the same area of the cervix. The more dilated and irregular the punctate and mosaic capillaries and the greater the intercapillary distance, the more atypical is the tissue on histologic examination. Similarly, the whiter the lesion, the more severe the dysplasia.

With microinvasive carcinoma, extremely irregular punctate and mosaic patterns are found, as are small atypical vessels. The irregularity in size, shape, and arrangement of the terminal vessels becomes even more striking in frankly invasive carcinoma, with exaggerated distortions of the vascular architecture producing comma-shaped, corkscrew-shaped, and dilated, blind-ended vessels.

BIOPSY AND ENDOCERVICAL CURETTAGE

If the colposcopic examination is satisfactory, which implies that the entire transformation zone has been visualized, a punch biopsy is taken from the worst area or areas, together with endocervical curettage. The endocervical curettage is not performed in patients who are pregnant.

A diagnostic cone biopsy of the cervix is indicated in the following circumstances:

1. Pap smear shows a high-grade lesion, and the colposcopic examination is unsatisfactory.

2. Endocervical curettage shows a high-grade lesion.

3. Pap smear shows a high-grade lesion that is not confirmed on punch biopsy.

4. Pap smear shows adenocarcinoma in situ.

5. Microinvasion is present on the punch biopsy.

Treatment of Intraepithelial Neoplasia

It is reasonable to observe biopsy-proven CIN I without active treatment because many cases spontaneously regress. Active treatment is indicated for CIN II and III.

Superficial ablative techniques, such as large loop excision of the transformation zone (LLETZ), cryosurgery, and carbon dioxide laser, are appropriate if the entire transformation zone is visible.

LARGE LOOP EXCISION OF THE TRANSFORMATION ZONE

LLETZ has gained popularity because the equipment is relatively inexpensive, it can be performed on an outpatient basis under local anesthesia, and tissue is obtained for histologic evaluation. Hence, occult invasive lesions should be more readily diagnosed. In unskilled hands, diathermy artifact may make histologic interpretation impossible.

LASER

Destruction of the transformation zone by carbon dioxide laser (light amplification by stimulated emission of radiation) ablation can be performed as an outpatient procedure, under local anesthesia. Bleeding may sometimes occur, but scarring is minimal, and large lesions may be destroyed with low failure rates (5% to 10%). The equipment is expensive, so laser has lost favor in most centers.

CRYOSURGERY

The cryosurgery technique is a relatively painless outpatient procedure that can be performed without anesthesia. There is no bleeding, and the equipment is inexpensive. However, there is a high failure rate for large lesions and for lesions extending down glandular crypts. It is mainly useful for CIN I or II involving 1 or 2 quadrants. The major side effect is a rather copious vaginal discharge that persists for several weeks.

CERVICAL CONIZATION

Cervical conization is mainly a diagnostic technique, but it may be used for treatment. Provided that the margins of resection are clear, cure rates are as high as those with hysterectomy for intraepithelial lesions. Bleeding, infection, cervical stenosis, and cervical incompetence are the major complications. Laser conization decreases the risk for cervical stenosis compared with cold-knife conization.

HYSTERECTOMY

Hysterectomy is rarely necessary for the treatment of CIN. It may be applicable when there is concomitant uterine or adnexal disease.

Persistence and recurrence rates combined are about 2% to 3% after hysterectomy. This number should be significantly reduced by using colposcopy and Schiller’s staining (Lugol’s iodine) preoperatively to exclude intraepithelial neoplasia in the upper vagina.

Invasive Cancer

SYMPTOMS

Invasive cancer usually presents with postcoital, intermenstrual, or postmenopausal vaginal bleeding. In patients who are not sexually active, bleeding from cervical cancer usually does not occur until the disease is quite advanced (unlike patients with endometrial cancer, who almost always bleed early). Persistent vaginal discharge, pelvic pain, leg swelling, and urinary frequency are usually seen with advanced disease. In developing countries, it is not uncommon for patients to present with loss of urine or stool from the vagina, because of fistula formation.

PHYSICAL FINDINGS

Patients with cervical cancer usually have a normal general physical examination. Weight loss occurs late in the disease. With advanced disease, there may be enlarged inguinal or supraclavicular lymph nodes, edema of the legs, or hepatomegaly, but these are not commonly seen.

On pelvic examination, the cervix may be ulcerative or exophytic (Figure 38-4). It usually bleeds on palpation, and there is often an associated serous, purulent, or bloody discharge. The lesion may involve the adjacent vagina and extend toward the introitus.

FIGURE 38-4 Invasive squamous cell carcinoma of the cervix. Note the irregular, ulcerated surface of the ectocervix. A biopsy of such a lesion is mandatory.

A rectovaginal examination is essential to determine the extent of disease. The diameter of the primary cancer and spread to the parametria are much more easily detected with a finger in the rectum, as is extension into the uterosacral ligaments.

PATHOLOGIC FEATURES

Most uterine cervical cancers are squamous in origin. Adenocarcinomas and adenosquamous carcinomas are increasing in incidence and account for about 20% to 25% of cases. Melanomas and sarcomas occur rarely.

PATTERNS OF SPREAD

Invasive cervical cancer spreads by direct invasion of cervical stroma, corpus, vagina, and parametrium; lymphatic spread to pelvic and then para-aortic lymph nodes (Figure 38-5); and hematogenous spread, particularly to the lungs, liver, and bone.

FIGURE 38-5 Grossly enlarged lymph node at the bifurcation of the common iliac artery in a patient with stage Ib2 carcinoma of the cervix. Large nodes such as this can cause ureteric obstruction.

PREOPERATIVE INVESTIGATIONS

The official International Federation of Gynecology and Obstetrics (FIGO) staging for cervical cancer is a clinical staging method based on physical examination and noninvasive testing (Table 38-1). Studies allowed include biopsies, cystoscopy, sigmoidoscopy, chest and skeletal radiographs, intravenous pyelography, and liver function tests. Lung metastases are seen in about 5% of patients with advanced disease and almost never in early disease.

TABLE 38-1 INTERNATIONAL FEDERATION OF GYNECOLOGY AND OBSTETRICS (FIGO) STAGING OF CERVICAL CARCINOMA

PREINVASIVE CARCINOMA
Stage 0	Carcinoma in situ, intraepithelial carcinoma (cases of stage 0 should not be included in any therapeutic statistics)
INVASIVE CARCINOMA
Stage I	The carcinoma is strictly confined to the cervix.
Stage Ia	Invasive cancer is identified only microscopically. All gross lesions even with superficial invasion are Ib cancers. Invasion is limited to a measured stromal invasion, with a maximal depth of 5 mm and a horizontal extension of not more than 7 mm.
Stage Ia1	Measured invasion of stroma not greater than 3 mm in depth and 7 mm in width
Stage Ia2	Measured invasion of stroma greater than 3 mm and not greater than 5 mm and width not greater than 7 mm
Stage Ib	Clinical lesions confined to the cervix or preclinical lesions greater than stage Ia
Stage Ib1	Clinical lesions not greater than 4 cm in size
Stage Ib2	Clinical lesions greater than 4 cm in size
Stage II	The carcinoma extends beyond the cervix but has not extended to the pelvic wall or to the lower third of the vagina.
Stage IIa	No obvious parametrial involvement
Stage IIb	Obvious parametrial involvement
Stage III	The carcinoma has extended to the pelvic wall. On rectal examination, there is no cancer-free space between the tumor and the pelvic wall. The tumor involves the lower third of the vagina. All cases with hydronephrosis or nonfunctioning kidney should be included, unless they are known to be due to another cause.
Stage IIIa	Tumor involves lower third of the vagina with no extension to the pelvic wall.
Stage IIIb	Extension onto the pelvic wall and/or hydronephrosis or nonfunctioning kidney
Stage IV	The carcinoma has extended beyond the true pelvis or has clinically involved the mucosa of the bladder or rectum. A bullous edema, as such, does not permit a case to be allotted to stage IV.
Stage IVa	Spread of the growth to adjacent organs
Stage IVb	Spread to distant organs

Abdominal and pelvic computed tomography or magnetic resonance imaging (MRI) may be helpful in planning management, but the results do not influence the FIGO stage. MRI is particularly helpful in defining the extent of the primary lesion, including any extension into the parametrium, bladder, or rectum. Neither is particularly sensitive for detecting lymph node metastases, and position-emission tomography is being increasingly used for this purpose. The incidence of para-aortic lymph node metastases is about 20% in stage II disease and 30% in stage III, and the status of the para-aortic nodes is the single most important prognostic factor.

Laboratory studies may reveal abnormalities with advanced disease, the most common being anemia from bleeding, elevated blood urea nitrogen and creatinine levels if the ureters are obstructed, and abnormal liver function tests if there are liver metastases. Ureteric obstruction occurs in about 30% of patients with stage III disease and in 50% of patients with stage IV disease. Hypercalcemia may denote bone metastases.

TREATMENT

Recurrent or Metastatic Disease

CHEMOTHERAPY

The effectiveness of chemotherapy is limited for metastatic cervical cancer.

Several drugs have been tested and found to be active in up to 35% of cases. Most responses are partial, and the patients usually progress within 12 months. The most active agents are cisplatin, bleomycin, mitomycin C, methotrexate, and cyclophosphamide.

PELVIC EXENTERATION

Pelvic exenteration is generally reserved for patients who have a central recurrence following pelvic irradiation. Total exenteration involves removal of the pelvic viscera, including the uterus, tubes, vagina, ovaries, bladder, and rectum (Figure 38-6). Depending on the site and extent of the disease, the operation may be limited to an anterior exenteration, which spares the rectum, or a posterior exenteration, which spares the bladder.

FIGURE 38-6 Organs removed in anterior exenteration (A), posterior exenteration (B), and total pelvic exenteration (C).

Following the extirpative surgery, pelvic reconstruction is necessary. If the bladder is removed, the ureters must be implanted into a portion of the small or large bowel that has been isolated from the remainder of the gastrointestinal tract to form a conduit. A continent conduit may be created, particularly in younger patients. When the disease is confined to the upper vagina and rectovaginal septum, the lower rectum and anal canal may be preserved and reanastomosed to the sigmoid colon. A temporary colostomy is often required to protect the reanastomosis because of the prior irradiation. Vaginal reconstruction can be performed using a split-thickness skin graft, bilateral gracilis myocutaneous grafts, a rectus abdominis myocutaneous flap, or a segment of large intestine.

Relatively few patients with recurrent cancer of the cervix are suitable to undergo pelvic exenteration because of metastases outside the pelvis or fixation of the tumor to structures that cannot be removed, such as the pelvic side wall. If an extensive metastatic workup is negative for cancer, patients undergo exploratory laparotomy with a view to pelvic exenteration. If the tumor is discovered to have spread to pelvic or para-aortic lymph nodes or to intraabdominal viscera, the procedure is abandoned.

In selecting patients who may be suitable for pelvic exenteration, the triad of unilateral leg edema, sciatic pain, and ureteral obstruction is ominous and indicates unresectable disease in the pelvis.

Cervical Carcinoma in Pregnancy

Carcinoma of the cervix associated with pregnancy usually implies diagnosis during pregnancy or within 6 months postpartum. It is relatively uncommon; invasive carcinoma occurs in about 1 in 2200 pregnancies.

SYMPTOMS

The symptoms are similar to those in nonpregnant patients, with painless vaginal bleeding being the most common. During pregnancy, this symptom can readily be attributed to conditions such as threatened abortion or placenta previa, so there is often an unnecessary delay in diagnosis.

DIAGNOSIS

A prenatal Pap smear leads to the diagnosis in most cases. Pregnancy tends to exaggerate the colposcopic features of CIN so that overdiagnosis is more likely than the reverse. Endocervical curettage should not be performed during pregnancy because of the risk for rupturing the membranes. Cone biopsy, if required, is best performed during the second trimester to avoid the possibility of induced abortion in the first trimester and severe hemorrhage and premature labor in the third trimester. Unfortunately, about half of the patients are not diagnosed until the postpartum period. The later the diagnosis is made, the more likely the cancer is to be in an advanced stage.

MANAGEMENT

CIN III diagnosed during pregnancy should be managed conservatively, with the pregnancy allowed to proceed to term, vaginal delivery anticipated, and appropriate therapy carried out 6 to 8 weeks postpartum.

Microinvasive carcinoma of the cervix diagnosed by conization of the cervix during pregnancy may also be managed conservatively, the pregnancy being allowed to continue to term. At term, either cesarean hysterectomy or vaginal delivery followed by postpartum extrafascial hysterectomy is appropriate, unless further childbearing is desired.

Frankly invasive cancer requires relatively urgent treatment. After 22 to 26 weeks, it is reasonable to continue the pregnancy until fetal viability (about 32 weeks) if the patient desires. The general principles of treatment are essentially the same as those in the nonpregnant patient. For early lesions, radical hysterectomy may be performed. Before 20 weeks’ gestation, this is performed with the fetus in situ. After that time, hysterotomy through a high incision in the uterine fundus is performed to remove the fetus, followed by radical hysterectomy and bilateral pelvic lymphadenectomy.

For some patients with early disease and for all patients with advanced disease, the alternative to radical surgery is radiation therapy. For patients with disease diagnosed in the first trimester, external irradiation is initiated to shrink the tumor. Abortion usually occurs spontaneously during the course of external therapy; if it does not, uterine curettage should be performed before brachytherapy. After the first trimester, it is preferable to perform a hysterotomy through a high incision in the corpus before instituting radiotherapy.

If a decision is made to await fetal viability, it is important to be certain by ultrasonography that the fetus is apparently healthy and to obtain a mature lecithin-to-sphingomyelin ratio to ensure fetal lung maturity before delivery. Neoadjuvant chemotherapy using cisplatin and etoposide has been used to try to “contain” the disease. Because of the increased risk for hemorrhage and infection likely to be associated with delivery through a cervix containing gross cancer, classic cesarean delivery is the preferred method. For patients in whom inadvertent vaginal delivery has occurred, there is no evidence to indicate that the prognosis is altered.

Prognosis for Cervical Cancer

Prognosis is related directly to clinical stage (Table 38-2).With more advanced stage of disease, the frequency of nodal metastasis escalates, and the 5-year survival rate diminishes. Adenocarcinomas and adenosquamous carcinomas have a somewhat lower 5-year survival rate than do squamous carcinomas, stage for stage.

TABLE 38-2 CARCINOMA OF THE CERVIX: SURVIVAL BY FIGO STAGE