Cervical Cancer

Cervical cancer is a disease in which the cells of the cervix become abnormal and start to grow uncontrollably, forming tumors.

Description

In the United States, cervical cancer is the fifth most common cancer among women aged 35–54, and the third most common cancer of the female reproductive tract. In some developing countries, it is the most common type of cancer. It generally begins as an abnormality in the cells on the outside of the cervix. The cervix is the lower part or neck of the uterus (womb). It connects the body of the uterus to the vagina (birth canal).

Approximately 90% of cervical cancers are squamous cell carcinomas. This type of cancer originates in the thin, flat, squamous cells on the surface of the ectocervix, the part of the cervix that is next to the vagina. (Squamous cells are the thin, flat cells of the surfaces of the skin and cervix and linings of various organs.) Another 10% of cervical cancers are of the adenocarcinoma type. This cancer originates in the mucus-producing cells of the inner or endocervix, near the body of the uterus. Occasionally, the cancer may have characteristics of both types and is called adenosquamous carcinoma or mixed carcinoma.

The initial changes that may occur in some cervical cells are not cancerous. However, these precancerous cells form a lesion called dysplasia or a squamous intraepithelial lesion (SIL), since it occurs within the epithelial or outer layer of cells. These abnormal cells can also be described as cervical intraepithelial neoplasia (CIN). Moderate to severe dysplasia may be called carcinoma in situ or non-invasive cervical cancer.

Dysplasia is a common condition and the abnormal cells often disappear without treatment. However, these precancerous cells can become cancerous. This may take years, although it can happen in less than a year. Eventually, the abnormal cells start to grow uncontrollably into the deeper layers of the cervix, becoming an invasive cervical cancer.

Although cervical cancer used to be one of the most common causes of cancer death among American women, in the past 40 years there has been a 75% decrease in mortality. This is primarily due to routine screening with Pap tests (Pap smear), to identify precancerous and early-invasive stages of cervical cancer. With treatment, these conditions have a cure rate of nearly 100%.

Worldwide, there are more than 400,000 new cases of cervical cancer diagnosed each year. The American Cancer Society (ACS) estimates that there will be 12,900 new cases of invasive cervical cancer diagnosed in the United States in 2001. More than one million women will be diagnosed with a precancerous lesion or non-invasive cancer of the cervix.

Older women are at the highest risk for cervical cancer. Although girls under the age of 15 rarely develop this cancer, the risk factor begins to increase in the late teens. Rates for carcinoma in situ peak between the ages of 20 and 30. In the United States, the incidence of invasive cervical cancer increases rapidly with age for African American women over the age of 25. The incidence rises more slowly for Caucasian women. However, women over age 65 account for more than 25% of all cases of invasive cervical cancer.

The incidence of cervical cancer is highest among poor women and among women in developing countries. In the United States, the death rates from cervical cancer are higher among Hispanic, Native American, and African American women than among Caucasian women. These groups of women are much less likely to receive regular Pap tests. Therefore, their cervical cancers usually are diagnosed at a much later stage, after the cancer has spread to other parts of the body.

Causes and symptoms

Human papilloma virus

Infection with the common human papilloma virus (HPV) is a cause of approximately 90% of all cervical cancers. There are more than 80 types of HPV. About 30 of these types can be transmitted sexually, including those that cause genital warts (papillomas). About half of the sexually transmitted HPVs are associated with cervical cancer. These "high-risk" HPVs produce a protein that can cause cervical epithelial cells to grow uncontrollably. The virus makes a second protein that interferes with tumor suppressors that are produced by the human immune system. The HPV-16 strain is thought to be a cause of about 50% of cervical cancers.

More than six million women in the United States have persistent HPV infections, for which there is no cure. Nevertheless, most women with HPV do not develop cervical cancer.

Symptoms of invasive cervical cancer

Most women do not have symptoms of cervical cancer until it has become invasive. At that point, the symptoms may include:

• unusual vaginal discharge
• light vaginal bleeding or spots of blood outside of normal menstruation
• pain or vaginal bleeding with sexual intercourse
• post-menopausal vaginal bleeding

Once the cancer has invaded the tissue surrounding the cervix, a woman may experience pain in the pelvic region and heavy bleeding from the vagina.

Diagnosis

The Pap test

Most often, cervical cancer is first detected with a Pap test that is performed as part of a regular pelvic examination. The vagina is spread with a metal or plastic instrument called a speculum. A swab is used to remove mucus and cells from the cervix. This sample is sent to a laboratory for microscopic examination.

The Pap test is a screening tool rather than a diagnostic tool. It is very efficient at detecting cervical abnormalities. The Bethesda System commonly is used to report Pap test results. A negative test means that no abnormalities are present in the cervical tissue. A positive Pap test describes abnormal cervical cells as low-grade or high-grade SIL, depending on the extent of dysplasia. About 5–10% of Pap tests show at least mild abnormalities. However, a number of factors other than cervical cancer can cause abnormalities, including inflammation from bacteria or yeast infections. A few months after the infection is treated, the Pap test is repeated.

Biopsy

Following an abnormal Pap test, a colposcopy is usually performed. The physician uses a magnifying scope to view the surface of the cervix. The cervix may be coated with an iodine solution that causes normal cells to turn brown and abnormal cells to turn white or yellow. This is called a Schiller test. If any abnormal areas are observed, a colposcopic biopsy may be performed. A biopsy is the removal of a small piece of tissue for microscopic examination by a pathologist.

Other types of cervical biopsies may be performed. An endocervical curettage is a biopsy in which a narrow instrument called a curette is used to scrape tissue from inside the opening of the cervix. A cone biopsy, or conization, is used to remove a cone-shaped piece of tissue from the cervix. In a cold knife cone biopsy, a surgical scalpel or laser is used to remove the tissue. A loop electrosurgical excision procedure (LEEP) is a cone biopsy using a wire that is heated by an electrical current. Cone biopsies can be used to determine whether abnormal cells have invaded below the surface of the cervix. They also can be used to treat many precancers and very early cancers. Biopsies may be performed with a local or general anesthetic. They may cause cramping and bleeding.

Diagnosing the stage

Following a diagnosis of cervical cancer, various procedures may be used to stage the disease (determine how far the cancer has spread). For example, additional pelvic exams may be performed under anesthesia.

There are several procedures for determining if cervical cancer has invaded the urinary tract. With cystoscopy, a lighted tube with a lens is inserted through the urethra (the urine tube from the bladder to the exterior) and into the bladder to examine these organs for cancerous cells. Tissue samples may be removed for microscopic examination by a pathologist. Intravenous urography (intravenous pyelogram or IVP) is an x ray of the urinary system, following the injection of special dye. The kidneys remove the dye from the bloodstream and the dye passes into the ureters (the tubes from the kidneys to the bladder) and bladder. IVP can detect a blocked ureter, caused by the spread of cancer to the pelvic lymph nodes (small glands that are part of the immune system).

A procedure called proctoscopy or sigmoidoscopy is similar to cystoscopy. It is used to determine whether the cancer has spread to the rectum or lower large intestine.

Computed tomography (CT or CAT) scans, ultrasound, or other imaging techniques may be used to determine the spread of cancer to various parts of the body. With a CT scan, an x-ray beam rotates around the body, taking images from various angles. It is used to determine if the cancer has spread to the lymph nodes. Magnetic resonance imaging (MRI), which uses a magnetic field to image the body, sometimes is used for evaluating the spread of cervical cancer. Chest x rays may be used to detect cervical cancer that has spread to the lungs.

Treatment

Following a diagnosis of cervical cancer, the physician takes a medical history and performs a complete physical examination. This includes an evaluation of symptoms and risk factors for cervical cancer. The lymph nodes are examined for evidence that the cancer has spread from the cervix. The choice of treatment depends on the clinical stage of the disease.

The FIGO system of staging

The International Federation of Gynecologists and Obstetricians (FIGO) system usually is used to stage cervical cancer:

• Stage 0: Carcinoma in situ; non-invasive cancer that is confined to the layer of cells lining the cervix
• Stage I: Cancer that has spread into the connective tissue of the cervix but is confined to the uterus
• Stage IA: Very small cancerous area that is visible only with a microscope
• Stage IA1: Invasion area is less than 3 mm (0.13 in) deep and 7 mm (0.33 in) wide
• Stage IA2: Invasion area is 3–5 mm (0.13–0.2 in) deep and less than 7 mm (0.33 in) wide
• Stage IB: Cancer can be seen without a microscope or is deeper than 5 mm (0.2 in) or wider than 7 mm (0.33 in)
• Stage IB1: Cancer is no larger than 4 cm (1.6 in)
• Stage IB2: Stage IB cancer is larger than 4 cm (1.6 in)
• Stage II: Cancer has spread from the cervix but is confined to the pelvic region
• Stage IIA: Cancer has spread to the upper region of the vagina, but not to the lower one-third of the vagina
• Stage IIB: Cancer has spread to the parametrial tissue adjacent to the cervix
• Stage III: Cancer has spread to the lower one-third of the vagina or to the wall of the pelvis and may be blocking the ureters
• Stage IIIA: Cancer has spread to the lower vagina but not to the pelvic wall
• Stage IIIB: Cancer has spread to the pelvic wall and/or is blocking the flow of urine through the ureters to the bladder
• Stage IV: Cancer has spread to other parts of the body
• Stage IVA: Cancer has spread to the bladder or rectum
• Stage IVB: Cancer has spread to distant organs such as the lungs
• Recurrent: Following treatment, cancer has returned to the cervix or some other part of the body

In addition to the stage of the cancer, factors such as a woman's age, general health, and preferences may influence the choice of treatment. The exact location of the cancer within the cervix and the type of cervical cancer also are important considerations.

Treatment of precancer and carcinoma in situ

Most low-grade SILs that are detected with Pap tests revert to normal without treatment. Most high-grade SILs require treatment. Treatments to remove precancerous cells include:

• cold knife cone biopsy
• LEEP
• cryosurgery (freezing the cells with a metal probe)
• cauterization or diathermy (burning off the cells)
• laser surgery (burning off the cells with a laser beam)

These methods also may be used to treat cancer that is confined to the surface of the cervix (stage 0) and other early-stage cervical cancers in women who may want to become pregnant. They may be used in conjunction with other treatments. These procedures may cause bleeding or cramping. All of these treatments require close follow-up to detect any recurrence of the cancer.

Surgery

A simple hysterectomy is used to treat some stages 0 and IA cervical cancers. Usually only the uterus is removed, although occasionally the fallopian tubes and ovaries are removed as well. The tissues adjoining the uterus, including the vagina, remain intact. The uterus may be removed either through the abdomen or the vagina.

In a radical hysterectomy, the uterus and adjoining tissues, including the ovaries, the upper region (1 in) of the vagina near the cervix, and the pelvic lymph nodes, are all removed. A radical hysterectomy usually involves abdominal surgery. However, it can be performed vaginally, in combination with a laparoscopic pelvic lymph node dissection. With laparoscopy, a tube is inserted through a very small surgical incision for the removal of the lymph nodes. These operations are used to treat stages IA2, IB, and IIA cervical cancers, particularly in young women. Following a hysterectomy, the tissue is examined to see if the cancer has spread and requires additional radiation treatment. Women who have had hysterectomies cannot become pregnant, but complications from a hysterectomy are rare.

If cervical cancer recurs following treatment, a pelvic exenteration (extensive surgery) may be performed. This includes a radical hysterectomy, with the additional removal of the bladder, rectum, part of the colon, and/or all of the vagina. Such operations require the creation of new openings for the urine and feces. A new vagina may be created surgically. Often the clitoris and other outer genitals are left intact.

Recovery from a pelvic exenteration may take six months to two years. This treatment is successful with 40–50% of recurrent cervical cancers that are confined to the pelvis. If the recurrent cancer has spread to other organs, radiation or chemotherapy may be used to alleviate some of the symptoms.

Radiation

Radiation therapy, which involves the use of high-dosage x rays or other high-energy waves to kill cancer cells, often is used for treating stages IB, IIA, and IIB cervical cancers, or in combination with surgery. With external-beam radiation therapy, the rays are focused on the pelvic area from a source outside the body. With implant or internal radiation therapy, a pellet of radioactive material is placed internally, near the tumor. Alternatively, thin needles may be used to insert the radioactive material directly into the tumor.

Radiation therapy to the pelvic region can have many side effects:

• skin reaction in the area of treatment
• fatigue
• upset stomach and loose bowels
• vaginal stenosis (narrowing of the vagina due to buildup of scar tissue) leading to painful sexual intercourse
• premature menopause in young women
• problems with urination

Chemotherapy

Chemotherapy, the use of one or more drugs to kill cancer cells, is used to treat disease that has spread beyond the cervix. Most often it is used following surgery or radiation treatment. Stages IIB, III, IV, and recurrent cervical cancers usually are treated with a combination of external and internal radiation and chemotherapy. The common drugs used for cervical cancer are cisplatin, ifosfamide, and fluorouracil. These may be injected or taken by mouth. The National Cancer Institute recommends that chemotherapy with cisplatin be considered for all women receiving radiation therapy for cervical cancer.

The side effects of chemotherapy depend on a number of factors, including the type of drug, the dosage, and the length of the treatment. Side effects may include:

• nausea and vomiting
• fatigue
• changes in appetite
• hair loss
• mouth or vaginal sores
• infections
• menstrual cycle changes
• premature menopause
• infertility
• bleeding or anemia (low red blood cell count)

With the exception of menopause and infertility, most of the side effects are temporary.

Alternative treatment

Biological therapy sometimes is used to treat cervical cancer, either alone or in combination with chemotherapy. Treatment with the immune-system protein interferon is used to boost the immune response. Biological therapy can cause temporary flu-like symptoms and other side effects.

Some research suggests that vitamin A (carotene) may help to prevent or stop cancerous changes in cells such as those on the surface of the cervix. Other studies suggest that vitamins C and E may reduce the risk of cervical cancer.

Prognosis

For cervical cancers that are diagnosed in the preinvasive stage, the five-year-survival rate is almost 100%. When cervical cancer is detected in the early invasive stages, approximately 91% of women survive five years or more. Stage IVB cervical cancer is not considered to be curable. The five-year-survival rate for all cervical cancers combined is about 70%. The death rate from cervical cancer continues to decline by about 2% each year. Women over age 65 account for 40–50% of all deaths from cervical cancer.

Prevention

Viral infections

Most cervical cancers are preventable. More than 90% of women with cervical cancer are infected with HPV. HPV infection is the single most important risk factor. This is particularly true for young women because the cells lining the cervix do not fully mature until age 18. These immature cells are more susceptible to cancer-causing agents and viruses.

Since HPV is a sexually-transmitted infection, sexual behaviors can put women at risk for HPV infection and cervical cancer. These behaviors include:

• sexual intercourse at age 16 or younger
• partners who began having intercourse at a young age
• multiple sexual partners
• sexual partners who have had multiple partners ("highrisk males")
• a partner who has had a previous sexual partner with cervical cancer

HPV infection may not produce any symptoms, so sexual partners may not know that they are infected. However, Pap tests can detect the infection. Condoms do not necessarily prevent HPV infection.

Infection with the human immunodeficiency virus (HIV) that causes acquired immunodeficiency syndrome (AIDS) is a risk factor for cervical cancer. Women who test positive for HIV may have impaired immune systems that cannot correct precancerous conditions. Furthermore, sexual behavior that puts women at risk for HIV infection, also puts them at risk for HPV infection. There is some evidence suggesting that another sexually transmitted virus, the genital herpes virus, also may be involved in cervical cancer.

Smoking

Smoking may double the risk of cervical cancer. Chemicals produced by tobacco smoke can damage the DNA of cervical cells. The risk increases with the number of years a woman smokes and the amount she smokes.

Diet and drugs

Diets that are low in fruits and vegetables increase the risk of cervical cancer. Women also have an increased risk of cervical cancer if their mothers took the drug diethylstilbestrol (DES) while they were pregnant. This drug was given to women between 1940 and 1971 to prevent miscarriages. Some statistical studies have suggested that the long-term use of oral contraceptives may slightly increase the risk of cervical cancer.

Pap tests

Most cases of cervical cancers are preventable, since they start with easily detectable precancerous changes. Therefore, the best prevention for cervical cancer is a regular Pap test. When precancerous changes are detected, appropriate treatment can prevent the development of invasive cancer. The ACS recommends that women have annual Pap tests beginning when they first start having sex or at age 18. Women who are past menopause or some women with hysterectomies continue to require Pap tests.

The National Breast and Cervical Cancer Early Detection Program provides free or low-cost Pap tests and treatment for women without health insurance, for older women, and for members of racial and ethnic minorities. The program is administered through individual states, under the direction of the Centers for Disease Control and Prevention.

Special concerns

If a woman is diagnosed with very early-stage (IA) cervical cancer while pregnant, the physician usually will recommend a hysterectomy after the baby is born. For later-stage cancers, the pregnancy is terminated or the baby is removed by cesarean section as soon as it can survive outside the womb. This is followed by a hysterectomy and/or radiation treatment. For the most advanced stages of cervical cancer, treatment is initiated despite the pregnancy.

Many women with cervical cancer have hysterectomies, which are major surgeries. Although normal activities, including sexual intercourse, can be resumed in four-eight weeks, a woman may have emotional problems following a hysterectomy. A strong support system can help with these difficulties.