Cervical cancer

Definition

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.

— Lata Cherath; Margaret Alic, Ph.D.

Key Terms: Adenocarcinoma, Biopsy, Carcinoma in situ, Cervical intraepithelial neoplasia, Cervix, Colposcopy, Conization, Dysplasia, Endocervical curettage, Human papilloma virus, Hysterectomy, Interferon, Laparoscopy, Loop electrosurgical excision procedure, Lymph nodes, Pap test, Pelvic exenteration, Squamous cells, Squamous intraepithelial lesion.

Definition

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 ecto-cervix, 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%.

Demographics

Worldwide, there are more than 400,000 new cases of cervical cancer diagnosed each year. The American Cancer Society (ACS) estimated 13,000 new cases of invasive cervical cancer in the United States in 2002. More than one million women were diagnosed with a precancerous lesion or non-invasive cancer of the cervix in 2001.

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 Papillomavirus

Infection with the common human papillomavirus (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 are 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 micro-scopic 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, ultra-sound, 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 Team

Pap smears usually are performed by a women's health specialist, a nurse practitioner, a family practice physician, or a gynecologist. These practitioners may treat precancerous conditions. Procedures for diagnosing cervical cancer are performed by a gynecologist. A pathologist examines the biopsied tissue for cancer cells. Following diagnosis, a specialist in cancers of the female reproductive system, a gynecological oncologist, as well as a radiation oncologist and a surgeon may join the team.

Clinical Staging, Treatments, and Prognosis

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 O 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 6 months to 2 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 (alopecia)
• 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 and Complementary Therapies

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 pre-invasive stage, the 5-year-survival rate is almost 100%. When cervical cancer is detected in the early invasive stages, approximately 91% of women survive 5 years or more. Stage IVB cervical cancer is not considered to be curable. The 5-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.

Coping With Cancer Treatment

Medications can ease some of the side effects of radiation and chemotherapy, such as nausea and menopausal symptoms. Premature menopause may require estrogenreplacement therapy, however in 2003, a large study called the Women's Health Initiative documented several health problems with hormone replacement therapy, so women should check with their physicians. Vaginal dilators and lubricants can relieve the effects of vaginal stenosis. A nutritious diet, rest, and a strong emotional support system help with recovery from treatment.

Following treatment for cervical cancer, additional tests are conducted to check for recurrence. These tests include frequent Pap smears, biopsies, and blood tests. X rays, CT or MRI scans, or other imaging studies such as ultrasound also may be used.

Clinical Trials

There are many clinical trials, ongoing throughout the United States, for the treatment of most stages of cervical cancer. These include the testing of new chemotherapy drugs, new methods of radiation therapy, and new combinations of surgery and radiation or chemotherapy. New methods for performing Pap tests also are being studied.

A new test for HPV, called the Hybrid Capture HPV test, is being studied. Results suggest that this test may be useful for determining which women with abnormal Pap test results should have colposcopy. Various types of HPV vaccines are being tested. These include vaccines that prevent HPV infection, vaccines for women infected with HPV, and vaccines for women with advanced cervical cancer. Scientists predict having FDA approval of an HPV vaccine by about 2008 or 2010.

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 ("high-risk 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. In 2003, a new DNA screening test was approved by the FDA to test for HPV at the same time as the Pap test. Condoms do not necessarily prevent HPV infection. However, in 2003, a preliminary study demonstrated that a vaccine against the type of HPV that causes the most cervical cancers showed promise in preventing HPV infection. Results were still preliminary.

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. A 2003 study also linked smoking to poorer outcomes and survivals in cervical cancer patients.

Diet and Drugs

Diets that are low in fruits and vegetables increase the risk of cervical cancer. A 2003 study also linked obesity to increased risk for cervical adenocarcinoma. Even women who were overweight had a higher incidence of the disease. The link appears to be increase levels of estrogen. Excessive fat tissue influences levels of estrogen and other sex hormones. 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. The ACS revised its guidelines for regular screening in late 2002. In brief, women should begin having Pap tests about three years after having sexual intercourse, but no later than 21 years of age. Women should continue screening every year with regular Pap tests until age 30. Once a woman has had three normal results in a row, she may get screened every two to three years. A doctor may suggest more frequent screening if a woman has certain risk factors for cervical cancer. Women who have had total hysterectomies including the removal of the cervix and those over age 70 who have had three normal results generally do not need to continue having Pap tests under the new guidelines.

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.

Questions to Ask the Doctor

• What type of biopsy will I have? What type of anesthetic will be used? What are the aftereffects?
• What type of cervical cancer do I have?
• What is the stage of my cancer?
• What are my treatment choices?
• Which treatment do you recommend and why?
• What should I do to prepare for treatment?
• What are the side effects of this treatment and how can I alleviate them?
• What is the recovery period for this treatment?
• Will I be able to get pregnant after this treatment?
• Are there clinical trials that may be appropriate for me?
• What is my prognosis?

Many women with cervical cancer have hysterectomies, which are major surgeries. Although normal activities, including sexual intercourse, can be resumed in 4-8 weeks, a woman may have emotional problems following a hysterectomy. A strong support system can help with these difficulties.

Resources

Books

Holland, Jimmie C., and Sheldon Lewis. The Human Side of Cancer: Living with Hope, Coping with Uncertainty. New York: HarperCollins, 2000.

Runowicz, Carolyn D., Jeanne A. Petrek, and Ted S. Gansler. Women and Cancer: A Thorough and Compassionate Resource for Patients and their Families. New York: Villard Books, 1999.

Periodicals

"American Cancer Society Issues New Early Detection Guidelines." Women's Health Weekly December 19, 2002: 12.

"Get Ready to Take Cervical Cancer Screening to the Next Level: Newly Approved Human Papillomavirus Test Offers 2-in-1 Package." Contraceptive Technology Update June 2003: 61–64.

"Obesity Linked to Cervical Adenocarcinoma, a Hormone-Dependent Cancer." Cancer Weekly July 29, 2003: 59.

"Study: HPV Test Is more Effective than Pap Smear for Cervical Cancer Screening." Biotech Week December 31, 2003: 143.

Van Kessel, Katherine, and Koutsky, Laura. "The HPV Vaccine: Will it One Day Wipe Out Cervical Cancer?" Contemporary OB/GYN November 2003: 71–75.

Walgate, Robert. "Vaccine Against Cervical Cancer Passes Proof of Principle." Bulletin of the World Health Organization January–February 2003: 73–81.

Worcester, Sharon. "Smoking Tied to Poorer Outcomes in Cervical Ca: Locally Advanced Disease." Family Practice News May 15, 2003: 29–31.

Organizations

American Cancer Society. 1599 Clifton Road, N.E., Atlanta, GA 30329. (800) ACS-2345. . Information, funds for cancer research, prevention programs, and patient services, including educational and support programs for patients and families and temporary accommodations for patients.

Centers for Disease Control and Prevention. National Center for Chronic Disease Prevention and Health Promotion. Mail Stop K-64. 4770 Buford Highway NE, Atlanta, GA 30341-3717. (770) 488-4751. (888) 842-6355. . Research and public education and outreach for disease prevention under the U.S. Department of Health and Human Services.

EyesOnThePrize.Org. 446 S. Anaheim Hills Road, #108, Anaheim Hills, CA 92807. . On-line information and emotional support for women with gynecologic cancer.

Gynecologic Cancer Foundation. 401 North Michigan Avenue, Chicago, IL 60611. (800) 444-4441. (312) 644-6610. . Research, education, and philanthropy for women with gynecologic cancer.

National Cancer Institute. Public Inquiries Office, Building 31, Room 10A31, 31 Center Drive, MSC 2580, Bethesda, MD 20892-2580. (800)-4-CANCER. . . Research, information, and clinical trials.

National Cervical Cancer Coalition. 16501 Sherman Way, Suite #110, Van Nuys, CA 91406. (800) 685-5531. (818) 909-3849. . Information, education, access to screening and treatment, and support services; sponsors the Cervical Cancer Quilt Project.

Other

"Cancer of the Cervix." CancerNet. Dec. 12, 2000. National Cancer Institute. NIH Publication No. 95-2047. [cited Apr. 3, 2001]. >http://cancernet.nci.nih.gov/wyntk_pubs/cervix.htm#2>.

"Cervical Cancer." Cancer Resource Center. American Cancer Society. Mar. 16, 2000. [cited Apr. 3, 2001]. .

"Cervical Cancer." National Institutes of Health Consensus Development Conference Statement. 1-3 Apr. 1996. [cited Apr. 3, 2001]. .

"Cervical Cytology: Evaluation and Management of Abnormalities." American College of Obstetricians and Gynecologists (ACOG) Techincal Bulletin. Number 183. August 1993.

—Lata Cherath, Ph.D.; Margaret Alic, Ph.D.; Teresa G. Odle

Invasive cervical cancer affects nearly 12,800 women in the United States annually, and in approximately 5,000 of these women the disease will be fatal. The incidence of cervical cancer is bimodal, with two peaks occurring between thirty-five years and sixty-four years of age. Since the advent of Pap smear screening, the incidence of cervical cancer has decreased in the United States; however it continues to be a leading cause of death for women in Third World countries.

A tremendous volume of experimental and epidemiological evidence suggests that cervical dysplasia (premalignant changes) and carcinoma (malignant changes) are caused by various subtypes of the human papillomavirus (HPV), with cocarcinogenic effects derived from tobacco abuse. HPV is sexually transmitted and is highly infectious. Women who have early coitus (prior to age eighteen) or more than two sexual partners in their lifetime have an increased risk for cervical cancer. HPV initially causes cervical dysplasia or intraepithelial neoplasm (CIN), which, if untreated, may progress to carcinoma. Although some of the smaller of these lesions may spontaneously regress, given enough time all CIN lesions carry the possibility of progression to carcinoma.

With early viral effects, often no visible features to the naked eye are observed, with the exception of occasional keratinizing lesions that appear as a whitish plaque. Therefore, most cervical dysplasia is identified by cervical cytology (e.g., the Pap smear). The Pap smear is the most important tool in the secondary prevention of cervical cancer.

The evaluation of a patient with cervical dysplasia requires a colposcopic examination. This examination uses a dilute 3 percent acetic solution to help delineate the cervical lesion under 10X to 20X magnification. The lesion should be biopsied and the determination of invasion needs to be made. If no invasion is identified, the lesion should be treated in the premalignant state; however, once the cellular basement membrane is penetrated, invasion into the deeper tissues occurs. Often a procedure known as a cervical conization is necessary to determine whether invasion has occurred and to what depth the invasion extends.

Women with cervical carcinoma often present with abnormal vaginal bleeding—postmenopausal, intermenstrual, postcoital, or increased menstrual flow. An excessive, malodouros vaginal discharge is often a presenting symptom. History of weight loss and sciatic pain are rare symptoms, but when present signify advanced stage disease.

The most common variety of invasive cervical cancer is squamous cell carcinoma, which accounts for the majority of cervical cancer. Adenocarcinoma of the cervix appears to be increasing in frequency relative to squamous cell carcinoma; recent studies suggest as many as 15 to 20 percent of cervical cancers are now adenocarcinomas. The adenocarcinomas are believed to have a poorer prognosis than squamous cell carcinomas of similar stage.

Cervical carcinomas spread by direct invasion into the cervical stroma and surrounding pelvic organs. The tumor can also spread through the lymphatic channels into regional lymph nodes. The major path of spread is lateral—through the paracervical lymphatics into the parametrium and, ultimately, into the lateral pelvic sidewall. The tumor may also spread inferiorly into the vaginal stroma, anteriorly into the bladder, or posteriorly into the rectum. These tumors are known to metastasize to the external iliac nodes, obturator nodes, internal iliac nodes, and common iliac nodes. After metastasis to the pelvic nodes, cervical cancer spreads beyond the pelvis to the paraaortic nodes, and ultimately the supraclavicular nodes. Once the diagnosis of cervical cancer is established, the stage of the disease is clinically established by an estimation of the extent of the disease. Stage I disease is localized to the cervix; stage II disease is that which has extended beyond the cervix, but not to the sidewall; stage III disease is that which extends to the pelvic sidewall; and stage IV disease extends beyond the true pelvis.

The management of stage I carcinoma can be accomplished by either surgery or radiation with chemosensitization. Both produce similar cure rates, which approach 90 percent for stage I disease. In younger patients, surgical intervention is the usual option. Surgery allows the patient to maintain ovarian function, since low doses of radiation will cause cessation of ovarian function. In elderly patients, radiation is often used instead of surgery.

Radiation may also have permanent effects on the bowel and bladder function (as may surgery), however, by tailoring the radicality of the surgery, one can often minimize bladder and bowel dysfunction. Once the tumor has extended beyond the cervix, radiation with chemosensitization is the only option for cure. As the disease advances beyond stage I, the chance for long-term survival decreases.

(SEE ALSO: Cancer; Human Papillomavirus Infection; Pap Smear; Screening)

Bibliography

Benedet, J. L.; Miller, D. M.; and Nickerson, K. G. (1992). "Results of Conservative Management of Cervical Intraepithelial Neoplasia." Obstetric Gynecology 79:105.

Carmichael, J. A., and Maskens, P. D. (1989). "Cervical Dysplasia and Human Papillomavirus." American Journal of Obstetrics and Gynecology 160:916.

Hopkins, M. P., and Morley, G. W. (1991). "Radical Hysterectomy versus Radiation Therapy for Stage Ib Squamous Cell Cancer of the Cervix." Cancer 68:272.

Mitchell, M. F.; Hittleman, W. N.; Hong, W. K. et al. (1994). "The Natural History of Cervical Epithelial Neoplasm." Cancer Epidemiology Biomarkers Prevention 3:619.

Morrow, C. P., and Curtin, J. P. (1996). Gynecologic Cancer Surgery. New York: Churchhill Livingstone.

Sartori, E.; Fallo, L.; LaFace, B. et al. (1995). "Extended Radical Hysterectomy in Early-Stage Carcinoma of the Uterine Cervix: Tailoring the Radicality." International Journal of Gynaecological Cancer 5:143.

— THOMAS J. RUTHERFORD

Cervical cancer
Classification and external resources
Histopathologic image (H&E stain) of carcinoma in situ, stage 0.
ICD-10	C53
ICD-9	180
OMIM	603956
DiseasesDB	2278
MedlinePlus	000893
eMedicine	med/324  radio/140
MeSH	D002583

This large squamous carcinoma (bottom of picture) has obliterated the cervix and invaded the lower uterine segment. The uterus also has a round leiomyoma up higher.

Cervical cancer is malignant cancer of the cervix uteri or cervical area. It may present with vaginal bleeding but symptoms may be absent until the cancer is in its advanced stages.^[1] Treatment consists of surgery (including local excision) in early stages and chemotherapy and radiotherapy in advanced stages of the disease.

Pap smear screening can identify potentially precancerous changes. Treatment of high grade changes can prevent the development of cancer. In developed countries, the widespread use of cervical screening programs has reduced the incidence of invasive cervical cancer by 50% or more.^{[citation needed]}

Human papillomavirus (HPV) infection is a necessary factor in the development of nearly all cases of cervical cancer.^[1][2] HPV vaccine effective against the two strains of HPV that cause the most cervical cancer has been licensed in the U.S. and the EU. These two HPV strains together are currently responsible for approximately 70%^[3][4] of all cervical cancers. Since the vaccine only covers some high-risk types, women should seek regular Pap smear screening, even after vaccination.^[5]

Contents 1 Classification 2 Signs and symptoms 3 Causes 3.1 Human papillomavirus infection 3.2 Cofactors 4 Diagnosis 4.1 Biopsy procedures 4.2 Pathologic types 4.3 Staging 5 Treatment 6 Prevention 6.1 Awareness 6.2 Screening 6.3 Preventive Vaccination 6.4 Condoms 6.5 Nutrition 6.5.1 Fruits and vegetables 6.5.2 Vitamin A 6.5.3 Vitamin C 6.5.4 Vitamin E 6.5.5 Folic acid 6.5.6 Carotenoids 6.5.7 CoQ10 6.5.8 Fish oil 7 Prognosis 8 Epidemiology 9 History 10 See also 11 References and Notes 12 External links

Classification

The naming and classification of cervical carcinoma percursor lesions has changed many times over the 20th century. The World Health Organization classification^[6][7] system was descriptive of the lesions, naming them mild, moderate or severe dysplasia or carcinoma in situ (CIS). The term, Cervical Intraepithelial Neoplasia (CIN) was developed to place emphasis on the spectrum of abnormality in these lesions, and to help standardise treatment.^[7] It classifies mild dysplasia as CIN1, moderate dysplasia as CIN2, and severe dysplasia and CIS as CIN3. The most recent classification is the Bethesda System, which divides all cervical epithelial presursor lesions into 2 groups: Low-grade Squamous Intraepithelial Lesion (LSIL) and High-grade Squamous Intraepithelial Lesion (HSIL). LSIL corresponds to CIN1, and HSIL includes CIN2 and CIN3.^[7] More recently, CIN2 and CIN3 have been combined into CIN2/3.

Signs and symptoms

The early stages of cervical cancer may be completely asymptomatic.^[1][8] Vaginal bleeding, contact bleeding or (rarely) a vaginal mass may indicate the presence of malignancy. Also, moderate pain during sexual intercourse and vaginal discharge are symptoms of cervical cancer. In advanced disease, metastases may be present in the abdomen, lungs or elsewhere.

Symptoms of advanced cervical cancer may include: loss of appetite, weight loss, fatigue, pelvic pain, back pain, leg pain, single swollen leg, heavy bleeding from the vagina, leaking of urine or faeces from the vagina,^[9] and bone fractures.

Causes

Human papillomavirus infection

The most important risk factor in the development of cervical cancer is infection with a high-risk strain of human papillomavirus. The virus cancer link works by triggering alterations in the cells of the cervix, which can lead to the development of cervical intraepithelial neoplasia, which can lead to cancer.

Women who have many sexual partners (or who have sex with men or women who had many other partners) have a greater risk.^[10][11]

More than 150 types of HPV are acknowledged to exist (some sources indicate more than 200 subtypes).^[12][13] Of these, 15 are classified as high-risk types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, and 82), 3 as probable high-risk (26, 53, and 66), and 12 as low-risk (6, 11, 40, 42, 43, 44, 54, 61, 70, 72, 81, and CP6108),^[14] but even those may cause cancer. Types 16 and 18 are generally acknowledged to cause about 70% of cervical cancer cases. Together with type 31, they are the prime risk factors for cervical cancer.^[15]

Genital warts are caused by various strains of HPV which are usually not related to cervical cancer.

The medically accepted paradigm, officially endorsed by the American Cancer Society and other organizations, is that a patient must have been infected with HPV to develop cervical cancer, and is hence viewed as a sexually transmitted disease, but most women infected with high risk HPV will not develop cervical cancer.^[16] Use of condoms reduces, but does not always prevent transmission. Likewise, HPV can be transmitted by skin-to-skin-contact with infected areas. In males, HPV is thought to grow preferentially in the epithelium of the glans penis, and cleaning of this area may be preventative.

Cofactors

The American Cancer Society provides the following list of risk factors for cervical cancer: human papillomavirus (HPV) infection, smoking, HIV infection, chlamydia infection, dietary factors, hormonal contraception, multiple pregnancies, exposure to the hormonal drug diethylstilbestrol (DES) and a family history of cervical cancer.^[10] There is a possible genetic risk associated with HLA-B7.^{[citation needed]}

Despite the development of an HPV vaccine, some researchers argue that routine neonatal male circumcision is an acceptable way to lower the risk of cervical cancer in their future female sexual partners. Others maintain that the benefits do not outweigh the risks and/or consider the removal of healthy genital tissue from infants to be unethical as it cannot be reasonably assumed that a male would choose to be circumcised. There has not been any definitive evidence to support the claim that male circumcision prevents cervical cancer, although some researchers say there is compelling epidemiological evidence that men who have been circumcised are less likely to be infected with HPV.^[17] However, in men with low-risk sexual behaviour and monogamous female partners, circumcision makes no difference to the risk of cervical cancer.^[18]

Diagnosis

Biopsy procedures

While the pap smear is an effective screening test, confirmation of the diagnosis of cervical cancer or pre-cancer requires a biopsy of the cervix. This is often done through colposcopy, a magnified visual inspection of the cervix aided by using a dilute acetic acid (e.g. vinegar) solution to highlight abnormal cells on the surface of the cervix.^[1]

Further diagnostic procedures are loop electrical excision procedure (LEEP) and conization, in which the inner lining of the cervix is removed to be examined pathologically. These are carried out if the biopsy confirms severe cervical intraepithelial neoplasia.

Pathologic types

Cervical intraepithelial neoplasia, the precursor to cervical cancer, is often diagnosed on examination of cervical biopsies by a pathologist. Histologic subtypes of invasive cervical carcinoma include the following:^[19][20] Though squamous cell carcinoma is the cervical cancer with the most incidence, the incidence of adenocarcinoma of the cervix has been increasing in recent decades^[1].

• squamous cell carcinoma (about 80-85%^{[citation needed]})
• adenocarcinoma (about 15% of cervical cancers in the UK^[6])
• adenosquamous carcinoma
• small cell carcinoma
• neuroendocrine carcinoma

Non-carcinoma malignancies which can rarely occur in the cervix include

• melanoma
• lymphoma

Note that the FIGO stage does not incorporate lymph node involvement in contrast to the TNM staging for most other cancers.

For cases treated surgically, information obtained from the pathologist can be used in assigning a separate pathologic stage but is not to replace the original clinical stage.

For premalignant dysplastic changes, the CIN (cervical intraepithelial neoplasia) grading is used.

Staging

Cervical cancer is staged by the International Federation of Gynecology and Obstetrics (FIGO) staging system, which is based on clinical examination, rather than surgical findings. It allows only the following diagnostic tests to be used in determining the stage: palpation, inspection, colposcopy, endocervical curettage, hysteroscopy, cystoscopy, proctoscopy, intravenous urography, and X-ray examination of the lungs and skeleton, and cervical conization.

The TNM staging system for cervical cancer is analogous to the FIGO stage.

• Stage 0 - full-thickness involvement of the epithelium without invasion into the stroma (carcinoma in situ)
• Stage I - limited to the cervix
  • IA - diagnosed only by microscopy; no visible lesions
    • IA1 - stromal invasion less than 3 mm in depth and 7 mm or less in horizontal spread
    • IA2 - stromal invasion between 3 and 5 mm with horizontal spread of 7 mm or less
  • IB - visible lesion or a microscopic lesion with more than 5 mm of depth or horizontal spread of more than 7 mm
    • IB1 - visible lesion 4 cm or less in greatest dimension
    • IB2 - visible lesion more than 4 cm
• Stage II - invades beyond cervix
  • IIA - without parametrial invasion, but involve upper 2/3 of vagina
  • IIB - with parametrial invasion
• Stage III - extends to pelvic wall or lower third of the vagina
  • IIIA - involves lower third of vagina
  • IIIB - extends to pelvic wall and/or causes hydronephrosis or non-functioning kidney
• IVA - invades mucosa of bladder or rectum and/or extends beyond true pelvis
• IVB - distant metastasis

Treatment

Microinvasive cancer (stage IA) is usually treated by hysterectomy (removal of the whole uterus including part of the vagina). For stage IA2, the lymph nodes are removed as well. An alternative for patients who desire to remain fertile is a local surgical procedure such as a loop electrical excision procedure (LEEP) or cone biopsy.^[21]

If a cone biopsy does not produce clear margins,^[22] one more possible treatment option for patients who want to preserve their fertility is a trachelectomy.^[23] This attempts to surgically remove the cancer while preserving the ovaries and uterus, providing for a more conservative operation than a hysterectomy. It is a viable option for those in stage I cervical cancer which has not spread; however, it is not yet considered a standard of care,^[24] as few doctors are skilled in this procedure. Even the most experienced surgeon cannot promise that a trachelectomy can be performed until after surgical microscopic examination, as the extent of the spread of cancer is unknown. If the surgeon is not able to microscopically confirm clear margins of cervical tissue once the patient is under general anesthesia in the operating room, a hysterectomy may still be needed. This can only be done during the same operation if the patient has given prior consent. Due to the possible risk of cancer spread to the lymph nodes in stage 1b cancers and some stage 1a cancers, the surgeon may also need to remove some lymph nodes from around the uterus for pathologic evaluation.

A radical trachelectomy can be performed abdominally^[25] or vaginally^[26] and there are conflicting opinions as to which is better.^[27] A radical abdominal trachelectomy with lymphadenectomy usually only requires a two to three day hospital stay, and most women recover very quickly (approximately six weeks). Complications are uncommon, although women who are able to conceive after surgery are susceptible to preterm labor and possible late miscarriage.^[28] It is generally recommended to wait at least one year before attempting to become pregnant after surgery.^[29] Recurrence in the residual cervix is very rare if the cancer has been cleared with the trachelectomy.^[24] Yet, it is recommended for patients to practice vigilant prevention and follow up care including pap screenings/colposcopy, with biopsies of the remaining lower uterine segment as needed (every 3-4 months for at least 5 years) to monitor for any recurrence in addition to minimizing any new exposures to HPV through safe sex practices until one is actively trying to conceive.

Early stages (IB1 and IIA less than 4 cm) can be treated with radical hysterectomy with removal of the lymph nodes or radiation therapy. Radiation therapy is given as external beam radiotherapy to the pelvis and brachytherapy (internal radiation). Patients treated with surgery who have high risk features found on pathologic examination are given radiation therapy with or without chemotherapy in order to reduce the risk of relapse.

Larger early stage tumors (IB2 and IIA more than 4 cm) may be treated with radiation therapy and cisplatin-based chemotherapy, hysterectomy (which then usually requires adjuvant radiation therapy), or cisplatin chemotherapy followed by hysterectomy.

Advanced stage tumors (IIB-IVA) are treated with radiation therapy and cisplatin-based chemotherapy.

On June 15, 2006, the US Food and Drug Administration approved the use of a combination of two chemotherapy drugs, hycamtin and cisplatin for women with late-stage (IVB) cervical cancer treatment.^[30] Combination treatment has significant risk of neutropenia, anemia, and thrombocytopenia side effects. Hycamtin is manufactured by GlaxoSmithKline.

Prevention

Awareness

According to the US National Cancer Institute's 2005 Health Information National Trends survey, only 40% of American women surveyed had heard of human papillomavirus (HPV) infection and only 20% had heard of its link to cervical cancer.^[31] In 2008 an estimated 3,870 women in the US will die of cervical cancer, and around 11,000 new cases are expected to be diagnosed.^[32]

Screening

The widespread introduction of the Papanicolaou test, or Pap smear for cervical cancer screening has been credited with dramatically reducing the incidence and mortality of cervical cancer in developed countries.^[8] Abnormal Pap smear results may suggest the presence of cervical intraepithelial neoplasia (potentially premalignant changes in the cervix) before a cancer has developed, allowing examination and possible preventive treatment. Recommendations for how often a Pap smear should be done vary from once a year to once every five years. The ]] (ACS) recommends that cervical cancer screening should begin approximately three years after the onset of vaginal intercourse and/or no later than twenty-one years of age.^[33] Guidelines vary on how long to continue screening, but well screened women who have not had abnormal smears can stop screening about age 65 (USPSTF) to 70 (ACS). If premalignant disease or cervical cancer is detected early, it can be monitored or treated relatively noninvasively, and without impairing fertility.

Until recently the Pap smear has remained the principal technology for preventing cervical cancer. However, following a rapid review of the published literature, originally commissioned by NICE ^[34], liquid based cytology has been incorporated within the UK national screening programme. Although it was probably intended to improve on the accuracy of the Pap test, its main advantage has been to reduce the number of inadequate smears from around 9% to around 1%.^[35] This reduces the need to recall women for a further smear.

Automated technologies have been developed with the aim of improving on the interpretation of smears, normally carried out by cytotechnologists. Unfortunately these on the whole have proven less useful; although the more recent reviews suggest that generally they may be no worse than human interpretation ^[36].

The HPV test is a newer technique for cervical cancer triage which detects the presence of human papillomavirus infection in the cervix. It is more sensitive than the pap smear (less likely to produce false negative results), but less specific (more likely to produce false positive results) and its role in routine screening is still evolving. Since more than 99% of invasive cervical cancers worldwide contain HPV, some researchers recommend that HPV testing be done together with routine cervical screening.^[15] But, given the prevalence of HPV (around 80% infection history among the sexually active population) others suggest that routine HPV testing would cause undue alarm to carriers.

HPV testing can reduce the incidence of grade 2 or 3 cervical intraepithelial neoplasia or cervical cancer detected by subsequent screening tests among women 32-38 years old according to a randomized controlled trial.^[37] The relative risk reduction was 41.3%. For patients at similar risk to those in this study (63.0% had CIN 2-3 or cancer), this leads to an absolute risk reduction of 26%. 3.8 patients must be treated for one to benefit (number needed to treat = 3.8). Click here to adjust these results for patients at higher or lower risk of CIN 2-3.

Preventive Vaccination

Main article: HPV vaccine

Merck & Co. has developed a vaccine against four strains of HPV (6,11,16,18), called Gardasil. It is now on the market after receiving approval from the US Food and Drug Administration on June 8, 2006.^[3] Gardasil has also been approved in the EU.^[38]

GlaxoSmithKline has developed a vaccine called Cervarix which has been shown to be 100% effective in preventing HPV strains 16 and 18 and is effective for more than four years.^[39] Cervarix has been approved some places and is in approval process elsewhere.^[40]

Neither Merck & Co. nor GlaxoSmithKline invented the vaccine. The vaccine's key developmental steps are claimed by the National Cancer Institute in the US, the University of Rochester in New York, Georgetown University in Washington, DC, Dartmouth College in Hanover, NH, and the Queensland University in Brisbane, Australia. Both Merck & Co. and GlaxoSmithKline have licensed patents from all of these parties.^[41]

Together, HPV types 16 and 18 currently cause about 70% of cervical cancer cases. HPV types 6 and 11 cause about 90% of genital wart cases.

HPV vaccines are targeted at girls and women of age 9 to 26 because the vaccine only works if given before infection occurs; therefore, public health workers are targeting girls before they begin having sex. The use of the vaccine in men to prevent genital warts and interrupt transmission to women is initially considered only a secondary market.

The high cost of this vaccine has been a cause for concern. Several countries have or are considering programs to fund HPV vaccination.

Condoms

Condoms may also be useful in treating potentially precancerous changes in the cervix. Exposure to semen appears to increase the risk of precancerous changes (CIN 3), and use of condoms helps to cause these changes to regress and helps clear HPV.^[42] One study suggests that prostaglandin in semen may fuel the growth of cervical and uterine tumours and that affected women may benefit from the use of condoms.^[43][44]

Nutrition

Fruits and vegetables

Higher levels of vegetable consumption were associated with a 54% decrease risk of HPV persistence.^[45] Consumption of papaya at least once a week was inversely associated with persistent HPV infection.^[46]

Vitamin A

There is weak evidence to suggest a significant deficiency of retinol can increase chances of cervical dysplasia, independently of HPV infection. A small (n~=500) case-control study of a narrow ethnic group (native Americans in New Mexico) assessed serum micro-nutrients as risk factors for cervical dysplasia. Subjects in the lowest serum retinol quartile were at increased risk of CIN I compared with women in the highest quartile.^[47]

However, the study population had low overall serum retinol, suggesting deficiency. A study of serum retinol in a well-nourished population reveals that the bottom 20% had serum retinol close to that of the highest levels in this New Mexico sub-population.^[48]

Vitamin C

Risk of type-specific, persistent HPV infection was lower among women reporting intake values of vitamin C in the upper quartile compared with those reporting intake in the lowest quartile.^[46]

Vitamin E

HPV clearance time was significantly shorter among women with the highest compared with the lowest serum levels of tocopherols, but significant trends in these associations were limited to infections lasting </=120 days. Clearance of persistent HPV infection (lasting >120 days) was not significantly associated with circulating levels of tocopherols. Results from this investigation support an association of micronutrients with the rapid clearance of incident oncogenic HPV infection of the uterine cervix.^[49]

A statistically significantly lower level of alpha-tocopherol was observed in the blood serum of HPV-positive patients with cervical intraepithelial neoplasia. The risk of dysplasia was four times higher for an alpha-tocopherol level < 7.95 mumol/l.^[50]

Folic acid

Higher folate status was inversely associated with becoming HPV test-positive. Women with higher folate status were significantly less likely to be repeatedly HPV test-positive and more likely to become test-negative. Studies have shown that lower levels of antioxidants coexisting with low levels of folic acid increases the risk of CIN development. Improving folate status in subjects at risk of getting infected or already infected with high-risk HPV may have a beneficial impact in the prevention of cervical cancer.^[51][52]

However, another study showed no relationship between folate status and cervical dysplasia.^[47]

Carotenoids

Higher circulating levels of carotenoids were associated with a significant decrease in the clearance time of type-specific HPV infection, particularly during the early stages of infection (</=120 days). Clearance of persistent HPV infection (lasting >120 days) was not significantly associated with circulating levels of carotenoids.^[49]

The likelihood of clearing an oncogenic HPV infection is significantly higher with increasing levels of lycopenes.^[53] A 56% reduction in HPV persistence risk was observed in women with the highest plasma [lycopene] concentrations compared with women with the lowest plasma lycopene concentrations. These data suggests that vegetable consumption and circulating lycopene may be protective against HPV persistence.^[45][46][54]

CoQ10

Women who had either CIN or cervical cancer had markedly lower levels of CoQ10 in their blood and in their cervical cells than the women who were healthy.^{[citation needed]}

Fish oil

In a 1999 study, Docosahexaenoic acid inhibited growth of HPV16 immortalized cells.^[55]

Prognosis

Prognosis depends on the stage of the cancer. With treatment, the 5-year relative survival rate for the earliest stage of invasive cervical cancer is 92%, and the overall (all stages combined) 5-year survival rate is about 72%. These statistics may be improved when applied to women newly diagnosed, bearing in mind that these outcomes may be partly based on the state of treatment five years ago when the women studied were first diagnosed.^[32]

With treatment, 80 to 90% of women with stage I cancer and 50 to 65% of those with stage II cancer are alive 5 years after diagnosis. Only 25 to 35% of women with stage III cancer and 15% or fewer of those with stage IV cancer are alive after 5 years.^[56]

According to the International Federation of Gynecology and Obstetrics, survival improves when radiotherapy is combined with cisplatin-based chemotherapy.^[57]

As the cancer metastasizes to other parts of the body, prognosis drops dramatically because treatment of local lesions is generally more effective than whole body treatments such as chemotherapy.

Interval evaluation of the patient after therapy is imperative. Recurrent cervical cancer detected at its earliest stages might be successfully treated with surgery, radiation, chemotherapy, or a combination of the three. Thirty-five percent of patients with invasive cervical cancer have persistent or recurrent disease after treatment.^[58]

Average years of potential life lost from cervical cancer are 25.3 (SEER Cancer Statistics Review 1975-2000, National Cancer Institute (NCI)). Approximately 4,600 women were projected to die in 2001 in the US of cervical cancer (DSTD), and the annual incidence was 13,000 in 2002 in the US, as calculated by SEER. Thus the ratio of deaths to incidence is approximately 35.4%.

Regular screening has meant that pre cancerous changes and early stage cervical cancers have been detected and treated early. Figures suggest that cervical screening is saving 5,000 lives each year in the UK by preventing cervical cancer.^[59] About 1,000 women per year die of cervical cancer in the UK.

Regular two-yearly Pap tests can reduce the incidence of cervical cancer by up to 90% in Australia, and save 1,200 Australian women dying from the disease each year. ^[60]

Epidemiology

Worldwide, cervical cancer is the fifth most deadly cancer in women.^[61] It affects about 16 per 100,000 women per year and kills about 9 per 100,000 per year.^[62]

In the United States, it is only the 8th most common cancer of women. In 1998, about 12,800 women were diagnosed in the US and about 4,800 died.^[8] Among gynecological cancers it ranks behind endometrial cancer and ovarian cancer. The incidence and mortality in the US are about half those for the rest of the world, which is due in part to the success of screening with the Pap smear.^[8] The incidence of new cases of cervical cancer in the United States was 7 per 100,000 women in 2004.^[63]

In the United Kingdom, the incidence is 9.1/100,000 per year (2005), similar to the rest of Northern Europe, and mortality is 3.1/100,000 per year (2006) (Cancer Research UK Cervical cancer statistics for the UK)^[64]. With a 42% reduction from 1988-1997 the NHS implemented screening programme has been highly successful, screening the highest risk age group (25–49 years) every 3 years, and those ages 50–64 every 5 years.

In Canada, an estimated 1,300 women will be diagnosed with cervical cancer in 2008 and 380 will die.^[65]

In Australia, there were 734 cases of cervical cancer (2005).The number of women diagnosed with cervical cancer has dropped on average by 4.5% each year since organised screening began in 1991 (1991-2005). ^[66].

Worldwide it is estimated that there are 473,000 cases of cervical cancer, and 253,500 deaths per year.^[67]

History

• 400 BCE - Hippocrates: cervical cancer incurable
• 1925 - Hans Hinselmann: invented colposcope
• 1928 - Papanicolaou: developed Pap technique
• 1941 - Papanicolaou and Trout: Pap screening
• 1946 - Ayer: spatula to scrape the cervix
• 1976 - Zur Hausen and Gisam: found HPV DNA in cervical cancer and warts
• 1988 - Bethesda System for Pap results developed

Epidemiologists working in the early 20th century noted that:

1. Cervical cancer was common in female sex workers.
2. It was rare in nuns, except for those who had been sexually active before entering the convent. (Rigoni in 1841)
3. It was more common in the second wives of men whose first wives had died from cervical cancer.
4. It was rare in Jewish women.^[68]
5. In 1935, Syverton and Berry discovered a relationship between RPV (Rabbit Papillomavirus) and skin cancer in rabbits. (HPV is species specific and therefore cannot be transmitted to rabbits)

This led to the deduction that cervical cancer could be caused by a sexually transmitted agent. Initial research in the 1950s and 1960s put the blame on smegma (e.g. Heins et al. 1958)^[69] , but it wasn't until the 1970s that human papillomavirus (HPV) was identified. A description by electron microscopy was given earlier in 1949 and HPV-DNA was identified in 1963. It has since been demonstrated that HPV is implicated in virtually all cervical cancers.^[4] Specific viral subtypes implicated are HPV 16, 18, 31, 45 and others.

See also

• List of cervical cancer patients
• Jade Goody
• Eva Peron

References and Notes

1. ^ ^{a b c d e} Kumar, Vinay; Abbas, Abul K.; Fausto, Nelson; & Mitchell, Richard N. (2007). Robbins Basic Pathology ((8th ed.) ed.). Saunders Elsevier. pp. 718–721. ISBN 978-1-4160-2973-1. 
2. ^ Walboomers JM, Jacobs MV, Manos MM, et al (1999). "Human papillomavirus is a necessary cause of invasive cervical cancer worldwide". J. Pathol. 189 (1): 12–9. doi:10.1002/(SICI)1096-9896(199909)189:1<12::AID-PATH431>3.0.CO;2-F. PMID 10451482. 
3. ^ ^{a b} "FDA Licenses New Vaccine for Prevention of Cervical Cancer". U.S. Food and Drug Administration. 2006-06-08. http://www.fda.gov/bbs/topics/NEWS/2006/NEW01385.html. Retrieved on 2007-12-02. 
4. ^ ^{a b} Lowy DR, Schiller JT (2006). "Prophylactic human papillomavirus vaccines.". J. Clin. Invest. 116 (5): 1167–73. doi:10.1172/JCI28607. PMID 16670757. http://www.jci.org/articles/view/JCI28607. Retrieved on 2007-12-01. 
5. ^ "Human Papillomavirus (HPV) Vaccines: Q & A - National Cancer Institute". http://www.cancer.gov/cancertopics/factsheet/risk/HPV-vaccine. Retrieved on 2008-07-18. 
6. ^ ^{a b} "Cancer Research UK website". http://info.cancerresearchuk.org/cancerstats/types/cervix/incidence/. Retrieved on 2009-01-03. 
7. ^ ^{a b c} DeMay, M (2007). Practical principles of cytopathology. Revised edition.. ISBN 978-0-89189-549-7. 
8. ^ ^{a b c d} Canavan TP, Doshi NR (2000). "Cervical cancer.". Am Fam Physician 61 (5): 1369–76. PMID 10735343. http://www.aafp.org/afp/20000301/1369.html. Retrieved on 2007-12-01. 
9. ^ Nanda, Rita (2006-06-09). "Cervical cancer". MedlinePlus Medical Encyclopedia. National Institutes of Health. http://www.nlm.nih.gov/medlineplus/ency/article/000893.htm. Retrieved on 2007-12-02. 
10. ^ ^{a b} "What Causes Cancer of the Cervix?". American Cancer Society. 2006-11-30. http://www.cancer.org/docroot/CRI/content/CRI_2_2_2X_What_causes_cancer_of_the_cervix_Can_it_be_prevented_8.asp?sitearea=. Retrieved on 2007-12-02. 
11. ^ Marrazzo JM, Koutsky LA, Kiviat NB, Kuypers JM, Stine K (2001). "Papanicolaou test screening and prevalence of genital human papillomavirus among women who have sex with women.". Am J Public Health 91 (6): 947–52. PMID 11392939. http://www.ajph.org/cgi/pmidlookup?view=long&pmid=11392939. Retrieved on 2007-12-30. 
12. ^ "HPV Type-Detect". Medical Diagnostic Laboratories. 2007-10-30. http://www.mdlab.com/html/testing/hpv_typedetect.html. Retrieved on 2007-12-02. 
13. ^ Gottlieb, Nicole (2002-04-24). "A Primer on HPV". Benchmarks. National Cancer Institute. http://www.cancer.gov/newscenter/benchmarks-vol2-issue4/page2. Retrieved on 2007-12-02. 
14. ^ Muñoz N, Bosch FX, de Sanjosé S, Herrero R, Castellsagué X, Shah KV, Snijders PJ, Meijer CJ (2003). "Epidemiologic classification of human papillomavirus types associated with cervical cancer.". N. Engl. J. Med. 348 (6): 518–27. doi:10.1056/NEJMoa021641. PMID 12571259. http://content.nejm.org/cgi/pmidlookup?view=short&pmid=12571259&promo=ONFLNS19. Retrieved on 2007-12-01. 
15. ^ ^{a b} Walboomers JM, Jacobs MV, Manos MM, Bosch FX, Kummer JA, Shah KV, Snijders PJ, Peto J, Meijer CJ, Muñoz N (1999). "Human papillomavirus is a necessary cause of invasive cervical cancer worldwide.". J. Pathol. 189 (1): 12–9. doi:10.1002/(SICI)1096-9896(199909)189:1<12::AID-PATH431>3.0.CO;2-F. PMID 10451482. 
16. ^ Snijders PJ, Steenbergen RD, Heideman DA, Meijer CJ (2006). "HPV-mediated cervical carcinogenesis: concepts and clinical implications.". J. Pathol. 208 (2): 152–64. doi:10.1002/path.1866. PMID 16362994. 
17. ^ Nader, Carol (2005-02-16). "Expert says circumcision makes sex safer". The Age (Fairfax Media). http://www.theage.com.au/articles/2005/02/15/1108230001471.html. Retrieved on 2007-12-02. 
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External links

• Cervical cancer at the Open Directory Project
• Cervical cancer at the Yahoo! Directory

v • d • e Papillomavirus - Human papillomavirus Related diseases Cervical cancer, Factor in other cancers (Anal, Vulvar, Penile, Orophyrengeal), Warts (genital, plantar, flat, respiratory papillomatosis), Papilloma, epidermodysplasia verruciformis Vaccine HPV vaccine (Gardasil, Cervarix) Screening Pap test - Cytopathology results Bethesda System Colposcopy Biopsy histology Cervical intraepithelial neoplasia (CIN), koilocyte Treatment Cervical conization, Loop electrical excision procedure (LEEP) History Georgios Papanikolaou, Harald zur Hausen

v • d • e Tumors: urogenital neoplasia · genital neoplasia (C51-C63/D25-29, 179-187/218-222) Female Ovaries Glandular and epithelial Clear cell adenocarcinoma · Endometrioid tumor CMS: Krukenberg tumor · Serous cystadenoma/Mucinous cystadenoma · Cystadenocarcinoma/Papillary serous cystadenocarcinoma Sex cord-gonadal stromal Sertoli-Leydig cell tumour · Thecoma · Granulosa cell tumour · Luteoma Connective tissue Fibroma (Meigs syndrome) · Surface epithelial-stromal tumor (Brenner tumour) Germ cell Dysgerminoma · Embryonal carcinoma · Gonadoblastoma · Teratoma · Choriocarcinoma Fallopian tube Adenomatoid tumor Uterus Uterine sarcoma · Leiomyosarcoma Endometrium (Endometrioid tumor), (Uterine papillary serous carcinoma), (Clear cell carcinoma) Adenomyoma Cervix (SCC, Cervical intraepithelial neoplasia) Vagina SCC · Botryoid rhabdomyosarcoma · Adenocarcinoma/Clear cell adenocarcinoma Vulva Papillary hidradenoma · Extramammary Paget's disease Placenta Choriocarcinoma Male Testicles Sex cord-gonadal stromal Sertoli-Leydig cell tumour (Sertoli cell tumor, Leydig cell tumor) Germ cell G Seminoma (Spermatocytic seminoma) · Intratubular germ cell neoplasia NG Embryonal carcinoma · Endodermal sinus tumor · Gonadoblastoma · Teratoma · Choriocarcinoma · Embryoma Prostate Adenocarcinoma · Prostatic intraepithelial neoplasia (HGPIN) · Small cell carcinoma · Transitional cell carcinoma Penis Carcinoma (Extramammary Paget's disease) · Bowen's disease · Bowenoid papulosis · Erythroplasia of Queyrat See also noncongenital, congenital

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