Medially reviewed by Dr. C.H. Weaver M.D. updated 8/2021

Cervical cancer is the third most common female cancer and the most common cause of death from gynecologic cancers worldwide. Each year in the United States, more than 13,000 people are diagnosed with cancer of the cervix and more than 4,000 will die of their disease.

Progress has been slow in the management of cervical cancer but there are some recent advances that offer hope. Over the past 50 years there have really only been three major developments in the management of cervical cancer.

  • The development of the Pap smear to facilitate early detection.
  • The recognition that a combination of cisplatin chemotherapy and radiation improves outcomes of locally advanced cancer.
  • The recognition that human papilloma virus causes cervical cancer, leading to the development of an effective vaccine. Routine HPV vaccination is recommended for both boys and girls age 11-12.

Precision medicine and immune-oncology represent the best hope for the future.

The cervix is a female reproductive organ that forms the lower portion of the uterus or womb. The uterus and cervix lie in the pelvis, on top of the vagina, in between the rectum and bladder. The cervix forms the part of the birth canal that opens to the vagina.

The surface layer of the cervix is mostly composed of squamous cells which merge with the glandular cells lining the cervical canal of the uterus. The area of merging is called the squamo-columnar junction and the area on the cervix outside of this junction is called the transformation zone. Cervical cancer occurs when cervical cells grow out of control, typically in the transformation zone. When cells grow out of control, they spread and grow throughout the cervix and may invade and destroy neighboring organs or break away and spread (metastasize) through the bloodstream and lymphatic system to other parts of the body.

Symptoms of Cervical Cancer

Early-stage cervical cancer generally produces no signs or symptoms, however symptoms of more advanced cervical cancer may include:

  • Vaginal bleeding after intercourse.
  • Vaginal bleeding between periods or after menopause
  • Watery, bloody vaginal discharge that may be heavy and have a foul odor
  • Pelvic pain or pain during intercourse

Cause of Cervical Cancer

Cervical cancer begins when healthy cells acquire a genetic change (mutation) that causes them to turn into abnormal cells. Although it isn’t clear what causes cervical cancer the human papilloma virus (HPV) clearly plays a role.

The type of cervical cancer helps determine the prognosis and treatment. The main types of cervical cancer are:

  • Squamous cell carcinoma begins in the thin, flat cells (squamous cells) lining the outer part of the cervix, which projects into the vagina.
  • Adenocarcinoma begins in the column-shaped glandular cells that line the cervical canal.

Risk factors for Cervical Cancer

Risk factors for cervical cancer include:

  • Human Papilloma Virus
  • Multiple sexual partners. The greater the number of sexual partners the greater the greater your chance of acquiring HPV.
  • Early sexual activity. Having sex at an early age increases the risk of HPV.
  • A weak immune system. Individuals are more likely to develop cervical cancer if their immune system is weakened by another health condition and infection with HPV.
  • Smoking. Smoking is associated with squamous cell cervical cancer.1,2

Diagnosis & Tests for Cervical Cancer

Doctors who care for women routinely perform pelvic examinations and a Papanicolaou (Pap) smear to screen for cervical cancer in the cells on the surface of the cervix. During a Pap smear, a sample of cells from the cervix is taken with a small wooden spatula or brush and examined under the microscope. Women may first become aware that they have cervical cancer when a suspicious area is identified during a pelvic examination or an abnormal Pap smear. If a suspicious or a precancerous lesion is found, a biopsy and additional tests will be recommended to determine whether a precancerous lesion or invasive cancer exists. A biopsy is the removal of a sample of tissue from the cervix in order to evaluate cervical cells under a microscope.

Cells taken from the surface of the cervix can appear abnormal, but may not be cancer. These abnormal cells, however, may be the first step in a series of changes that lead to cancer. Doctors refer to the abnormal cells as “precancerous” and have used different terms to refer to them, such as squamous intraepithelial lesions, dysplasia, cervical intraepithelial neoplasia or carcinoma in situ. Precancerous disease involves only the surface of the cervix. When the abnormal cells begin to spread deeper into the cervix, they are referred to as invasive cancer of the cervix.

Physicians may use a colposcope (lighted microscope) to better visualize the cervix or to perform a biopsy. If the doctor cannot determine whether the abnormal cells are only on the surface of the cervix, an endocervical curettage or conization may be recommended.

  • Endocervical Curettage: This procedure may be performed at the same time as the punch biopsy, especially if there is concern that there may be abnormal tissue past the opening of the cervix that cannot be seen with the colposcope. During an endocervical curettage, a small spoon-shaped instrument called a curette is used to scrape cells away from inside the endocervical canal. These cells are then sent to the lab for examination under a microscope.
  • Conization: If the information obtained from colposcopy, biopsy and/or curettage is inconclusive, a physician might perform a conization. During a conization, or cone biopsy, the physician removes a cone-shaped sample of tissue from the cervical canal. The sample is then sent to the lab for examination. Conization can also serve as the primary treatment of precancerous cervical cancer, as a large sample is removed and can sometimes remove any cancerous tissue in the process. This is a fairly intrusive procedure and can involve significant complications.
  • Loop Electrosurgical Excision Procedure (LEEP): Loop electrosurgical excision procedure (LEEP), also called large loop excision of the transformation zone (LLETZ), is simpler and less invasive than conization. During LEEP, a physician applies a local anesthetic to the cervix and then inserts a wire loop into the vagina. A high frequency electrical current is run through the wire to remove abnormal tissue from both the cervix and the endocervical canal. Like conization, LEEP can be used not only as a diagnostic tool, but also as treatment, as large and deep sections of abnormal tissue can be removed.
  • Endometrial biopsy: An endometrial biopsy refers to the removal of a tissue sample from the lining of the uterus (the endometrium). Endometrial biopsy may be performed in some women whose Pap test indicates atypical glandular cells.

Infrequently, it may still remain unclear whether the abnormal cells are confined to the cervix or arise from inside the uterus. In this situation, a dilatation and curettage (D and C) may be recommended. During a D and C, the cervical opening is stretched (dilated) and a curette is inserted to remove cells from the lining of the uterus and cervical canal.

HPV DNA Test The HPV DNA test involves testing cells collected from the cervix for infection with any of the types of HPV that are most likely to lead to cervical cancer.1,2

Staging of Cervical Cancer

When diagnosed with cervical cancer further tests are necessary to determine the extent of spread (stage) of the cancer. Cancer’s stage is a key factor in determining the best treatment.

Imaging tests. Tests such as X-rays, CT scans, magnetic resonance imaging (MRI) and positron emission tomography (PET) are used to help determine the stage and whether the cancer has spread beyond the cervix.

Precision Medicine & Personalized Cervical Cancer Care

The purpose of precision cancer medicine is not to categorize or classify cancers solely by site of origin, but to define the genomic alterations in the cancers DNA that are driving that specific cancer. Cancer used to be diagnosed solely by a visual microscopic examination of tumor tissue and all patients received the same chemotherapy. Precision cancer medicine utilizes molecular diagnostic & genomic testing, including DNA sequencing, to identify cancer-driving abnormalities in a cancer’s genome. Once a genetic abnormality is identified, a specific targeted therapy can be designed to attack a specific mutation or other cancer-related change in the DNA programming of the cancer cells. Precision cancer medicine uses targeted drugs and immunotherapies engineered to directly attack the cancer cells with specific abnormalities, leaving normal cells largely unharmed. Precision medicines are being developed for the treatment of cervical cancer and patients should ask their doctor about whether testing is appropriate.

Stages of Cervical Cancer

Stage 0 - Precancerous Changes to the Cervix-Precancerous lesion involves only the cells on the surface of the cervix.

Stage I Cervical Cancer-Cancer is confined to the cervix, and may be evident only under microscopic evaluation (stage IA) or apparent by visible or physical examination (stage IB).

Stage II Cervical Cancer-Cancer has spread beyond the cervix to involve the tissues surrounding the cervix (parametria) or the upper portion of the vagina.

Stage III Cervical Cancer-Cancer spreads beyond the cervix to the lower vagina or to the sides of the pelvis, or causes a blockage of drainage from the kidney, a condition called hydronephrosis.

Stage IV Cervical Cancer-Cancer invades structures adjacent to the cervix such as the bladder or rectum or has spread to other parts of the body such as the liver or lungs.

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Recurrent Cervical Cancer-Cervical cancer is still detected or has returned (recurred/relapsed) following an initial treatment with surgery, radiation therapy, and/or chemotherapy.

Screening & Prevention of Cervical Cancer

Physicians and individuals alike recognize that the best “treatment” of cancer is preventing its occurrence in the first place or detecting it early when it may be most treatable. Each year in the United States, there are an estimated 12,000 new cases of cervical cancer and 4,000 deaths due to the disease.1 Widespread use of a screening test called the Pap smear has led to a decline in the number of deaths resulting from cervical cancer. Continued progress and education about screening may allow for earlier detection and higher cure rates.

The chance of an individual developing cancer depends on both genetic and non-genetic factors. A genetic factor is an inherited, unchangeable trait, while a non-genetic factor is a variable in a person´s environment, which can often be changed. Non-genetic factors may include diet, exercise, or exposure to other substances present in our surroundings. These non-genetic factors are often referred to as environmental factors. Some non-genetic factors play a role in facilitating the process of healthy cells turning cancerous (i.e. the correlation between (HPV and cervical cancer) while other cancers have no known environmental correlation but are known to have a genetic predisposition. A genetic predisposition means that a person may be at higher risk for a certain cancer if a family member has that type of cancer.

Heredity or Genetic Factors

At this time, researchers have not identified any genetic factors that contribute to the development of cervical cancer.

Environmental or Non-Genetic Factors

HPV infection: The most important cause of cervical cancer is infection with a high-risk type of human papillomavirus (HPV). Human papillomaviruses consist of a group of more than 100 different viruses.2 Some types of HPV cause warts on the hands or feet; others cause genital warts; and some have been linked with cancer, most notably cervical cancer. The types of HPV most commonly linked with cervical cancer are HPV 16 and HPV 18, but several other high-risk types contribute to cancer as well.

The types of HPV that cause cervical cancer or genital warts are transmitted sexually. HPV infection is extremely common and generally occurs soon after an individual becomes sexually active. Although most infections resolve on their own, some persist and can lead to precancerous or cancerous changes to the cervix, vulva, vagina, penis, and anus. Persistent infections appear to pose the greatest cancer threat.

Sexual activity at an early age and with a greater number of partners: Sexual activity at a younger age and an increasing number of sexual partners are both associated with an increased risk of HPV infection and subsequent development of cervical cancer. Women who experience first sexual intercourse at age 17 years or younger or women who have had six or more lifetime sexual partners have approximately two to three times the risk of squamous cell carcinoma or adenocarcinoma of the cervix, compared with women aged 21 years or older or who have a single sexual partner.3

Chlamydia: Chlamydia trachomatis is another common sexually transmitted infection, and is frequently reported among women with cervical cancer. To clarify the role of chlamydia in cervical cancer, researchers in Sweden conducted a study to determine whether women with a history of chlamydia were more likely to have persistent HPV infections than women without a history of chlamydia.4 The researchers found that women who reported a history of chlamydia were roughly twice as likely to have persistent HPV as women without a history of chlamydia. Women who reported using condoms were less likely to have persistent HPV.

Human Immunodeficiency Virus (HIV): Human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2) are both associated with the development of acquired immunodeficiency syndrome (AIDS). Infection with HIV-1 or HIV-2 may contribute to the development of cervical cancer by suppressing the immune system.

Cigarette smoking: Cigarette smoking is consistently linked with an increased risk of developing cervical cancer. A recent study suggests that the link between smoking and cervical cancer may be explained at least in part by increased persistence of high-risk HPV infections in women who smoke.5

Reproductive factors: Among women infected with HPV, risk of cervical cancer appears to be increased among women who have had a greater number of full-term pregnancies or a longer duration of oral contraceptive use.6

Prevention of Cervical Cancer

Important approaches to the prevention of cervical cancer include prevention of HPV infection, as well as detection and treatment of precancerous changes to the cervix.

HPV vaccine: The development of vaccines that prevent infection with two high-risk types of HPV has heralded the start of a new era in cervical cancer prevention. Gardasil® and Cervarix® both protect against HPV types 16 and 18. Gardasil also protects against HPV types 6 and 11, which account for most cases of genital warts. Because HPV types 16 and 18 are thought to account for roughly 70 percent of all cases of cervical cancer, widespread use an HPV vaccine has the potential to eliminate most (but not all) cases of cervical cancer and precancerous changes to the cervix. It is important to note that these vaccines are intended to prevent infection with HPV and not to treat existing infections or cervical cancer. Because infection with HPV is extremely common and generally occurs soon after an individual becomes sexually active, vaccination is likely to have the greatest effect when administered before the teen years.2

Condom use: Because vaccination does not protect against all high-risk types of HPV, supplementing use of the vaccine with other approaches to HPV prevention will be important. Results from a study conducted among female college students suggest that consistent use of condoms reduces the likelihood of developing an HPV infection. During the year after first sexual intercourse, 37% of women became infected with HPV. Compared to women whose partners used condoms less than 5% of the time, women whose partners used condoms 100% of the time were 70% less likely to become infected with HPV, and women whose partners used condoms more than half of the time (but less than 100% of the time) were 50% less likely to become infected with HPV.7

Detection and Treatment of Precancerous Changes to the Cervix: Cervical cancer is generally preceded by precancerous changes to the cervix. Detection and treatment of these precancerous changes can prevent the development of cancer. The best way to identify precancerous cervical changes is through cervical cancer screening. Screening is discussed in the section below.

Screening and Early Detection of Cervical Cancer

For many types of cancer, progress in the areas of cancer screening and treatment has offered promise for earlier detection and higher cure rates. The term screening refers to the regular use of certain examinations or tests in persons who do not have any symptoms of a cancer but are at high risk for that cancer. When individuals are at high risk for a type of cancer, this means that they have certain characteristics or exposures, called risk factors that make them more likely to develop that type of cancer than those who do not have these risk factors. The risk factors are different for different types of cancer. An awareness of these risk factors is important because 

1) some risk factors can be changed (such as smoking or dietary intake), thus decreasing the risk for developing the associated cancer; and 

2) persons who are at high risk for developing a cancer can often undergo regular screening measures that are recommended for that cancer type. Researchers continue to study which characteristics or exposures are associated with an increased risk for various cancers, allowing for the use of more effective prevention, early detection, and treatment strategies.

Cervical cancer incidence and mortality have decreased substantially over the past 40 years, largely due to screening. Simply stated, screening saves lives.

The New HPV test ‘is simply better’ than the PAP Smear

The Pap test had long been the standard for cervical cancer screening. However, studies have suggested cytology-based screening is less efficient for those who have undergone HPV vaccination, resulting in a high rate of false-positive results. The FDA approved the HPV test in 2014 as a primary screening tool because it is superior to the Pap test. Research suggests that women screened for cervical cancer via primary HPV testing had a lower likelihood of developing cancerous lesions than women who underwent standard cytology testing. Updated guidelines issued by the American Cancer Society (ACS) in July 2020 recommend that cervical cancer screening with the HPV test be performed every 5 years beginning at age 25 and continuing to 65 years.13-15

The recommendation relies solely on the HPV test as the preferred test and phases out the Pap test and co-testing with the Pap test and HPV testing. The ACS says the update is based on “decades of studies comparing the effectiveness of HPV testing compared with cytology and bolstered by evidence of the impact of HPV vaccination, including a dramatic decline in cervical pre cancers and, more recently, cervical cancers among young women”. Not all physicians are in agreement with the recommendation citing research that HPV testing alone misses twice as much cervical cancer as co-testing. Women should discuss the role of co-testing with their doctor.14

  • Those aged 25 to 65 should have a primary HPV test every 5 years. If primary HPV testing is not available, screening may be done with either a co-test that combines an HPV test with a Papanicolaou (Pap) test every 5 years or a Pap test alone every 3 years.
  • Screening is not recommended for women over 65 who have had at least three consecutive negative Pap tests or at least two negative HPV tests in the past 10 years, with the most recent test in the past 5 years. Women in this age group who have a history of cervical pre-cancer (CIN2 or a more severe diagnosis) should continue routine screening for at least 20 years, even if this extends beyond age 65.
  • Women who have undergone a hysterectomy (with removal of the cervix) for reasons not related to cervical cancer or pre-cancer should no longer be screened.
  • Women who have been vaccinated against HPV should follow the age-specific recommendations in these guidelines (for unvaccinated women). Currently, there are no alternative screening recommendations for women vaccinated against HPV.

Could Global HPV Vaccine Programs Eradicate Cervical Cancer-HPV Related Diseases

The new guidelines are not intended for women with a history of cervical cancer, women who were exposed to DES (diethylstilbestrol) during a pregnancy, and women who are immunosuppressed (e.g., HIV positive).

References:

  1. American Cancer Society. Cancer Facts & Figures 2021.
  2. National Cancer Institute Fact Sheet. Human Papillomaviruses and Cancer: Questions and Answers.
  3. Berrington de González A, Green J; International Collaboration of Epidemiological Studies of Cervical Cancer: Comparison of risk factors for invasive squamous cell carcinoma and adenocarcinoma of the cervix: collaborative reanalysis of individual data on 8,097 women with squamous cell carcinoma and 1,374 women with adenocarcinoma from 12 epidemiological studies. Int J Cancer 120 (4): 885-91, 2007.
  4. Silins I, Ryd W, Strand A et al. Chlamydia trachomatis infection and persistence of human papillomavirus. International Journal of Cancer. 2005;116:110-115.
  5. Koshiol J, Schroeder J, Jamieson DJ et al. Smoking and Time to Clearance of Human Papillomavirus Infection in HIV-Seropositive and HIV-Seronegative Women. American Journal of Epidemiology. 2006;164:176-183.
  6. National Cancer Institute. Cervical Cancer (PDQ®): Prevention.
  7. Winer RL, Hughes JP, Feng Q et al. Condom Use and the Risk of Genital Human Papillomavirus Infection in Young Women. New England Journal of Medicine. 2006;354:2645-54.
  8. ACOG news release. First Cervical Cancer Screening Delayed Until Age 21. Less Frequent Pap Tests Recommended.November 20, 2009.
  9. Davey E, Barratt A, Irwig L et al. Effect of Study Design and Quality on Unsatisfactory Rates, Cytology Classifications, and Accuracy in Liquid-Based Versus Conventional Cervical Cytology: A Systematic Review. Lancet. 2006;367:122-32.
  10. Solomon D, Davey D, Kurman R et al. The 2001 Bethesda System: Terminology for Reporting Results of Cervical Cytology. JAMA. 2002;287:2114-2119.
  11. Wright TC, Cox JT, Massad LS, Twiggs LB, Wilkinson EJ. 2001 Consensus Guidelines for the Management of Women with Cervical Cytological Abnormalities. JAMA. 2002;287:2120-2129.
  12. Moyer VA on behalf of the US Preventive Services Task Force. Screening for cervical cancer: US Preventive Services Task Force Recommendation Statement. Annals of Internal Medicine. Early online publication March 14, 2012.
  13. The American Cancer Society Guidelines for the Prevention and Early Detection of Cervical Cancer.https://www.cancer.org/cancer/cervical-cancer/detection-diagnosis-staging/cervical-cancer-screening-guidelines.html#:~:text=Cervical%20cancer%20testing%20(screening%29%20should,test%20alone%20every%203%20years

  14. ACOG statement on cervical cancer screening guidelines. Available at: www.acog.org/news/news-releases/2020/07/acog-statement-on-cervical-cancer-screening-guidelines. Accessed Oct. 5, 2020.

  15. Kaufman HW, et al. Am J Clin Pathol. 2020.doi:10.1093/ajcp/aqaa074.