Christopher Dolinsky, MD and Christine Hill-Kayser, MD
Updated By Lara Bonner Millar, MD
Abramson Cancer Center of the University of Pennsylvania
Last Modified: December 18, 2013
The cervix is the name for the lowest part of the uterus. The uterus is an organ that only women have, and it is where a baby grows and develops when a woman is pregnant. During pregnancy, the uterus has an enormous increase in size. When a woman is not pregnant, the uterus is a small, pear-shaped organ that sits between a woman's rectum and her bladder. The cervix connects the uterus with the birth canal (the vagina). The cervix can both be visualized and sampled by your doctor during a routine pelvic examination in his or her office.
Cervical cancer develops when cells in the cervix begin to grow out of control and can then invade nearby tissues or spread throughout the body. Large collections of cells that grow abnormally are called tumors. Some tumors are not cancer, because they cannot spread or threaten someone's life. These are called benign tumors. The tumors that can spread throughout the body or invade nearby tissues are considered cancer and are called malignant tumors. Usually, cervix cancer is very slow growing, although in certain circumstances it can grow and spread quickly.
Cancers are characterized by the cells that they originally form from. The most common type of cervical cancer is called squamous cell carcinoma; it comes from cells that lie on the surface of the cervix known as squamous cells. Squamous cell cervical cancer compromises about 80% of all cervical cancers. The second most common form is adenocarcinoma; it comes from cells that make up glands in the cervix. The percentage of cervical cancers that are adenocarcinomas has risen since the 1970s, although no one knows exactly why. About 3% to 5% of cervical cancers have characteristics of both squamous and adenocarcinomas and are called adenosquamous carcinomas. There are a few other very rare types like small cell and neuroendocrine carcinoma that are so infrequent that they will not be discussed further here.
Cervical cancer is vastly more common in developing nations than it is in developed nations, and it is fairly rare in the United States. In the U.S. in 2013, an estimated 12,340 women in the United States were diagnosed with cervical cancer and 4,030 women in the United States died from cervical cancer. This puts cervical cancer as the 12th most common cancer that women develop, and the 14th most common cause of cancer death for women in the U.S. However, cervical cancer is the 2nd most common cause of cancer death in developing nations, with about 370,000 new cases annually having a 50% mortality rate. Decades ago, cervical cancer was the number one cause of cancer deaths in women in the U.S. There has been a 75% decrease in incidence and mortality from cervical cancer in developed nations over the past 50 years. Most of this decrease is attributed to the effective institution of cervical cancer screening programs (pap and/or HPV testing) in the wealthier nations.
Although there are several known risk factors for getting cervical cancer, no one knows exactly why one woman gets it and another doesn't. One of the most important risk factors for cervical cancer is infection with a virus called HPV (human papilloma virus). HPV is a sexually transmitted disease that is incredibly common in the population; most college-aged men and women have been exposed to HPV. HPV is the virus that causes genital warts, but having genital warts doesn't necessarily mean you are going to get cervical cancer. There are different subtypes, or strains, of HPV. Only certain subtypes are likely to cause cervical cancer, and the subtypes that cause warts are unlikely to cause a cancer. Often, infection with HPV causes no symptoms at all, until a woman develops a pre-cancerous lesion of the cervix. It should be stressed that only a very small percentage of women who have HPV will develop cervical cancer; so simply having HPV doesn't mean that you will get sick. However, almost all cervical cancers have evidence of HPV virus in them, so infection is a major risk factor for developing it.
Because infection with a sexually transmitted disease is a risk factor for cervical cancer, any risk factors for developing sexually transmitted diseases are also risk factors for developing cervical cancer. Women who have had multiple male sexual partners, began having sexual intercourse at an early age, or have had male sexual partners who are considered high risk (meaning that they have had many sexual partners and/or began having sexual intercourse at an early age) are at a higher risk for developing cervical cancer. Also, contracting any other sexually transmitted diseases (like herpes, gonorrhea, syphilis, or Chlamydia) increases a woman's risk. HIV infection is another risk factor for cervical cancer, but it may be so for a slightly different reason. It seems that any condition that weakens your immune system also increases your risk for developing cervical cancer. Conditions that weaken your immune system include HIV, having had an organ transplantation, and Hodgkin's disease. Another important risk factor for developing cervical cancer is smoking. Smokers are at least twice as likely as non-smokers to develop cervix tumors. Smoking may also increase the importance of the other risk factors for cancer. Finally, being in a low socioeconomic group seems to increase the likelihood for developing and dying from cervical cancer. This may be because of increased smoking rates, or perhaps because there are more barriers to getting annual screening exams. Cervical cancer is one of the few cancers that affects young women (in their twenties and even their teens), so no one who is sexually active is really too young to begin screening. Additionally, the risk for cervical cancer doesn't ever decline, so no one is too old to continue screening. Remember that all risk factors are based on probabilities, and even someone without any risk factors can still get cervical cancer. Proper screening and early detection are our best weapons in reducing the mortality associated with this disease.
Fortunately, there are several actions that women can take to decrease the risk of dying from cervix cancer. The first of these is undergoing regular Pap testing. Pap tests will be discussed further in the next section, but the reason that women have had such a drastic drop in cervical cancer cases and deaths in this country has been because of the Pap test and annual screening.
Recently, two vaccines, called Gardasil and Ceravix have been developed. These vaccines have been demonstrated to be effective in preventing infection with some strains of HPV, when given before a person is exposed to HPV. For this reason, is the vaccines are recommended and approved for girls and young women ages 9 – 26 years. Vaccination can also be given to boys, ages 9-26, to prevent genital warts and further spread of HPV in women and men. HPV is also a cause of penile and anal cancers and head & neck cancers.
For further prevention, women should try to reduce risk factors as much as possible. Don't start smoking, and if you are already a smoker, it is time to quit. Smoking has been shown to decrease the immune system’s ability to clear an HPV infection. Women can limit their numbers of sexual partners, and delay the onset of sexual activity to reduce risk, as more partners increases the likelihood of infection. Unfortunately, condoms do not protect you from developing HPV, so even though they can protect you from other sexually transmitted diseases and HIV, they cannot help lower your risk for being infected with HPV.
Many people are interested in preventing cervical cancer with vitamins or diets. Studies looking at beta-carotene and folic acid for preventing cervical cancer have shown no benefit. Some people think that anti-oxidants (like vitamin A and vitamin E) may play a role in cervical cancer prevention, but there is currently no convincing data that would suggest so. Further studies need to be performed before any nutritional recommendations can be made regarding cervix cancer prevention.
Cervical cancer is considered a preventable disease. It usually takes a very long time for pre-cancerous lesions to progress to invasive cancers and we have effective screening methods that can detect pre-cancerous lesions that can generally be cured without serious side effects. Effective screening programs in the United States have led to the drastic decline in the numbers of cervical cancer deaths in the last 50 years. For women who do end up with cervical cancer in developed nations, 60% of them either have never been screened or haven't been screened in the last five years. The importance of regular cervical cancer screening cannot be overstated.
The current hallmark of cervical cancer screening is the Pap test. Pap is short for Papanicolaou, the inventor of the test, who published a breakthrough paper back in 1941. A Pap test is easily performed in your doctor's office. During a pelvic examination, your doctor uses a wooden spatula and/or a brush to get samples of cervical cells. These cells are placed on a slide, fixed, and sent to a laboratory where an expert in examining cells under a microscope can look for cancerous changes. Many women find the exam uncomfortable, but rarely painful. Depending on the results of the test, your doctor may need to perform further examinations.
Although the Pap test is highly effective, it isn't a perfect test. Sometimes, the test may miss cells that have potential to become an invasive cancer. The test shouldn't be performed when you are menstruating; and if collection goes perfectly, even the best laboratories can miss abnormal cells. This is why women need to have the tests performed on a regular basis.
In November 2009, the America College of Obstetricians and Gynecologists (ACOG) released updated guidelines which recommend that women have their first Pap test at age 21. From ages 21 to 30, screening should be done every 2 years. Women 30 years and older, who have had three consecutive normal Paps, may decrease the screening to every three years. However, after having a new sexual partner, these women need to go back to yearly Pap testing. The ACOG guidelines also note that women with certain risk factors may need more frequent screening. These risk factors include being infected with human immunodeficiency virus (HIV), being immunosuppressed, having been exposed to diethylstilbestrol (DES) before birth, and having previously been treated for certain cervical abnormalities or cancer.
Women aged 65 to 70 years who have had at least three normal Pap tests and no abnormal Pap tests in the last 10 years may decide, after talking with their doctor, to stop having Pap tests. Women who have had a hysterectomy (surgery to remove the uterus and cervix) do not need to have a Pap test, unless the surgery was done as a treatment for a precancerous condition or cancer. Women who have had a "subtotal or supracervical" hysterectomy still have a cervix, and need to continue Pap testing. Women who have received the HPV vaccine should follow the same guidelines as unvaccinated women, as the vaccine does not prevent infection with all strains of HPV.
HPV testing is frequently done along with the Pap test. HPV testing can theoretically find the vast majority of women who are at risk for developing cervical cancer. The subtype of HPV predicts how likely it is to lead to a cervical cancer. The DNA of cervical cells can be tested to identify high-risk types of HPV that may be present. The FDA has approved HPV DNA tests for follow-up testing of women with abnormalities on a pap test. HPV DNA tests are also approved for general cervical cancer screening of women over the age of 30 when done together with a Pap test. Talk to your doctor about your options and the availability of HPV testing in your area. There are currently no approved tests to detect HPV infections in men.
Unfortunately, the early stages of cervical cancer usually do not have any symptoms. This is why it is important to have screening Pap tests. As a tumor grows in size, it can produce a variety of symptoms including:
Many of these symptoms are non-specific, and could represent a variety of different conditions; however, your doctor needs to see you if you have any of these problems.
The most common reason for your doctor to pursue the diagnosis of cervical cancer is if you have an abnormal Pap test. Pap tests exist to find pre-cancerous lesions in your cervix. A pre-cancerous lesion means that there are abnormal appearing cancer cells, but they haven't invaded past a tissue barrier in your cervix; thus a pre-cancerous lesion cannot spread or harm you. However, if left untreated, a pre-cancerous lesion can evolve to an invasive cancer. Pap tests are reported as no abnormal cells, abnormal cells of undetermined significance, low risk abnormal cells or high risk abnormal cells. Depending on your specific case, your doctor will decide how to proceed.
A report of no abnormal cells equates to a negative test, meaning you simply need to follow-up in one year. The abnormal cells of undetermined significance can be handled in three different ways. Women can either get a repeat Pap test in 4-6 months, they can get HPV testing, or they can be referred for colposcopy. Colposcopy is a procedure done during a pelvic exam with the aide of a colposcope, which is like a microscope. By using acetic acid on the cervix and examining it with a colposcope, your doctor can look for abnormal areas of your cervix. Then, the most abnormal areas can be biopsied. A biopsy is the only way to know for sure if you have cancer, because it allows your doctors to get cells that can be examined under a microscope. Once the tissue is removed, a doctor known as a pathologist will review the specimen. Colposcopy is uncomfortable, but not painful, and can be done in your gynecologist's office. Your doctor will decide how to proceed with the workup of a Pap test showing abnormal cells of undetermined significance depending on the details of your case. If repeat Pap tests are not normal, then you will be referred for colposcopy. If you test positive for HPV, you will be referred for colposcopy. Generally, most patients with low risk abnormal cells, or high risk abnormal cells will be immediately referred for colposcopy. If you are pregnant, an adolescent, HIV positive, or post-menopausal, your doctor may have slightly different recommendations. Also, sometimes your Pap test will show cells that look abnormal but could have come from higher in your uterus. There is a chance that if this happens, you will need to have your uterine lining sampled. Talk to your doctor about your Pap test results, and what you need to do next after an abnormal Pap smear.
If you are having symptoms (bleeding/discharge) from a cervical cancer, then it can probably be visualized during a pelvic exam. Any time your doctor can see a cervical tumor on pelvic exam, it will be immediately biopsied. When abnormal appearing tissue is noticed during a colposcopy, then it needs to be biopsied as well. There are a few different ways to do a biopsy. A punch biopsy may be used to remove a small section of the cervix. A LEEP (loop electrosurgical excision procedure) is another method to do a biopsy where a thin slice of the cervix is removed. Finally, a conization or cone biopsy may be performed. A cone biopsy removes a thicker section of the cervix, and allows the pathologist to see if malignant cells have invaded underneath the surface. The cone biopsy has the added value of sometimes being able to cure a pre-cancerous lesion that is localized to a small area. Treatments for cervical cancer and pre-cancerous lesions will be discussed further in the next section.
In order to guide treatment and offer some insight into prognosis, cervical cancer is staged into different groups. There are a few different staging systems, but the most popular one for cervical cancer is the FIGO system (International Federation of Gynecologists and Obstetricians). The FIGO system is a clinical staging system which means that the cancer is staged by a doctor's physical examination and the results of a biopsy. The FIGO staging system is for invasive cervical cancers, not pre-cancerous lesions. A simplified version of the FIGO staging system is:
Because the physical exam is so important for staging a cervical cancer, your doctors may want to do the most thorough examination while you are under anesthesia Other times, your doctors will want the results of other radiologic tests to better characterize your specific cancer. Tests like CAT scans (3-D x-rays) or MRIs (like a CAT scans but done with magnets) can examine the cervix and localized lymph nodes. X-rays may be taken of your bones and/or chest. Sometimes, your doctors may want to have a look in your bladder and do a cystoscopy, in which a lighted scope is inserted through your urethra into your bladder. You may get also get a proctosigmoidoscopy, which uses a lighted scope to examine your rectum and colon. Each patient is an individual so the specific tests people get will vary; but overall, your doctors want to know as much about your particular tumor as possible so that they can plan the best available treatments.
Women who have pre-cancerous lesions demonstrated on biopsy after colposcopy have a few different options how to proceed. A woman may decide on a specific option depending on whether or not she plans to have children in the future, her current health status and life expectancy, and her concerns about the future and the possibility of having a cancer come back. You should talk to your doctor about you fears, concerns and preferences. Sometimes, women with low grade lesions may choose to not have any further treatment, especially if the biopsy removed the entire lesion. If you decide to do this, you will need frequent pelvic exams and Pap tests. There are several; different ways to remove pre-cancerous lesions without removing the entire uterus (and thus preserving a woman's ability to have a baby in the future). Women can have cryosurgery (freezing off the abnormal lesion), a LEEP (the same type of electrosurgical procedure used for biopsies), a conization (the thicker type of biopsy that gets tissue under the surface), or have the cells removed with a laser. Your doctor can discuss the benefits and drawbacks of each of these modalities. Women who do not have any plans to have children in the future and are particularly worried about their chances of getting an invasive cancer may elect to have a hysterectomy (a surgery that removes your uterus and cervix). This procedure is much more invasive than any of the previous treatment modalities, but can provide peace of mind to women finished with childbearing.
Surgery is generally only employed in early stage cervical cancers. The purpose of surgery is to remove as much disease as possible, but it usually isn't used unless all of the cancer can be removed at the time of surgery. Cancers that have a high chance of already being in the lymph nodes are not treated with surgery (lymph nodes are small, pea-sized pieces of tissue that filter and clean lymph, a liquid waste product). There are a few different types of surgeries that can be performed. The earliest stage IA tumors can sometimes be treated with only a hysterectomy (removal of the uterus and cervix). Bigger stage IA, stage IB, and occasionally stage IIA tumors can be treated with more extensive hysterectomies coupled with lymphadenectomies (procedures that remove lymph nodes in the pelvis). Depending on the amount of disease, your surgeon may have to remove tissues around the uterus, as well as part of the vagina and the fallopian tubes. One of the benefits of surgery in young women is that sometimes their ovaries can be left, so that they do not go through menopause at an early age. Higher stage disease is usually treated with radiation and chemotherapy, but sometimes surgery is employed if cervical cancer comes back after it has already been treated. A pelvic exenteration is reserved for recurrent cervical cancers. A pelvic exenteration is a major surgery in which the uterus, cervix, fallopian tubes, ovaries, vagina, bladder, rectum and part of the colon are removed. This surgery is not commonly employed, but is occasionally used for recurrent cancers.
Radiation therapy has proven very effective in treating cervical cancer. Radiation therapy uses high energy x-rays to kill cancer cells. Radiation therapy is another option besides surgery for early stage cervical cancer; and when advanced stage cervical cancer needs to be treated, it is usually done with radiation therapy. Surgery and radiation have been shown to be equivalent treatments for early stage cervical cancers, and radiation helps avoid surgery in patients who are too ill to risk having anesthesia. Radiation has the benefit of being able to treat all of the disease in the radiation field; thus lymph nodes can be treated as well as the primary tumor in the course of the same treatment.
Radiation therapy for cervical cancer either comes from an external source (outside of the patient, known as external beam radiation) or an internal source (inside the patient, known as brachytherapy). External beam radiation therapy requires patients to come in 5 days a week for up 6-8 weeks to a radiation therapy treatment center. The treatment takes just a few minutes, and it is painless. With all cervical cancers above stage IB, the standard approach with radiotherapy is to use external beam radiation coupled with internal brachytherapy. Brachytherapy (also called intracavitary irradiation) allows your radiation oncologist to "boost" the radiation dose to the tumor site. This provides an added impact to the tumor, while sparing your normal tissues. This is done by inserting a hollow, metal tube with two egg shaped cartridges into your vagina. Then a small radioactive source is placed in the tube and cartridges. A computer has calculated how long the source needs to be there, but usually for what is called low dose rate (LDR) brachytherapy, you will need to have the source in for a few days. This procedure is done in the hospital, because for those few days you have to remain in bed. Another type of brachytherapy, called high dose rate (HDR) brachytherapy, uses more powerful sources that only stay in for a few minutes. Although this option usually sounds more appealing to patients, there is debate as to which type is more effective and some institutions favor one over the other. Talk to your radiation oncologist about your options and your doctor’s opinions as to HDR versus LDR for cervical cancer treatment.
Another use of radiation is for palliation - meaning that patients with very advanced cases of cervical cancer are treated with the intent of easing their pain or symptoms, rather than trying to cure their disease.
Sometimes, women with early stage are treated with surgery, but after the results of the surgery, it becomes clear that they will need radiation as well. In any setting, radiation is often combined with chemotherapy, and, depending on your case, your doctor will decide on the best possible treatment arrangement for your lifestyle and wishes.
Despite the fact that tumors are removed by surgery or treated with radiation, there is always a risk of recurrence because there may be microscopic cancer cells left in the body. In order to decrease a patient's risk of a recurrence, she may be offered chemotherapy. Chemotherapy is the use of anti-cancer drugs that go throughout the entire body. Practically all patients who are in good medical condition and receiving radiation for stage IIA or higher cervical cancer will be offered chemotherapy in addition to their radiation. It may even be offered for earlier stage cases depending individual aspects of the patient and her disease. There have been many studies that demonstrate the usefulness of adding chemotherapy to radiation in terms of decreasing mortality from cervical cancer.
There are many different chemotherapy drugs, and they are often given in combinations for a series of months. Depending on the type of chemotherapy regimen you receive, you may get medication every week or few weeks; and you usually have to go to a clinic to get the chemotherapy because many of the drugs have to be given through a vein. The most commonly employed regimens use a drug called Cisplatin combined with another medication, typically paclitaxel, topotecan or gemcitabine. Other chemotherapy medications that may be used to treat cervical cancer include: bevacizumab (a targeted therapy), 5-FU, docetaxel, ifosfamide, irinotecan and mitomycin. There are advantages and disadvantages to each of the different regimens that your gynecologic oncologist or medical oncologist will discuss with you. Based on your own health, your personal values and wishes, and side effects you may wish to avoid, you can work with your doctors to come up with the best regimen for your lifestyle.
Once a patient has been treated for cervix cancer, she needs to be closely followed for a recurrence. At first, you will have follow-up visits fairly often. The longer you are free of disease, the less often you will have to go for checkups. Your doctor will tell you when he or she wants follow-up visits, Pap tests, and/ or scans depending on your case. Your doctor will also do pelvic exams regularly during your office visits. It is very important that you let your doctor know about any symptoms you are experiencing and that you keep all of your follow-up appointments.
Clinical trials are extremely important in furthering our knowledge and the treatment of this disease. It is though clinical trials that we know what we do today, and exciting new therapies are always being tested. Talk to your healthcare provider about participating in clinical trials in your area or search for trials using the OncoLink Clinical Trials Matching program.
Cancer survivorship is a relatively new focus of oncology care. With some 13 million cancer survivors in the US alone, there is a need to help patients transition from active treatment to survivorship. What happens next, how do you get back to normal, what should you know and do to live healthy going forward? A survivorship care plan can be a first step in educating yourself about navigating life after cancer and helping you communicate knowledgeably with your healthcare providers. Create a care plan today on OncoLink.
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