Cervix Cancer – Causes, Diagnosis and Treatment
Cervical cancer is one of the most common cancers worldwide, especially in poor countries, with approximately 260,000 deaths annually. Invasive cervical cancer accounts for 6 percent of all cancers that afflict women in the United States. About 10,400 cases of invasive carcinoma of the cervix are diagnosed in the United States each year, while there are at least 500,000 new cases of a preinvasive cervical cancer—known as a squamous intraepithelial lesion—where the cancer cells are confined to the surface skin of the cervix.
Since 1940, there has been a steady decrease in the yearly incidence of carcinoma of the cervix because many women have been screened with Pap smears, detecting cancer before it becomes invasive. It is estimated that over half the women diagnosed with cancer of the cervix have never been screened for cervical cancer, and an additional 10 percent have not been screened within the past five years.
Types Over 90 percent of cervical carcinomas start in the surface cells on the cervix and are known as squamous cell carcinomas. Five to 9 percent start in endocervical glandular tissue (adenocarcinoma). There are several types of adenocarcinomas. Sixty percent are the endocervical cell type, 20 percent are also endometrioid or clear cell carcinomas, and 20 percent are adenosquamous carcinomas. Adenocarcinomas are more difficult to diagnose but are treated the same way as squamous cell carcinomas, with a similar survival rate, stage for stage.
There are two rare types of cervical cancers, known as small cell carcinoma and cervical sarcoma, both of which have a poor prognosis.
There are two categories of preinvasive squamous lesions: The first is known as a low-grade squamous intraepithelial lesion (LGSIL). It was also known in the past as mild dysplasia or cervical intraepithelial neoplasia (CIN-1). Most cases of LGSIL do not progress to invasive cancer. The second category is known as a high-grade squamous intraepithelial lesion (HGSIL), which in the past was also known as moderate dysplasia (CIN-2), or severe dysplasia (carcinoma in situ, or CIN-3). Most physicians believe that about two-thirds of all cases of HGSIL progress to invasive cancer if left untreated. This transformation takes anywhere from two to thirty years, with about five to ten years on the average.
How It Spreads Once the cervical cancer becomes invasive, it can spread locally to the upper vagina and into the tissues surrounding the upper vagina and the cervix (the parametrium). Eventually it grows toward the pelvic sidewall, obstructing the ureters (tubes that drain urine from the kidney to the bladder). It can also spread directly into the bladder and rectum.
Cervical cancer cells can also invade the lymphatic system and spread to the lymph nodes around the vessels on the pelvic walls. Eventually they may spread to the lymph nodes higher in the pelvis, the aortic lymph nodes, the nodes above the collarbone, and even occasionally to the groin nodes.
Distant metastases can also occur through the bloodstream to the lower vagina, vulva, lung, liver, and brain. Distant metastases are more common in women with cancer spread to the lymph nodes or higher-stage cancer. Invasion of the pelvic nerves is common in advanced cases. There may also be spread within the abdomen when the tumor penetrates the full thickness of the cervix.
What Causes It Most scientists believe that the human papillomavirus (HPV) causes preinvasive and invasive cervical cancer. Preinvasive cervical cancer is thought to develop within six months to five years after exposure to HPV, while invasive cancer is thought to develop within one to ten years after exposure. The human papillomavirus is the most common sexually transmitted illness in the United States, with approximately 20 million men and women currently infected. It is estimated that as many as 6 million people become infected every year. The Centers for Disease Control and Prevention (CDC) has estimated that 50 percent of sexually active people will be exposed to the human papillomavirus in their lifetime. Over forty types of HPV exclusively infect the genital skin of the cervix, vulva, vagina, urethra, anus, and penis.
There are two general groups of human papillomavirus: the low-risk group for causing cancer, with HPV types 6 and 11 being the most common, and the high-risk group for developing cancer, with HPV types 16 and 18. The low-risk types usually result in genital warts, low-grade squamous intraepithelial lesions (LGSIL), and on very rare occasions respiratory tract warts in children exposed during birth.
Genital warts most often appear on the external genitalia or near the anus. However, warts can also occur on the cervix and the vagina. It is estimated that genital warts may occur within weeks, months, or years after exposure, or not at all. Genital warts are usually not symptomatic, although they may cause itching, burning, or occasional bleeding. They are treated after careful evaluation with cryotherapy (freezing), laser, topical medications, or topical anticancer drugs.
The high-risk HPV types are responsible for most cases of high-grade squamous intraepithelial lesions (HGSIL), adenocarcinoma in situ, and cancer (both squamous cell and adenocarcinoma).
Exposure to HPV does not necessarily result in warts, precancerous changes, or cancer (either squamous cell or adenocarcinoma). Similarly, most people do not have symptoms after exposure to the virus. It is not clear how long the infection with HPV lasts either with or without treatment.
Cancers of female pelvic organs
The risk factors for preinvasive cervical cancer and cervical cancer are the same. The average age of women with invasive cervical cancer in the United States is between thirty-five and fifty-five, while the average age of women with HGSIL is between twenty-five and thirty-five. The difference is attributed to the long latent period of progression of a precancerous lesion confined to the cervical skin to an invasive cervical cancer.
Circumcision is no longer believed to lower the risk of cervical carcinoma.
At Significantly Higher Risk
• Anything that results in an increased risk of exposure to genital HPV
• A history of genital HPV (warts, preinvasive lesions)
• Suppression of the immune system from corticosteroids, organ transplants, therapy for other cancers, or HIV
• A history of herpes simplex virus infection
• Early age at first intercourse
• Multiple sexual partners
• Cigarette smoking
• Women whose male partners either have had penile warts, have had multiple sexual partners, or have had previous partners with cervical cancer
Liquid-based cytology and HPV DNA testing is now widely performed in the United States. It has resulted in an increased accuracy in the diagnosis of both premalignant and malignant changes in the female lower genital tract. The abnormal findings on physical exam, Pap smear, or colposcopy (magnification 7.5 to 15 times) are confirmed with a biopsy.
The American College of Obstetricians and Gynecologists recommends that a Pap smear be performed on all women by age eighteen or who are sexually active, regardless of age. Women who have multiple sexual partners should be screened annually, but those in long-term, stable relationships who have had three consecutive negative yearly Pap smears may be screened less often.
A major problem with the Pap smear is that it is often thought to be normal when it is actually abnormal. The estimated false negative rate is about 10 percent, half of which can be attributed to faulty sampling techniques. The pathologist examining the cells can make an error, or the health care provider may not sample the cervix adequately. It is important to have both the squamous cell component and the endocervical component present on the Pap (in women with a cervix) in order to have a reliable Pap smear. Sometimes women are asked to return for another Pap smear if they lack the endocervical component. Testing for HPV can help triage women with a mildly abnormal Pap smear, or atypical squamous cell of undetermined significance (ASCUS).
Unfortunately, adenocarcinomas and adenosquamous carcinomas are more difficult to detect on Pap smears, since they start higher up in the cervical canal and may not be sampled by the Pap smear.
Pap Smear Diagnoses
• Atypical squamous cell of undetermined significance (ASCUS)
• Low-grade squamous intraepithelial lesion (LGSIL)
• High-grade squamous intraepithelial lesion (HGSIL)
• Atypical glandular cells of undetermined significance (AGUS)
• Adenocarcinoma in situ (ACIS)
• Cancer-type specific
Partners Partners of women with an HPV infection, warts, squamous intrapithelial lesions (SIL), or cancer should be carefully examined as well for genital warts, precancerous skin changes, and cancer.
Prevention and Vaccination
Recently, a human papillomavirus recombinant vaccine known as Gardasil has been developed and approved for use. Gardasil is quadrivalent, which means it can protect against infection with human papillomavirus types 6, 11, 16, and 18. Gardasil will not protect against HPV types other than types 6, 11, 16, and 18. It will, however, prevent approximately 70 percent of the cervical cancers and 90 percent of the cases of genital warts. The vaccine also does not protect against HPV types that an individual has already been exposed to. It will not protect against other sexually transmitted illnesses.
Currently, it is recommended that women ages nine through twenty-six be vaccinated. Three injections of the vaccine are required. The second injection is given two months after the first dose, and the third dose is given six months after the first dose.
All three doses are required for significant protection, although there may be some benefit from only one or two injections of the vaccine. Side effects, generally mild and uncommon, include pain, swelling, itching, redness, fever, nausea, and dizziness.
The vaccine will not substitute for routine cervical screening, a careful pelvic exam, and a Pap smear. It is not recommended in those women infected with HIV or who are pregnant.
Common Signs and Symptoms
In many cases of cervical cancer, and in almost all cases of preinvasive cancer, there are no symptoms. The most common symptoms in women with cancer include abnormal vaginal bleeding or discharge, bleeding after intercourse, and back, pelvic, or leg pain.
• Most women with cervical cancer will have a normal general physical examination.
• Careful evaluation of the external genitalia.
• Lymph nodes in the groin and above the collarbone should be examined to detect any enlargement.
• A pelvic and rectal examination is important to detect disease in the tissue surrounding the cervix and vagina.
Blood and Other Tests
• Complete blood count.
• Liver function chemistries.
• Kidney function chemistries.
• The levels of the serum carcinoembryonic antigen (CEA) in the blood should be measured in women with advanced cancer. CEA is elevated in about 20 percent of all women with cervical carcinomas. Although CEA is not accurate enough to use for screening, it is useful to monitor the response to treatment and for follow-up to detect recurrent disease.
• Chest X-ray.
• CT or MRI scan of the chest, abdomen, and pelvis.
• PET/CT scan in advanced cases.
Endoscopy and Biopsy
• Cystoscopy in advanced cases of cancer.
• Sigmoidoscopy in advanced cases of cancer.
• All women with an abnormal Pap smear or cervical lesions should undergo an office colposcopic examination. A colposcope is an instrument that can magnify the cervix from 7.5 to 15 times. Usually 3 to 5 percent acetic acid is applied to the cervix and/or vagina to facilitate detection of abnormal changes.
• The definitive diagnosis of an adenocarcinoma or squamous intraepithelial lesion (SIL) is made on a single biopsy, usually performed in the office. Early cancers are occasionally diagnosed on a large biopsy of the cervix, either with a LEEP (loop electrosurgical excision procedure) or a cold-knife cone biopsy. A cervical LEEP is a biopsy performed in the office with an anesthetic or in the operating room. A LEEP is used for diagnosis and/or treatment of SIL. A cervical LEEP or conization is performed when (1) colposcopy cannot determine if there is an invasive cancer; (2) when there are no obvious lesions on the cervix, and the Pap smear is consistently abnormal; (3) when a colposcopically directed biopsy does not adequately account for abnormal cells found on a Pap smear; (4) when a diagnosis of microinvasion (early invasion) is found on the biopsy; (5) when an SIL is identified by a scraping from the cervical canal (endocervical curettage); or (6) when there is a diagnosis of adenocarcinoma in situ of the cervix.
Most gynecologic oncologists use the FIGO (International Federation of Gynecologists and Obstetricians) classification, which divides cervical cancer into five stages, with further divisions in each stage. HGSIL on biopsy or carcinoma in situ is Stage 0. A cancer confined to the cervix is Stage I. In Stage II, the disease either extends beyond the cervix but not to the pelvic sidewall, or involves the vagina but not the lower third. A Stage III carcinoma extends to the pelvic sidewall, involves the lower third of the vagina, or obstructs one or both of the ureters. In Stage IV, the cancer has spread to distant organs beyond the true pelvis or involves the lining of the bladder or rectum.
Squamous cell carcinoma and adenocarcinoma are generally treated similarly. Radical surgery and radiation therapy are equally effective treatments for early-stage disease (Stage IB and a small IIA). For carcinomas more advanced than Stage IIA, treatment is with radiation therapy and chemotherapy. Higher stages are generally treated with higher doses of radiation therapy as well.
Surgery For younger women, surgery is usually recommended because one can preserve the ovaries, thereby preventing premature menopause. It also avoids the vaginal scarring that can result from radiation. Lastly, there is a small chance that women who survive many years after radiation therapy will develop a second malignancy in the radiated area.
Radical exenterative surgery—removal of the rectum and/or bladder and the cervix, uterus, and vagina—is usually reserved for recurrent carcinoma confined to the central pelvis.
Surgery may also be used to stage cervical cancer, since other methods, even CT, MRI, and PET scans, are notoriously inaccurate in detecting lymph node metastasis and intra-abdominal spread in the more advanced stages. Unfortunately, there is no reliable way to diagnose microscopic metastases to the pelvic and para-aortic nodes without removing them, so many gynecologic oncologists recommend a surgical staging procedure before radiation therapy to evaluate the intra-abdominal surfaces and the status of the pelvic and aortic lymph nodes.
Surgical staging is done, if possible, through an approach outside the lining of the abdominal cavity (extraperitoneal). This avoids the manipulation of the intra-abdominal organs as much as possible (as in an intra-abdominal operation) and results in fewer complications following radiation therapy.
The incidence of cancerous pelvic and para-aortic nodes increases with more advanced disease, and there may be a survival advantage to removing the involved nodes. Women with microscopic metastases to the pelvic and aortic nodes can be cured if the nodes are removed. Usually radiation therapy and chemotherapy is given postoperatively to improve the cure rate. Generally, two-thirds of women with pelvic node metastases are cured, while only one-third of women are cured if the aortic nodes are positive.
Women with positive para-aortic nodes may have distant metastases to the lymph nodes above the collarbone (10 percent of cases). If the neck nodes are positive, then only palliative therapy is warranted.
Radiation Several radiation modalities may be used depending on the stage of the disease—usually a combination of external-beam therapy and intracavitary therapy (the insertion of radioactive substances around the tumor or into the tumor [interstitial radiation]). Intracavitary radiation may be of two types—low-dose-rate and high-dose-rate (see this post, “What Happens in Radiation Therapy”).
Chemotherapy It is now standard therapy to give chemotherapy simultaneously with radiation therapy in women with advanced cervical cancers. Chemotherapy is also being actively investigated for women at high risk for recurrent disease, regardless of the stage (i.e., for those with multiple pelvic lymph node or aortic lymph node metastases).
Treatment by Stage
Stage 0 (Squamous Cell Carcinoma)
Carcinoma in situ (intraepithelial carcinoma). High-grade squamous intraepithelial lesion.
Standard Treatment There are four treatment options for this early-stage tumor:
1. A LEEP (loop electrosurgical excision procedure) is similar to a cone biopsy and is for both diagnostic and therapeutic indications. It is usually performed in the office with a local anesthetic with only rare side effects. A portion of the face and canal of the cervix is removed.
2. A cervical cold-knife conization is performed when a LEEP is not appropriate—usually for recurrent disease or difficult anatomy.
3. Laser vaporization therapy may be recommended for larger lesions.
4. Freezing the cervix (cryotherapy) can be performed in the doctor’s office and has a negligible complication rate. It is used less frequently nowadays.
Occasionally a hysterectomy may be recommended.
Five-Year Survival 100 percent
Stage 0 (Adenocarcinoma)
Standard Treatment Adenocarcinoma in situ (confined to the surface of the cervix) is often difficult to diagnose. The diagnosis is usually made with a cervical biopsy or an endocervical curettage. In all cases, a conization is required to rule out a truly invasive lesion.
For women who may want to have children, a LEEP or cone biopsy may cure the disease if the surgical margins (or edges) do not show any evidence of disease. Even so, adenocarcinoma in situ or an invasive adenocarcinoma is occasionally found in the residual cervix even if the cone biopsy has negative margins.
For those who have completed childbearing, the treatment of choice is a simple vaginal or abdominal hysterectomy.
Five-Year Survival 100 percent
Stage I is cancer confined to the cervix. Stage IA involves a carcinoma of the cervix diagnosed only microscopically. All visible lesions, even those with minimal invasion, are Stage IB. Stage IA is further divided into two stages based on the depth of invasion of the cervix.
In Stage IA1, there is less than 3 mm of invasion and the invasion is less than 7 mm wide.
Standard Treatment When the depth of invasion is less than 3 mm from the surface and there is no vascular space involvement, a total vaginal or abdominal hysterectomy with or without removal of the tubes and ovaries is usually recommended. However, a cervical LEEP or conization may be curative if the edges (margins) of the biopsy are free of disease and if there is no vascular space involvement. This may be the appropriate therapy for those women who want to preserve their fertility or who want to avoid a hysterectomy.
Five-Year Survival 100 percent
The depth of stromal invasion is greater than 3 mm and less than 5 mm from the surface of the cervix. It must also be less than 7 mm wide.
Standard Treatment In the United States, women with cancer invading greater than 3 mm into the cervix or those with invasive cancer less than that, but with blood vessel involvement, are treated like those women with Stage IB1 disease.
Five-Year Survival 85 to 95 percent
Lesions are larger than Stage IA2 but are still confined to the cervix.
Cervical cancer confined to the cervix but no greater than 1½ inches (4 cm) in size.
Cervical cancer confined to the cervix but greater than 1½ inches (4 cm) in size.
Standard Treatment There are two options for treatment. A radical hysterectomy may be done, with removal of the lymph nodes from the blood vessels from both sides of the pelvis and from around the aorta. An alternative is external-beam radiation (given in divided doses five days a week for five weeks) followed two weeks later by intracavitary or interstitial radiation (low-dose- or high-dose-rate). Both options result in an equal rate of cure. The choice depends on available local expertise, the age of the patient, and the patient’s medical condition. Small lesions (Stage IB1) are usually operated on, while large ones are often treated with surgery or radiation. Women who have metastatic disease in the removed lymph nodes are frequently treated with external-beam radiation therapy with concurrent chemotherapy to the affected area following surgery.
A radical abdominal hysterectomy and a bilateral pelvic and aortic lymph node dissection is usually performed through either a midline incision or a large lower transverse abdominal incision.
Investigational Recently, a procedure known as a radical trachelectomy has been performed for Stage IA2 and early small IB1 cancers. A large portion of the cervix and a portion of the vagina and surrounding tissues are removed and a pelvic/aortic lymph node dissection is performed. This allows preservation of the cervix and uterus. There are a small series of patients in the literature with encouraging results.
However, more recently, a number of gynecologic oncologists have been performing the same operation using a minimally invasive surgical technique (known as laparoscopy). The entire procedure is performed through four to five small incisions in the abdominal wall. One just below the navel, the second above, the third just above the pubic bone, and the other two on opposite sides of the pelvis. Although this procedure is still investigational, as the technique is learned by more laparoscopists, it will become more widely available. Its limitations are primarily based on the patient’s weight, as obese women are not good candidates. There are also a number of gynecologic oncologists who believe that the lymph nodes should be removed laparoscopically and the radical hysterectomy performed through the vagina. Generally, the complication rate of these techniques is higher than that of an open incision.
Stage IB2 cervical cancers (greater than 1½ inches [4 cm]) confined to the cervix may be treated with surgery alone, radiation therapy followed by surgery six weeks later, radiation therapy and concurrent chemotherapy alone, or chemotherapy followed by radical hysterectomy.
Five-Year Survival 70 to 95 percent
The cancer is one that either extends beyond the cervix (but not to the pelvic sidewall) or involves the vagina (but not the lower third).
In Stage IIA, there is no obvious involvement of the tissue surrounding the cervix (parametrium), but there is involvement of up to the inner two-thirds of the vagina.
Standard Treatment Treatment with either a radical hysterectomy and removal of the lymph nodes or external-beam radiation therapy followed by intracavitary or interstitial radiation given with concurrent chemotherapy is standard.
Women with large lesions of the cervix are sometimes managed with preoperative radiation therapy with concurrent chemotherapy, followed by a hysterectomy and lymph node dissection.
Women who have metastatic disease in the lymph nodes are usually given external-beam radiation therapy to the pelvis and sometimes the para-aortic region with concurrent chemotherapy after surgery.
Five-Year Survival Approaching 70 to 95 percent
There is obvious parametrial involvement but no extension to the pelvic sidewall.
Standard Treatment Concurrent chemotherapy and external-beam radiation therapy are given in divided doses over five weeks, followed by intracavitary or interstitial radiation.
Five-Year Survival 65 to 80 percent
• High-dose-rate brachytherapy, which allows for shorter treatment times in an outpatient or office setting.
• Various types, doses, and timing of chemotherapy.
The cancer extends to the pelvic sidewall, involves the lower third of the vagina, or obstructs one or both ureters or there is a nonfunctioning kidney.
Stage IIIA is defined as having no extension to the pelvic sidewall, but the tumor involves the lower third of the vagina.
There is extension to the pelvic sidewall or obstruction of one or both ureters (the tubes that connect the kidney to the bladder), or there is a nonfunctioning kidney.
Standard Treatment External-beam radiation therapy followed by intracavitary or interstitial radiation therapy with chemotherapy is standard.
Five-Year Survival 40 to 60 percent
Investigational Same as for Stage IIB.
Stage IV is defined as cancer that has spread to distant organs beyond the true pelvis or involves the lining of the bladder or rectum.
In Stage IVA, a biopsy has shown that either the lining of the bladder or the rectum is involved with cancer.
Standard Treatment This stage is usually treated with radiation therapy and chemotherapy or by the surgical removal of the uterus, the vagina, and the bladder and/or rectum (pelvic exenteration).
Five-Year Survival 20 to 30 percent
In Stage IVB, there is spread to distant organs.
Standard Treatment Radiation may be used to relieve the symptoms of pelvic disease or isolated distant metastases. A number of chemotherapeutic drugs are useful for treating metastatic cervical cancer, but they are rarely curative. They include cisplatin or carboplatin, which has a response rate of 15 to 25 percent, and ifosfamide, which has a response rate of 30 percent. Other drugs such as paclitaxel (Taxol), doxorubicin (Adriamycin), cyclophosphamide (Cytoxan), and 5-fluorouracil may be recommended.
Combination chemotherapy, including cisplatin + etoposide + bleomycin, has a response rate of about 50 percent. Other drug combinations that have been used in women with metastatic disease include mitomycin-C + bleomycin + cisplatin, carboplatin + ifosfamide, and cisplatin + ifosfamide with or without bleomycin.
Investigational Many of the drugs used in the standard treatment are being tested in different combinations and doses.
A Pap smear and careful examination of the pelvis, abdomen, and lymph nodes are performed every three months for the first two years after treatment, and then every six months for three more years.
• Routine chest X-rays and pelvic and abdominal CT scans or PET scans are often performed even in the absence of symptoms.
• The serum levels of carcinoembryonic antigen may be measured at each visit if they were elevated prior to treatment.
Symptoms of recurrent cervical carcinoma may include vaginal bleeding or discharge; pain in the pelvis, back, or legs; leg swelling (edema); chronic cough; and weight loss.
• Cervical cancer can recur in the vagina, pelvis, lymph nodes, lung, or liver.
• If radiation was not given previously, recurrences that are confined to the pelvis may be treated with external-beam radiation and intracavitary or interstitial radiation therapy with concurrent chemotherapy.
• In selected cases with a recurrent cancer in the vagina, bladder, or rectum in which radiation therapy was already given, the only option is to remove the vagina, uterus, and bladder and/or rectum with the creation of an artificial bladder (pelvic exenteration). The five-year survival rate after a pelvic exenteration is about 50 percent.
• Women with recurrent tumors that cannot be surgically removed or with metastatic disease are usually treated with chemotherapy. Commonly used drugs include single-agent cisplatin or carboplatin. Other regimens include cisplatin or carboplatin + ifosfamide, vincristine + mitomycin-C + bleomycin + cisplatin, and bleomycin + mitomycin-C + 5-fluorouracil, (paclitaxol) Taxol, etoposide, cyclophosphamide (Cytoxan), gemcitabine (Gemzar), or doxorubicin liposomal (Doxil).
• Those with unresectable pelvic disease may be reirradiated with interstitial radiation or given pelvic arterial chemotherapy.
The Most Important Questions You Can Ask
• What qualifications do you have for treating cancer? Will a specialist in gynecologic oncology be involved in my care?
• What is the advantage of surgery versus radiation therapy?
• If the cancer is advanced, will a staging surgery be performed?
• Is the HPV vaccine appropriate for me?