Cervical cancer: malignant cancer of the cervix or cervical area. It may present with vaginal bleeding but symptoms may be absent until the cancer is in its advanced stages, which has made cervical cancer the focus of intense screening efforts using the Pap smear. In developed countries, the widespread use of cervical screening programs has reduced the incidence of invasive cervical cancer by 50% or more.
Treatment consists of surgery (including local excision) in early stages and chemotherapy and radiotherapy in advanced stages of the disease. An effective HPV vaccine against the two most common cancer-causing strains of HPV has recently been licensed in the U.S. (see Vaccine section, below). These two HPV strains together are responsible for approximately 70% of all cervical cancers. Experts recommend that women combine the benefits of both programs by seeking regular Pap smear screening, even after vaccination.
Cervical cancer is a carcinoma, typically composed of squamous cells, and is similar in some respects to squamous cell cancers of the head and neck and anus. All three of these diseases may be associated with human papillomavirus infection.
Signs and symptoms
The early stages of cervical cancer may be completely asymptomatic. 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 feces from the vagina, and bone fractures.
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, use of the hormonal drug diethylstilbestrol (DES) and a family history of cervical cancer.
Human papillomavirus infection
The most important risk factor in the development of cervical cancer is infection with a high-risk strain of human papillomavirus. Women who have many sexual partners (or who have sex with men who had many partners) have a greater chance.
More than 60 types of HPV are acknowledged to exist (some sources indicate more than 200 subtypes). 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), but even those may cause cancer. Types 16 and 18 are generally acknowledged to cause about 70% of the cancer cases. Although most HPV infections clear up on their own, the infections could increase to major abnormalities or cervical cancer.
The presence of strains 16, 18 and 31 is the prime risk factor for cervical cancer, and Walboomers et al. reported that the presence of HPV is a necessary condition for the development of cervical cancer. A virus cancer link with HPV has been found to trigger alterations in the cells of the cervix, leading to the development of cervical intraepithelial neoplasia and cancer. (1999)
Genital warts although caused by different HPV types have no relation 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 not all women infected with HPV develop cervical cancer. Use of condoms 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.
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. However, in men with low-risk sexual behaviour and monogamous female partners, circumcision makes no difference to the risk of cervical cancer.
In the Canadian provinces of Ontario, Prince Edward Island, Newfoundland and Nova Scotia, free vaccinations to protect women against HPV are slated to begin in September 2007 and will be offered to girls 11-14 in age. Similar vaccination programs are also being planned in British Columbia and Quebec.
Australia has decided to fund the HPV vaccine under the National Immunisation Program commencing in the 2007 school year. In the U.K. a similar free vaccination program is being considered, while in the United States, many states[attribution needed] are preparing bills to handle issuing the HPV vaccine.
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 an acetic acid (e.g. vinegar) solution to highlight abnormal cells on the surface of the cervix.
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.
Cervical intraepithelial neoplasia, the precursor to cervical cancer, is often diagnosed on examiniation of cervical biopsies by a pathologist. Histologic subtypes of invasive cervical carcinoma include the following:
- squamous cell carcinoma (about 80-85%)
- adenosquamous carcinoma
- small cell carcinoma
- neuroendocrine carcinoma
Non-carcinoma malignancies which can rarely occur in the cervix include
- IVA - invades mucosa of bladder or rectum and/or extends beyond true pelvis
- IVB - distant metastasis
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.
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,
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 thanproctoscopy, intravenous urography, and X-ray examination of the lungs and skeleton, and cervical conization. 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
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.
If a cone biopsy does not produce clear margins, one more possible treatment option for patients who want to preserve their fertility is a trachelectomy. 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, 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 or vaginally and there are conflicting opinions as to which is better. 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. It is generally recommended to wait at least one year before attempting to become pregnant after surgery. Recurrence in the residual cervix is very rare if the cancer has been cleared with the trachelectomy.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. Combination treatment has significant risk of neutropenia, anemia, and thrombocytopenia side effects. Hycamtin is manufactured by GlaxoSmithKline.
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. In 2006 an estimated 10,000 women in the US will be diagnosed with this type of cancer and nearly 4,000 will die from it.
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. The pap smear suggests the presence of cervical intraepithelial neoplasia (premalignant changes in the cervix) before a cancer has developed, allowing for further workup. Recommendations for how often a Pap smear should be done vary from once a year to once every five years. The American Cancer Society 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. If premalignant disease or cervical cancer is detected early, it can be treated relatively noninvasively, and without impairing fertility.
The HPV test is a newer technique for cervical cancer screening 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. 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.
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. Gardasil is 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. Gardasil has also been approved in the EU.<
GlaxoSmithKline has developed a vaccine called Cervarix™ which has been shown to be 100% effective in preventing HPV strains 16 and 18 and is 100% effective for more than four years. These strains together cause about 70% of cervical cancer cases. Cervarix should be approved by year's end.
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 QueenslandUniversity in Brisbane, Australia. Both Merck & Co. and GlaxoSmithKline have licensed patents from all of these parties.
Prognosis depends on the stage of the cancer. 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.
According to the International Federation of Gynecology and Obstetrics, survival improves when radiotherapy is combined with cisplatin-based chemotherapy.
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.
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.
Worldwide, cervical cancer is the fifth most deadly cancer in women. It affects about 1 per 123 women per year and kills about 9 per 100,000 per year.
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. 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.
In Great Britain, the incidence is 8.8/100,000 per year (2001), similar to the rest of Northern Europe, and mortality is 2.8/100,000 per year (2003) (Cancer Research UK Cervical cancer statistics for the UK). 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.
A study published in 2002  reports that male circumcision can reduce the risk of penile HPV infection in a man, and so the risk of cervical cancer in his female partner. The authors state that "it would not make sense to promote circumcision as a way to control cervical cancer in the US, where Pap smears usually detect it at a treatable stage". However, Menczer quotes research that male circumcision probably does not contribute to a lower incidence of cervical cancer in Jewish populations.
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.