Cervical cancer is malignant cancer of the cervix uteri or cervical area. It may present with vaginal bleeding but symptoms may be absent until the cancer is in its advanced stages. Treatment consists of surgery (including local excision) in early stages and chemotherapy and radiotherapy in advanced stages of the disease.
Pap smear screening can identify potentially precancerous changes. Treatment of high grade changes can prevent the development of cancer. In developed countries, the widespread use of cervical screening programs has reduced the incidence of invasive cervical cancer by 50% or more.
Human papillomavirus (HPV) infection is a necessary factor in the development of nearly all cases of cervical cancer. HPV vaccine effective against the two strains of HPV that cause the most cervical cancer has been licensed in the U.S. and the EU. These two HPV strains together are currently responsible for approximately 70% of all cervical cancers. Since the vaccine only covers some high-risk types, women should seek regular Pap smear screening, even after vaccination.
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 most important risk factor in the development of cervical cancer is infection with a high-risk strain of human papillomavirus. The virus cancer link works by triggering alterations in the cells of the cervix, which can lead to the development of cervical intraepithelial neoplasia, which can lead to cancer.
Women who have many sexual partners (or who have sex with men or women who had many partners) have a greater risk.
More than 250 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 cervical cancer cases. Together with type 31, they are the prime risk factors for cervical cancer.
Genital warts are caused by various strains of HPV which are usually not related to cervical cancer.
The medically accepted paradigm, officially endorsed by the American Cancer Society and other organizations, is that a patient must have been infected with HPV to develop cervical cancer, and is hence viewed as a sexually transmitted disease, but most women infected with high risk HPV will not develop cervical cancer. Use of condoms reduces, but does not always prevent transmission. Likewise, HPV can be transmitted by skin-to-skin-contact with infected areas. In males, HPV is thought to grow preferentially in the epithelium of the glans penis, and cleaning of this area may be preventative.
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.
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.
Non-carcinoma malignancies which can rarely occur in the cervix include
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.
The TNM staging system for cervical cancer is analogous to the FIGO stage.
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.
Until recently the pap smear has remained the principal technology for preventing cervical cancer. However, following a rapid review of the published literature, originally commissioned by NICE , liquid based cytology has been incorporated within the UK national screening programme. Although it was probably intended to improve on the accuracy of the pap test, its main advantage has been to reduce the number of inadequate smears from around 9% to around 1%. This reduces the need to recall women for a further smear.
Automated technologies have been developed with the aim of improving on the interpretation of smears, normally carried out by cytotechnicians. Unfortunately these on the whole have proven less useful; although the more recent reviews suggest that generally they may be no worse than human interpretation .
The HPV test is a newer technique for cervical cancer triage which detects the presence of human papillomavirus infection in the cervix. It is more sensitive than the pap smear (less likely to produce false negative results), but less specific (more likely to produce false positive results) and its role in routine screening is still evolving. Since more than 99% of invasive cervical cancers worldwide contain HPV, some researchers recommend that HPV testing be done together with routine cervical screening. But, given the prevalence of HPV (around 80% infection history among the sexually active population) others suggest that routine HPV testing would cause undue alarm to carriers.
HPV testing can reduce the incidence of grade 2 or 3 cervical intraepithelial neoplasia or cervical cancer detected by subsequent screening tests among women 32-38 years old according to a randomized controlled trial. The relative risk reduction was 41.3%. For patients at similar risk to those in this study (63.0% had CIN 2-3 or cancer), this leads to an absolute risk reduction of 26%. 3.8 patients must be treated for one to benefit (number needed to treat = 3.8). Click here to adjust these results for patients at higher or lower risk of CIN 2-3.
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 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 effective for more than four years. Cervarix has been approved some places and is in approval process elsewhere.
Neither Merck & Co. nor GlaxoSmithKline invented the vaccine. The vaccine's key developmental steps are claimed by the National Cancer Institute in the US, the University of Rochester in New York, Georgetown University in Washington, DC, Dartmouth College in Hanover, NH, and the Queensland University in Brisbane, Australia. Both Merck & Co. and GlaxoSmithKline have licensed patents from all of these parties.
Together, HPV types 16 and 18 currently cause about 70% of cervical cancer cases. HPV types 6 and 11 cause about 90% of genital wart cases.
HPV vaccines are targeted at girls and women of age 9 to 26 because the vaccine only works if given before infection occurs; therefore, public health workers are targeting girls before they begin having sex. The use of the vaccine in men to prevent genital warts and interrupt transmission to women is initially considered only a secondary market.
The high cost of this vaccine has been a cause for concern. Several countries have or are considering programs to fund HPV vaccination.
Condoms may also be useful in treating potentially precancerous changes in the cervix. Exposure to semen appears to increase the risk of precancerous changes (CIN 3), and use of condoms helps to cause these changes to regress and helps clear HPV. 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.
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.
About 1,000 women per year die of cervical cancer in the UK.
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.
Worldwide it is estimated that there are 473,000 cases of cervical cancer, and 253,500 deaths per year.
Epidemiologists working in the early 20th century noted that:
This led to the deduction that cervical cancer could be caused by a sexually transmitted agent. Initial research in the 1950s and 1960s put the blame on smegma (e.g. Heins et al 1958) , but it wasn't until the 1970s that human papillomavirus (HPV) was identified. A description by electron microscopy was given earlier in 1949 and HPV-DNA was identified in 1963. It has since been demonstrated that HPV is implicated in virtually all cervical cancers. Specific viral subtypes implicated are HPV 16, 18, 31, 45 and others.