Cervical cancer

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Cervical Cancer
Classification and external resources
Adenosquamous carcinoma high mag.jpg
Micrograph of a cervical adenosquamous carcinoma, a type of cervical cancer. H&E stain.
ICD-10 C53
ICD-9 180
OMIM 603956
DiseasesDB 2278
MedlinePlus 000893
eMedicine med/324 radio/140
NCI Cervical cancer
MeSH D002583

Cervical cancer is cancer arising from the cervix.[1] It is due to the abnormal growth of cells that have the ability to invade or spread to other parts of the body.[2] Early on there are typically no symptoms. Later symptoms may include: abnormal vaginal bleeding, pelvic pain or pain during sex.[1]

Human papillomavirus (HPV) infection appears to be involved in the development of more than 90% of cases.[3][4] Most people who have had HPV infections; however, do not develop cervical cancer.[5][6] Other risk factors include: smoking, a weak immune system, birth control pills, starting sex at a young age and having many sexual partners, but these are less important.[1][7] Cervical cancer typically develops from precancerous changes over 10 to 20 years.[5] There are a few types of cervical cancer. About 90% are squamous cell carcinomas, 10% are adenocarcinoma and a small number are other types.[7] Diagnosis is typically by cervical screening followed by a biopsy. Medical imaging is then done to determine whether or not the cancer has spread.[1]

HPV vaccines protect against two high risk strains of this family of viruses and may prevent up to 65 to 75% of cervical cancers.[8][9] As there still is a risk of cancer, guidelines recommend continuing regular Pap smears.[8] Other methods of prevention include: never having sex and the use of condoms.[10] Cervical cancer screening using the Pap smear or acetic acid can identify precancerous changes which when treatmented can prevent the development of cancer.[11] Treatment of cervical cancer may consists of some combination of surgery, chemotherapy and radiotherapy.[1] Five year survival rates in the United States are 68%.[12] Outcomes however depend very much on how early the cancer is detected.[7]

Worldwide, cervical cancer is both the fourth most common cause of cancer and the fourth most common cause of death from cancer in women.[5] In 2012, it was estimated that there were 528,000 cases of cervical cancer, and 266,000 deaths.[5] This is about 8% of the total cases and total deaths from cancer.[13] Approximately 70% of cervical cancers occur in developing countries.[5] In low income countries it is the most common cause of cancer death.[11] In developed countries, the widespread use of cervical screening programs has dramatically reduced rates of cervical cancer.[14] In medical research, the most famous cell line known as HeLa was developed from cervical cancer cells of a woman name Henrietta Lacks.[15]

Signs and symptoms[edit]

The early stages of cervical cancer may be completely asymptomatic.[3][14] 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, swollen legs, heavy bleeding from the vagina, bone fractures, and/or (rarely) leakage of urine or faeces from the vagina.[16]

Causes[edit]

In most cases, cells infected with the HPV virus heal on their own. In some cases, however, the virus continues to spread and becomes an invasive cancer.
Cervix in relation to upper part of vagina and posterior portion of uterus., showing difference in covering epithelium of inner structures.

Infection with some types of human papilloma virus (HPV) is the greatest risk factor for cervical cancer, followed by smoking.[17] Other risk factors include human immunodeficiency virus.[17] Not all of the causes of cervical cancer are known, however, and several other contributing factors have been implicated.[18]

Human papillomavirus[edit]

Human papillomavirus type 16 and 18 are the cause of 75% of cervical cancer globally while 31 and 45 are the cause of another 10%.[19]

Women who have many sexual partners (or who have sex with men who have had many other partners) have a greater risk.[20][21]

Of the 150-200 types of HPV known,[22][23] 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).[24]

Genital warts, which are a form of benign tumor of epithelial cells, are also caused by various strains of HPV. However, these serotypes are usually not related to cervical cancer. It is common to have multiple strains at the same time, including those that can cause cervical cancer along with those that cause warts. 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 (although many dispute that, technically, it is the causative agent, not the cancer, that is a sexually transmitted disease), but most women infected with high risk HPV will not develop cervical cancer.[25] 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, there is no commercially available test for HPV, although HPV is thought to grow preferentially in the epithelium of the glans penis, and cleaning of this area may be preventative.[citation needed]

Smoking[edit]

Smoking has also been linked to the development of cervical cancer.[26][27][28] There are a few different ways that smoking can increase the risk of cervical cancer in women which can be by direct and indirect methods of inducing cervical cancer.[26][28][29] A direct way of contracting this cancer is a female smoker has a higher chance of CIN3 occurring which has the potential of forming cervical cancer.[26] When CIN3 lesions lead to cancer, most of them have the assistance of the HPV virus, but that is not always the case which is why it can be considered a direct link to cervical cancer.[29] Heavy smoking and long term smoking seem to have more of a risk of getting the CIN3 lesions than lighter smoking or not smoking at all.[30] Although smoking has been linked to cervical cancer, it aids in the development of HPV which is the leading cause of this type of cancer.[28] Also, not only does it aid in the development of HPV, but if the woman is already HPV-positive she is at an even greater likelihood of contracting cervical cancer.[30]

Diagnosis[edit]

Cervical cancer seen on a T2 weighted saggital MR image of the pelvis.

Biopsy[edit]

The pap smear can be used as a screening test, but is false negative in up to 50% of cases of cervical cancer.[31][32] 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 a dilute acetic acid (e.g. vinegar) solution to highlight abnormal cells on the surface of the cervix.[3] Medical devices used for biopsy of the cervix include punch forceps, SpiraBrush CX, SoftBiopsy or Soft-ECC.

Colposcopic impression, the estimate of disease severity based on the visual inspection, forms part of the diagnosis.

Further diagnostic and treatment 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.

This large squamous carcinoma (bottom of picture) has obliterated the cervix and invaded the lower uterine segment. The uterus also has a round leiomyoma up higher.

Precancerous lesions[edit]

Histopathologic image (H&E stain) of carcinoma in situ, stage 0.

Cervical intraepithelial neoplasia, the potential precursor to cervical cancer, is often diagnosed on examination of cervical biopsies by a pathologist. For premalignant dysplastic changes, the CIN (cervical intraepithelial neoplasia) grading is used.

The naming and histologic classification of cervical carcinoma percursor lesions has changed many times over the 20th century. The World Health Organization classification[33][34] system was descriptive of the lesions, naming them mild, moderate or severe dysplasia or carcinoma in situ (CIS). The term, Cervical Intraepithelial Neoplasia (CIN) was developed to place emphasis on the spectrum of abnormality in these lesions, and to help standardise treatment.[34] It classifies mild dysplasia as CIN1, moderate dysplasia as CIN2, and severe dysplasia and CIS as CIN3. More recently, CIN2 and CIN3 have been combined into CIN2/3. These results are what a pathologist might report from a biopsy.

These should not be confused with the Bethesda System terms for Pap smear (cytopathology) results. Among the Bethesda results: Low-grade Squamous Intraepithelial Lesion (LSIL) and High-grade Squamous Intraepithelial Lesion (HSIL). An LSIL Pap may correspond to CIN1, and HSIL may correspond to CIN2 and CIN3,[34] however they are results of different tests, and the Pap smear results need not match the histologic findings.

Cancer subtypes[edit]

Histologic subtypes of invasive cervical carcinoma include the following:[35][36] Though squamous cell carcinoma is the cervical cancer with the most incidence, the incidence of adenocarcinoma of the cervix has been increasing in recent decades.[3]

Non-carcinoma malignancies which can rarely occur in the cervix include

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.

Staging[edit]

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, proctoscopy, intravenous urography, and X-ray examination of the lungs and skeleton, and cervical conization.

Prevention [edit]

Screening[edit]

Main articles: Cervical screening and Pap test

Cervical screening by the Papanicolaou test, or Pap smear, for cervical cancer has been credited with dramatically reducing the number of cases of and mortality from cervical cancer in developed countries.[14] Pap smear screening every 3–5 years with appropriate follow-up can reduce cervical cancer incidence by up to 80%.[37] Abnormal results may suggest the presence of pre cancerous changes allowing examination and possible preventive treatment. If precancerous disease or cervical cancer is detected early, it can be monitored or treated relatively noninvasively, with little impairment of fertility.[citation needed] Personal invitations encouraging women to get screened are effective at increasing the likelihood they will do so. Educational materials also help increase the likelihood women will go for screening, but they are not as effective as invitations.[38]

According to the 2010 European guidelines for cervical cancer screening, the age at which to commence screening ranges between 20–30 years of age, "but preferentially not before age 25 or 30 years", and depends on burden of the disease in the population and the available resources.[39] In the United States the rate of cervical cancer is 0.1% among women under 20 years of age, so the American Cancer Society as well as the American College of Obstetricians and Gynecologists strongly recommend that screening begin at age 21, regardless of age at sexual initiation or other risk-related behaviors.[40][41][42] For healthy women aged 21–29 who have never had an abnormal Pap smear, cervical cancer screening with cervical cytology (Pap smear) should occur every 3 years, regardless of HPV vaccination status.[43] The preferred screening for women aged 30–65 is "co-testing", which includes a combination of cervical cytology screening and HPV testing, every 5 years.[43] However, it is acceptable to screen this age group with a Pap smear alone every 3 years.[43] In women over the age of 65, screening for cervical cancer may be discontinued in the absence of abnormal screening results within the prior 10 years and no history of CIN 2 or higher.[43]

Liquid-based cytology is another potential screening method.[44][45] 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%.[46] This reduces the need to recall women for a further smear. The United States Preventive Services Task Force supports screening every 5 years in those who are between 30 and 65 years when cytology is used in combination with HPV testing.[47]

Vaccination[edit]

There are two HPV vaccines (Gardasil and Cervarix) which reduce the risk of cancerous or precancerous changes of the cervix and perineum by about 93% and 62%, respectively.[48]

HPV vaccines are typically given to women age 9 to 26 as the vaccine is only effective if given before infection occurs. The vaccines have been shown to be effective for at least 4[49] to 6[50] years, and it is believed they will be effective for longer;[51] however, the duration of effectiveness and whether a booster will be needed is unknown. The high cost of this vaccine has been a cause for concern. Several countries have considered (or are considering) programs to fund HPV vaccination.

Condoms[edit]

Condoms are thought to offer some protection against cervical cancer.[52] Evidence on whether condoms protect against HPV infection is mixed, but they may protect against genital warts and the precursors to cervical cancer.[52] They also provide protection against other STDs, such as HIV and Chlamydia, which are associated with greater risks of developing cervical cancer.

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.[53] 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.[54][55]

Nutrition[edit]

Vitamin A is associated with a lower risk[56] as is vitamin B12, vitamin C, vitamin E, and beta-carotene.[57]

Treatment[edit]

The treatment of cervical cancer varies worldwide, largely due to large variances in disease burden in developed and developing nations, access to surgeons skilled in radical pelvic surgery, and the emergence of "fertility sparing therapy" in developed nations. Because cervical cancers are radiosensitive, radiation may be used in all stages where surgical options do not exist.

Microinvasive cancer (stage IA) may be treated by hysterectomy (removal of the whole uterus including part of the vagina). For stage IA2, the lymph nodes are removed as well. Alternatives include local surgical procedures such as a loop electrical excision procedure (LEEP) or cone biopsy.[58] For 1A1 disease, a cone biopsy (aka cervical conization) is considered curative.

If a cone biopsy does not produce clear margins[59] (findings on biopsy showing that the tumor is surrounded by cancer free tissue, suggesting all of the tumor is removed), one more possible treatment option for patients who want to preserve their fertility is a trachelectomy.[60] 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,[61] 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[62] or vaginally[63] and there are conflicting opinions as to which is better.[64] 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.[65] It is generally recommended to wait at least one year before attempting to become pregnant after surgery.[66] Recurrence in the residual cervix is very rare if the cancer has been cleared with the trachelectomy.[61] 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. When cisplatin is present, it is thought to be the most active single agent in periodic diseases.[67]

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.[68] Combination treatment has significant risk of neutropenia, anemia, and thrombocytopenia side effects. Hycamtin is manufactured by GlaxoSmithKline.

Prognosis[edit]

Prognosis depends on the stage of the cancer. There is a high chance of a survival rate around 100 for women with microscopic forms of cervical cancer.[69] With treatment, the 5-year relative survival rate for the earliest stage of invasive cervical cancer is 92%, and the overall (all stages combined) 5-year survival rate is about 72%. These statistics may be improved when applied to women newly diagnosed, bearing in mind that these outcomes may be partly based on the state of treatment five years ago when the women studied were first diagnosed.[70]

With treatment, 80 to 90% of women with stage I cancer and 60 to 75% of those with stage II cancer are alive 5 years after diagnosis. Survival rates decrease to 30 to 40% for women with stage III cancer and 15% or fewer of those with stage IV cancer 5 years after diagnosis.[71]

According to the International Federation of Gynecology and Obstetrics, survival improves when radiotherapy is combined with cisplatin-based chemotherapy.[72]

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.[73]

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.[74] About 1,000 women per year die of cervical cancer in the UK.

Epidemiology[edit]

Age-standardized death from cervical cancer per 100,000 inhabitants in 2004.[75]
  no data
  <2.4
  2.4-4.8
  4.8-7.2
  7.2-9.6
  9.6-12
  12-14.4
  14.4-16.8
  16.8-19.2
  19.2-21.6
  21.6-24
  24-26.4
  >26.4

Worldwide, cervical cancer is both the fourth most common cause of cancer and deaths from cancer death women.[5] In 2012, it was estimated that there were 528,000 cases of cervical cancer, and 266,000 deaths.[5] It is the second most common cause of female specific cancer after breast cancer accounting for around 8% of both total cancer cases and total cancer deaths in women.[13] Approximately 80% of cervical cancers occur in developing countries.[76]

In the United States, it is only the 8th most common cancer of women. The median age at diagnosis is 48. Hispanic women are significantly more likely to be diagnosed with cervical cancer than the general population.[77] In 1998, about 12,800 women were diagnosed in the US and about 4,800 died.[14] In 2008 in the US an estimated 11,000 new cases were expected to be diagnosed, and about 3,870 were expected to die of cervical cancer.[70] 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.[14] The incidence of new cases of cervical cancer in the United States was 7 per 100,000 women in 2004.[78] Cervical cancer deaths decreased by approximately 74% in the last 50 years, largely due to widespread Pap smear screening.[79] The annual direct medical cost of cervical cancer prevention and treatment prior to introduction of the HPV vaccine was estimated at $6 billion.[79]

In the European Union, there were about 34,000 new cases per year and over 16,000 deaths due to cervical cancer in 2004.[37]

In the United Kingdom, the age-standardised (European) incidence is 8.5/100,000 per year (2006). It is the twelfth most common cancer in women, accounting for 2% of all female cancers, and is the second most common cancer in the under 35s females, after breast cancer. The UK's European age-standardised mortality is 2.4/100,000 per year (2007) (Cancer Research UK Cervical cancer statistics for the UK).[80] 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.

In Canada, an estimated 1,300 women will be diagnosed with cervical cancer in 2008 and 380 will die.[81]

In Australia, there were 734 cases of cervical cancer (2005). The number of women diagnosed with cervical cancer has dropped on average by 4.5% each year since organised screening began in 1991 (1991–2005).[82] Regular two-yearly Pap tests can reduce the incidence of cervical cancer by up to 90% in Australia, and save 1,200 Australian women dying from the disease each year.[83]

History[edit]

Epidemiologists working in the early 20th century noted that cervical cancer behaved like a sexually transmitted disease. In summary:

  1. Cervical cancer was common in female sex workers.
  2. It was rare in nuns, except for those who had been sexually active before entering the convent. (Rigoni in 1841)
  3. It was more common in the second wives of men whose first wives had died from cervical cancer.
  4. It was rare in Jewish women.[84]
  5. In 1935, Syverton and Berry discovered a relationship between RPV (Rabbit Papillomavirus) and skin cancer in rabbits. (HPV is species-specific and therefore cannot be transmitted to rabbits)

This led to the suspicion that cervical cancer could be caused by a sexually transmitted agent. Initial research in the 1940s and 1950s put the blame on smegma (e.g. Heins et al. 1958).[85] During the 1960s and 1970s it was suspected that infection with herpes simplex virus was the cause of the disease. In summary, HSV was seen as a likely cause[86] because it is known to survive in the female reproductive tract, to be transmitted sexually in a way compatible with known risk factors, such as promiscuity and low socioeconomic status. Herpes viruses were also implicated in other malignant diseases, including Burkitt's lymphoma, Nasopharyngeal carcinoma, Marek's disease and the Lucké renal adenocarcinoma. HSV was recovered from cervical tumour cells.

A description of human papillomavirus (HPV) by electron microscopy was given in 1949, and HPV-DNA was identified in 1963.[citation needed] It was not until the 1980s that HPV was identified in cervical cancer tissue.[87] It has since been demonstrated that HPV is implicated in virtually all cervical cancers.[88] Specific viral subtypes implicated are HPV 16, 18, 31, 45 and others.

In work that was initiated in the mid 1980s, the HPV vaccine was developed, in parallel, by researchers at Georgetown University Medical Center, the University of Rochester, the University of Queensland in Australia, and the U.S. National Cancer Institute.[89] In 2006, the U.S. Food and Drug Administration (FDA) approved the first preventive HPV vaccine, marketed by Merck & Co. under the trade name Gardasil.

Society and culture[edit]

Australia[edit]

In Australia, Aboriginal women are more than five times more likely to die from cervical cancer than non-Aboriginal women, suggesting that Aboriginal women are less likely to have regular Pap tests.[90] There are several factors that may limit indigenous women from engaging in regular cervical screening practices, including sensitivity in discussing the topic in Aboriginal communities, embarrassment, anxiety and fear about the procedure.[91] Difficulty in accessing screening services (for example, transport difficulties) and a lack of female GPs, trained pap smear providers and trained female Aboriginal Health Workers are also issues.[91]

The Australian Cervical Cancer Foundation (ACCF) was established in 2008 with the vision 'to protect and enhance women’s health by eliminating cervical cancer and enabling treatment for women with cervical cancer and related health issues, in Australia and in developing countries.'[92] Ian Frazer, one of the developers of the Gardasil cervical cancer vaccine, is the scientific advisor to ACCF.[93]

Janette Howard, the wife of former Australian Prime Minister John Howard, was diagnosed with cervical cancer in 1996, and first spoke on her battle with the disease in 2006.[94] Many people had assumed Mrs Howard had suffered from breast cancer.[94]

Japan[edit]

Since 2010, girls in Japan have been eligible to receive the cervical cancer vaccination for free.[95] In June 2013, the Japanese Ministry of Health, Labor and Welfare mandated that, before administering the vaccine, medical institutions must inform girls that the Ministry does not recommend it.[95] However, the vaccine is still available at no cost to Japanese girls who choose to accept the vaccination.[95]

Nordic countries[edit]

All of the Nordic countries have cervical cancer screening programs in place.[96] Pap smear was integrated into clinical practice in the Nordic countries in the 1960s.[96]

United States of America[edit]

A 2007 survey of 3,076 American women found only 40% had heard of HPV infection and less than half of those knew it causes cervical cancer.[97]

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Further reading[edit]

  • Harper DM, Franco EL, Wheeler C, Ferris DG, Jenkins D, Schuind A, Zahaf T, Innis B, Naud P, De Carvalho NS, Roteli-Martins CM, Teixeira J, Blatter MM, Korn AP, Quint W, Dubin G (2004). "Efficacy of a bivalent L1 virus-like particle vaccine in prevention of infection with human papillomavirus types 16 and 18 in young women: a randomised controlled trial". Lancet 364 (9447): 1757–65. doi:10.1016/S0140-6736(04)17398-4. PMID 15541448. 
  • Peto J, Gilham C, Fletcher O, Matthews FE (2004). "The cervical cancer epidemic that screening has prevented in the UK". Lancet 364 (9430): 249–56. doi:10.1016/S0140-6736(04)16674-9. PMID 15262102. 

External links[edit]