Cervical cancer

Cervical Cancer
Classification and external resources

Histopathologic image (H&E stain) of carcinoma in situ, stage 0.
ICD-10 C53
ICD-9 180
OMIM 603956
DiseasesDB 2278
MedlinePlus 000893
eMedicine med/324 radio/140
MeSH D002583

Cervical cancer is the term for a malignant neoplasm arising from cells originating in the cervix uteri. One of the most common symptoms of cervical cancer is abnormal vaginal bleeding, but in some cases there may be no obvious symptoms until the cancer has progressed to an advanced stage.[1] Treatment usually consists of surgery (including local excision) in early stages, and chemotherapy and/or radiotherapy in more advanced stages of the disease.

Cancer screening using the Pap smear can identify precancerous and potentially precancerous changes in cervical cells and tissue. Treatment of high-grade changes can prevent the development of cancer in many victims. 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 appears to be a necessary factor in the development of almost all cases (90+%) of cervical cancer.[1][2] HPV vaccines effective against the two strains of this large family of viruses that currently cause approximately 70% of cases of cervical cancer have been licensed in the U.S, Canada, Australia and the EU.[3][4] Since the vaccines only cover some of the cancer causing ("high-risk") types of HPV, women should seek regular Pap smear screening, even after vaccination.[5]

The cervix is the narrow portion of the uterus where it joins with the top of the vagina. Most cervical cancers are squamous cell carcinomas, arising in the squamous (flattened) epithelial cells that line the cervix. Adenocarcinoma, arising in glandular epithelial cells is the second most common type. Very rarely, cancer can arise in other types of cells in the cervix.

Contents

Signs and symptoms

The early stages of cervical cancer may be completely asymptomatic.[1][6] 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 (rarely).[7]

Causes

Infection with some types of human papilloma virus (HPV) is the greatest risk factor for cervical cancer followed by smoking.[8] Other risk factors include human immunodeficiency virus.[8] Not all of the causes of cervical cancer are known, however, and several other contributing factors have been implicated.[9]

Human papillomavirus

Human papillomavirus is the cause of 70% of cervical cancer globally.[10]

Women who have many sexual partners (or who have sex with men who had many other partners) have a greater risk.[11][12]

Of the 150-200 types of HPV known, [13][14] 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).[15] 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.[16]

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.[17] 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.

Cofactors

Other risk factors for cervical cancer include: chlamydia infection, stress and stress-related disorders, dietary factors, hormonal contraception, multiple pregnancies, exposure to the hormonal drug diethylstilbestrol, and family history of cervical cancer.[11] Early age at first intercourse and first pregnancy are also considered risk factors, magnified by early use of oral contraceptives.[18]

Diagnosis

Biopsy

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 a dilute acetic acid (e.g. vinegar) solution to highlight abnormal cells on the surface of the cervix.[1] Medical devices used for biopsy of the cervix include punch forceps or SpiraBrush CX.

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.

Precancerous lesions

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[19][20] 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.[20] 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,[20] however they are results of different tests, and the Pap smear results need not match the histologic findings.

Cancer subtypes

Histologic subtypes of invasive cervical carcinoma include the following:[21][22] 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.[1]

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

Main article: Cervical cancer staging

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

Screening

The widespread introduction of cervical screening by 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.[6] Pap smear screening every 3–5 years with appropriate follow-up can reduce cervical cancer incidence by up to 80%.[23] Abnormal results may suggest the presence of pre cancerous changes allowing examination and possible preventive treatment. If premalignant disease or cervical cancer is detected early, it can be monitored or treated relatively noninvasively, with little impairment of fertility.

Cervical cancer screening is typically recommended starting three years or more after first sex, or starting at age 21 to 25.[24][25] Recommendations for how often a Pap smear should be done vary from once a year to once every five years, in the absence of abnormal results.[23] Guidelines vary on how long to continue screening, but well screened women who have not had abnormal smears can stop screening about age 60 to 70.[24][25][26]

liquid based cytology is another potential screening menthod [27] 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%.[28] This reduces the need to recall women for a further smear.

Vaccination

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%. [10]

HPV vaccines are typically give 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[5] to 6[29] years, and it is believed they will be effective for longer,[30] 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 or are considering programs to fund HPV vaccination.

Condoms

Condoms offer some protection against cervical cancer.[31] Evidence on whether condoms protect against HPV infection is mixed, but they may protect against genital warts and the precursors to cervical cancer.[31] 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.[32] 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.[33][34]

Nutrition

Vitamin A is associated with a lower risk[35] as is vitamin B12, vitamin C, vitamin E, and beta-carotene.[36]

Treatment

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.[37] For 1A1 disease, a cone biopsy is considered curative.

If a cone biopsy does not produce clear margins,[38] one more possible treatment option for patients who want to preserve their fertility is a trachelectomy.[39] 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,[40] 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[41] or vaginally[42] and there are conflicting opinions as to which is better.[43] 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.[44] It is generally recommended to wait at least one year before attempting to become pregnant after surgery.[45] Recurrence in the residual cervix is very rare if the cancer has been cleared with the trachelectomy.[40] 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.[46] Combination treatment has significant risk of neutropenia, anemia, and thrombocytopenia side effects. Hycamtin is manufactured by GlaxoSmithKline.

Prognosis

Prognosis depends on the stage of the cancer. 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.[47]

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.[48]

According to the International Federation of Gynecology and Obstetrics, survival improves when radiotherapy is combined with cisplatin-based chemotherapy.[49]

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.[50]

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

Epidemiology

Worldwide, cervical cancer is twelfth most common[53] and the fifth most deadly cancer in women.[54] It affects about 16 per 100,000 women per year and kills about 9 per 100,000 per year.[55] Approximately 80% of cervical cancers occur in developing countries[56] Worldwide, in 2008, it was estimated that there were 473,000 cases of cervical cancer, and 253,500 deaths per year.[57]

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.[6] 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.[47] 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.[6] The incidence of new cases of cervical cancer in the United States was 7 per 100,000 women in 2004.[58] Cervical cancer deaths decreased by approximately 74% in the last 50 years, largely due to widespread Pap smear screening.[53] The annual direct medical cost of cervical cancer prevention and treatment is prior to introduction of the HPV vaccine was estimated at $6 billion.[53]

In the European Union, there were about 34,000 new cases per year and over 16,000 deaths due to cervical cancer in 2004.[23]

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).[59] 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.[60]

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).[61] 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.[62]

History

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.[63]
  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).[64] 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[65] 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. It was not until the 1980s that HPV was identified in cervical cancer tissue.[66] It has since been demonstrated that HPV is implicated in virtually all cervical cancers.[4] 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.[67] 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

According to a survey, only 40% of American women had heard of human papillomavirus (HPV) infection and only 20% had heard of its link to cervical cancer.[68]

References

  1. ^ a b c d e Kumar, Vinay; Abbas, Abul K.; Fausto, Nelson; & Mitchell, Richard N. (2007). Robbins Basic Pathology ((8th ed.) ed.). Saunders Elsevier. pp. 718–721. ISBN 978-1-4160-2973-1. 
  2. ^ Walboomers JM, Jacobs MV, Manos MM, et al (1999). "Human papillomavirus is a necessary cause of invasive cervical cancer worldwide". J. Pathol. 189 (1): 12–9. doi:10.1002/(SICI)1096-9896(199909)189:1<12::AID-PATH431>3.0.CO;2-F. PMID 10451482. 
  3. ^ "FDA Licenses New Vaccine for Prevention of Cervical Cancer". U.S. Food and Drug Administration. 2006-06-08. http://www.fda.gov/bbs/topics/NEWS/2006/NEW01385.html. Retrieved 2007-12-02. 
  4. ^ a b Lowy DR, Schiller JT (2006). "Prophylactic human papillomavirus vaccines". J. Clin. Invest. 116 (5): 1167–73. doi:10.1172/JCI28607. PMC 1451224. PMID 16670757. http://www.jci.org/articles/view/JCI28607. Retrieved 2007-12-01. 
  5. ^ a b "Human Papillomavirus (HPV) Vaccines: Q & A - National Cancer Institute". http://www.cancer.gov/cancertopics/factsheet/risk/HPV-vaccine. Retrieved 2008-07-18. 
  6. ^ a b c d Canavan TP, Doshi NR (2000). "Cervical cancer". Am Fam Physician 61 (5): 1369–76. PMID 10735343. http://www.aafp.org/afp/20000301/1369.html. Retrieved 2007-12-01. 
  7. ^ Nanda, Rita (2006-06-09). "Cervical cancer". MedlinePlus Medical Encyclopedia. National Institutes of Health. http://www.nlm.nih.gov/medlineplus/ency/article/000893.htm. Retrieved 2007-12-02. 
  8. ^ a b Gadducci, A; Barsotti, C, Cosio, S, Domenici, L, Riccardo Genazzani, A (2011 Aug). "Smoking habit, immune suppression, oral contraceptive use, and hormone replacement therapy use and cervical carcinogenesis: a review of the literature.". Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology 27 (8): 597-604. PMID 21438669. 
  9. ^ Stuart Campbell; Ash Monga (2006). Gynaecology by Ten Teachers (18 ed.). Hodder Education. ISBN 0340816627. 
  10. ^ a b Medeiros, LR; Rosa, DD, da Rosa, MI, Bozzetti, MC, Zanini, RR (2009 Oct). "Efficacy of human papillomavirus vaccines: a systematic quantitative review.". International journal of gynecological cancer : official journal of the International Gynecological Cancer Society 19 (7): 1166-76. PMID 19823051. 
  11. ^ a b "What Causes Cancer of the Cervix?". American Cancer Society. 2006-11-30. Archived from the original on 2007-10-13. http://web.archive.org/web/20071013160516/http://cancer.org/docroot/CRI/content/CRI_2_2_2X_What_causes_cancer_of_the_cervix_Can_it_be_prevented_8.asp?sitearea=. Retrieved 2007-12-02. 
  12. ^ Marrazzo JM, Koutsky LA, Kiviat NB, Kuypers JM, Stine K (2001). "Papanicolaou test screening and prevalence of genital human papillomavirus among women who have sex with women". Am J Public Health 91 (6): 947–52. doi:10.2105/AJPH.91.6.947. PMC 1446473. PMID 11392939. http://www.ajph.org/cgi/pmidlookup?view=long&pmid=11392939. Retrieved 2007-12-30. 
  13. ^ "HPV Type-Detect". Medical Diagnostic Laboratories. 2007-10-30. Archived from the original on 2007-09-27. http://web.archive.org/web/20070927092931/http://www.mdlab.com/html/testing/hpv_typedetect.html. Retrieved 2007-12-02. 
  14. ^ Gottlieb, Nicole (2002-04-24). "A Primer on HPV". Benchmarks. National Cancer Institute. http://www.cancer.gov/newscenter/benchmarks-vol2-issue4/page2. Retrieved 2007-12-02. 
  15. ^ Muñoz N, Bosch FX, de Sanjosé S, Herrero R, Castellsagué X, Shah KV, Snijders PJ, Meijer CJ (2003). "Epidemiologic classification of human papillomavirus types associated with cervical cancer". N. Engl. J. Med. 348 (6): 518–27. doi:10.1056/NEJMoa021641. PMID 12571259. http://content.nejm.org/cgi/pmidlookup?view=short&pmid=12571259&promo=ONFLNS19. Retrieved 2007-12-01. 
  16. ^ Walboomers JM, Jacobs MV, Manos MM, Bosch FX, Kummer JA, Shah KV, Snijders PJ, Peto J, Meijer CJ, Muñoz N (1999). "Human papillomavirus is a necessary cause of invasive cervical cancer worldwide". J. Pathol. 189 (1): 12–9. doi:10.1002/(SICI)1096-9896(199909)189:1<12::AID-PATH431>3.0.CO;2-F. PMID 10451482. 
  17. ^ Snijders PJ, Steenbergen RD, Heideman DA, Meijer CJ (2006). "HPV-mediated cervical carcinogenesis: concepts and clinical implications". J. Pathol. 208 (2): 152–64. doi:10.1002/path.1866. PMID 16362994. 
  18. ^ Louie, K S; De Sanjose, S; Diaz, M; Castellsagué, X; Herrero, R; Meijer, C J; Shah, K; Franceschi, S et al. (March 10, 2009). [Early age at first sexual intercourse and early pregnancy are risk factors for cervical cancer in developing countries "Early age at first sexual intercourse and early pregnancy are risk factors for cervical cancer in developing countries"]. British Journal of Cancer 100 (7): 1191–1197. doi:10.1038/sj.bjc.6604974. PMC 2670004. PMID 19277042. Early age at first sexual intercourse and early pregnancy are risk factors for cervical cancer in developing countries. 
  19. ^ a b "Cancer Research UK website". http://info.cancerresearchuk.org/cancerstats/types/cervix/incidence/. Retrieved 2009-01-03. 
  20. ^ a b c DeMay, M (2007). Practical principles of cytopathology. Revised edition.. Chicago, IL: American Society for Clinical Pathology Press. ISBN 978-0-89189-549-7. 
  21. ^ Garcia, Agustin; Omid Hamid, Anthony El-Khoueiry (2006-07-06). "Cervical Cancer". eMedicine. WebMD. http://www.emedicine.com/med/topic324.htm#section~workup. Retrieved 2007-12-02. 
  22. ^ Dolinsky, Christopher (2006-07-17). "Cervical Cancer: The Basics". OncoLink (Abramson Cancer Center of the University of Pennsylvania). http://www.oncolink.upenn.edu/types/article.cfm?c=6&s=17&ss=129&id=8226. Retrieved 2007-12-02. 
  23. ^ a b c M. Arbyn; et al. (2010). "European Guidelines for Quality Assurance in Cervical Cancer Screening. Second Edition—Summary Document". Annals of Oncology 21 (3): 448–458. doi:10.1093/annonc/mdp471. PMC 2826099. PMID 20176693. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2826099. 
  24. ^ a b U.S. Preventive Services Task Force (2003). "Screening for Cervical Cancer: Recommendations and Rationale. AHRQ Publication No. 03-515A". Rockville, MD.: Agency for Healthcare Research and Quality. http://www.ahrq.gov/clinic/3rduspstf/cervcan/cervcanrr.htm. Retrieved June 5, 2010.. 
  25. ^ a b Saslow D, Runowicz CD, Solomon D, et al (2002). "American Cancer Society guideline for the early detection of cervical neoplasia and cancer". CA: a cancer journal for clinicians 52 (6): 342–62. doi:10.3322/canjclin.52.6.342. PMID 12469763. 
  26. ^ Strander B (2009). "At what age should cervical screening stop?". Brit Med J 338: 1022–23. doi:10.1136/bmj.b809. 
  27. ^ Payne N, Chilcott J, McGoogan E (2000). "Liquid-based cytology in cervical screening: a rapid and systematic review". Health technology assessment (Winchester, England) 4 (18): 1–73. PMID 10932023. http://www.hta.ac.uk/execsumm/summ418.htm. 
  28. ^ "Liquid Based Cytology (LBC): NHS Cervical Screening Programme". http://www.cancerscreening.nhs.uk/cervical/lbc.html. Retrieved 2010-10-01. 
  29. ^ Harper D, Gall S, Naud P, Quint W, Dubin G, Jenkins D, et al. (2008). "Sustained immunogenicity and high efficacy against HPV 16/18 related cervical neoplasia: Long-term follow up through 6.4 years in women vaccinated with Cervarix (GSK's HPV-16/18 AS04 candidate vaccine)". Gynecol Oncol 109: 158–159. doi:10.1016/j.ygyno.2008.02.017. 
  30. ^ &Na; (2010 Sep). "Committee opinion no. 467: human papillomavirus vaccination". Obstet Gynecol 116 (3): 800–3. doi:10.1097/AOG.0b013e3181f680c8. PMID 20733476. 
  31. ^ a b Manhart LE, Koutsky LA. (2002). "Do condoms prevent genital HPV infection, external genital warts, or cervical neoplasia? A meta-analysis". Sex Transm Dis 29 (11): 725–35. doi:10.1097/00007435-200211000-00018. PMID 12438912. 
  32. ^ Cornelis J.A. Hogewoning, Maaike C.G. Bleeker, et al. (2003). "Condom use Promotes the Regression of Cervical Intraepithelial Neoplasia and Clearance of HPV: Randomized Clinical Trial". International Journal of Cancer 107 (5): 811–816. doi:10.1002/ijc.11474. PMID 14566832. 
  33. ^ "Semen 'may fuel cervical cancer'". BBC. 2006-08-31. http://news.bbc.co.uk/2/hi/health/5303054.stm. Retrieved 2007-12-02. 
  34. ^ "Semen can worsen cervical cancer". Medical Research Council (UK). http://www.mrc.ac.uk/NewsViewsAndEvents/News/MRC002621. Retrieved 2007-12-02. 
  35. ^ Zhang, X; Dai, B, Zhang, B, Wang, Z (2011 Oct 15). "Vitamin A and risk of cervical cancer: A meta-analysis.". Gynecologic oncology. PMID 22005522. 
  36. ^ Myung, SK; Ju, W, Kim, SC, Kim, H, Korean Meta-analysis (KORMA) Study, Group (2011 Oct). "Vitamin or antioxidant intake (or serum level) and risk of cervical neoplasm: a meta-analysis.". BJOG : an international journal of obstetrics and gynaecology 118 (11): 1285-91. PMID 21749626. 
  37. ^ Erstad, Shannon (2007-01-12). "Cone biopsy (conization) for abnormal cervical cell changes". WebMD. http://www.webmd.com/cancer/cervical-cancer/cone-biopsy-conization-for-abnormal-cervical-cell-changes. Retrieved 2007-12-02. 
  38. ^ Jones WB, Mercer GO, Lewis JL, Rubin SC, Hoskins WJ (1993). "Early invasive carcinoma of the cervix". Gynecol. Oncol. 51 (1): 26–32. doi:10.1006/gyno.1993.1241. PMID 8244170. http://linkinghub.elsevier.com/retrieve/pii/S0090-8258(83)71241-2. Retrieved 2007-12-01. 
  39. ^ Dolson, Laura (2001). "Trachelectomy". http://www.baymoon.com/~gyncancer/library/glossary/bldeftrachelect.htm. Retrieved 2007-12-02. 
  40. ^ a b Burnett AF (2006). "Radical trachelectomy with laparoscopic lymphadenectomy: review of oncologic and obstetrical outcomes". Curr. Opin. Obstet. Gynecol. 18 (1): 8–13. doi:10.1097/01.gco.0000192968.75190.dc. PMID 16493253. http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?an=00001703-200602000-00004. Retrieved 2007-12-01. 
  41. ^ Cibula D, Ungár L, Svárovský J, Zivný J, Freitag P (2005). "[Abdominal radical trachelectomy--technique and experience] [Abdominal radical trachelectomy--technique and experience]" (in Czech). Ceska Gynekol 70 (2): 117–22. PMID 15918265. 
  42. ^ Plante M, Renaud MC, Hoskins IA, Roy M (2005). "Vaginal radical trachelectomy: a valuable fertility-preserving option in the management of early-stage cervical cancer. A series of 50 pregnancies and review of the literature". Gynecol. Oncol. 98 (1): 3–10. doi:10.1016/j.ygyno.2005.04.014. PMID 15936061. http://linkinghub.elsevier.com/retrieve/pii/S0090-8258(05)00270-2. Retrieved 2007-12-01. 
  43. ^ Roy M, Plante M, Renaud MC, Têtu B (1996). "Vaginal radical hysterectomy versus abdominal radical hysterectomy in the treatment of early-stage cervical cancer". Gynecol. Oncol. 62 (3): 336–9. doi:10.1006/gyno.1996.0245. PMID 8812529. http://linkinghub.elsevier.com/retrieve/pii/S0090-8258(96)90245-0. Retrieved 2007-12-01. 
  44. ^ Dargent D, Martin X, Sacchetoni A, Mathevet P (2000). "Laparoscopic vaginal radical trachelectomy: a treatment to preserve the fertility of cervical carcinoma patients". Cancer 88 (8): 1877–82. doi:10.1002/(SICI)1097-0142(20000415)88:8<1877::AID-CNCR17>3.0.CO;2-W. PMID 10760765. 
  45. ^ Schlaerth JB, Spirtos NM, Schlaerth AC (2003). "Radical trachelectomy and pelvic lymphadenectomy with uterine preservation in the treatment of cervical cancer". Am. J. Obstet. Gynecol. 188 (1): 29–34. doi:10.1067/mob.2003.124. PMID 12548192. 
  46. ^ "FDA Approves First Drug Treatment for Late-Stage Cervical Cancer". U.S. Food and Drug Administration. 2006-06-15. http://www.fda.gov/bbs/topics/NEWS/2006/NEW01391.html. Retrieved 2007-12-02. 
  47. ^ a b "What Are the Key Statistics About Cervical Cancer?". American Cancer Society. 2006-08-04. Archived from the original on 2007-10-30. http://web.archive.org/web/20071030194439/http://www.cancer.org/docroot/CRI/content/CRI_2_4_1X_What_are_the_key_statistics_for_cervical_cancer_8.asp?sitearea=. Retrieved 2007-12-02. 
  48. ^ "Cervical Cancer". Cervical Cancer: Cancers of the Female Reproductive System: Merck Manual Home Edition. Merck Manual Home Edition. http://www.merck.com/mmhe/sec22/ch252/ch252d.html. Retrieved 2007-03-24. 
  49. ^ Committee on Practice Bulletins-Gynecology (2002). "ACOG practice bulletin. Diagnosis and treatment of cervical carcinomas, number 35, May 2002". Obstetrics and gynecology 99 (5 Pt 1): 855–67. PMID 11978302. 
  50. ^ "Cervical Cancer". Cervical Cancer: Pathology, Symptoms and Signs, Diagnosis, Prognosis and Treatment. Armenian Health Network, Health.am. http://www.health.am/cr/cervical-cancer/. 
  51. ^ "Cervical cancer statistics and prognosis". Cancer Research UK. http://www.cancerhelp.org.uk/help/default.asp?page=9260. Retrieved 2007-03-24. 
  52. ^ "WHO Disease and injury country estimates". World Health Organization. 2009. http://www.who.int/healthinfo/global_burden_disease/estimates_country/en/index.html. Retrieved Nov. 11, 2009. 
  53. ^ a b c Edward P. Armstrong (April 2010). "Prophylaxis of Cervical Cancer and Related Cervical Disease: A Review of the Cost-Effectiveness of Vaccination Against Oncogenic HPV Types". Journal of Managed Care Pharmacy 16 (3): 217–30. PMID 20331326. 
  54. ^ World Health Organization (February 2006). "Fact sheet No. 297: Cancer". http://www.who.int/mediacentre/factsheets/fs297/en/index.html. Retrieved 2007-12-01. 
  55. ^ "GLOBOCAN 2002 database: summary table by cancer". Archived from the original on 2008-06-16. http://web.archive.org/web/20080616085344/http://www-dep.iarc.fr/GLOBOCAN/Table1_sel1.htm. Retrieved 2008-10-26. 
  56. ^ Kent, A (2010). "HPV Vaccination and Testing". Reviews in obstetrics and gynecology 3 (1): 33–4. PMC 2876324. PMID 20508781. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2876324.  edit
  57. ^ "NCCC National Cervical Cancer Coalition". Archived from the original on 2008-08-22. http://web.archive.org/web/20080822004150/http://www.nccc-online.org/. Retrieved 2008-07-01. 
  58. ^ SEER cancer statistics
  59. ^ http://info.cancerresearchuk.org/cancerstats/types/cervix/mortality/
  60. ^ Noni MacDonald, Matthew B. Stanbrook, and Paul C. Hébert (September 9, 2008). "Human papillomavirus vaccine risk and reality [Human papillomavirus vaccine risk and reality.]" (in French). CMAJ 179 (6): 503, 505. doi:10.1503/cmaj.081238. PMC 2527393. PMID 18762616. http://www.cmaj.ca/cgi/content/full/179/6/503. Retrieved 2008-11-17. 
  61. ^ http://www.papscreen.org.au/browse.asp?ContainerID=c15
  62. ^ http://www.papscreen.org.au/
  63. ^ Menczer J (2003). "The low incidence of cervical cancer in Jewish women: has the puzzle finally been solved?" (PDF). Isr. Med. Assoc. J. 5 (2): 120–3. PMID 12674663. http://www.ima.org.il/imaj/ar03feb-11.pdf. Retrieved 2007-12-01. 
  64. ^ Heins Jr, HC; EJ Dennis, HR Pratt-Thomas (1958-10-01). "The possible role of smegma in carcinoma of the cervix". American Journal of Obstetrics & Gynecology 76 (4): 726–33. PMID 13583012. 
  65. ^ Alexander, E.R. (1973-06). "Possible Etiologies of Cancer of the Cervix Other Than Herpesvirus". Cancer Research 33 (6): 1485–90. ISSN 0008-5472. PMID 4352386. http://www.ncbi.nlm.nih.gov/pubmed/4352386. Retrieved 2008-08-06. 
  66. ^ Dürst, M; L Gissmann, H Ikenberg, H zur Hausen (1983-06). "A papillomavirus DNA from a cervical carcinoma and its prevalence in cancer biopsy samples from different geographic regions". Proceedings of the National Academy of Sciences of the United States of America 80 (12): 3812–5. doi:10.1073/pnas.80.12.3812. ISSN 0027-8424. PMC 394142. PMID 6304740. http://www.ncbi.nlm.nih.gov/pubmed/6304740. Retrieved 2008-08-06. .
  67. ^ McNeil C (April 2006). [jnci.oxfordjournals.org/cgi/content/full/98/7/433 "Who invented the VLP cervical cancer vaccines?"]. J. Natl. Cancer Inst. 98 (7): 433. doi:10.1093/jnci/djj144. PMID 16595773. jnci.oxfordjournals.org/cgi/content/full/98/7/433. Retrieved 2009-11-11.  PMID 16595773
  68. ^ Tiro JA, Meissner HI, Kobrin S, Chollette V (2007). "What do women in the U.S. know about human papillomavirus and cervical cancer?". Cancer Epidemiol. Biomarkers Prev. 16 (2): 288–94. doi:10.1158/1055-9965.EPI-06-0756. PMID 17267388. http://cebp.aacrjournals.org/cgi/pmidlookup?view=long&pmid=17267388. Retrieved 2007-12-01. 

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M: VIR

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drugJ(dnaa, rnaa, rtva, vacc)
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M: ♀ FRS

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