Cervical cancer

Cervical cancer is a 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.[11] Early on, typically no symptoms are seen.[1] Later symptoms may include abnormal vaginal bleeding, pelvic pain, or pain during sexual intercourse.[1] While bleeding after sex may not be serious, it may also indicate the presence of cervical cancer.[12]

Human papillomavirus infection (HPV) causes more than 90% of cases;[4][5] most people who have had HPV infections, however, do not develop cervical cancer.[2][13] 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][3] Cervical cancer typically develops from precancerous changes over 10 to 20 years.[2] About 90% of cervical cancer cases are squamous cell carcinomas, 10% are adenocarcinoma, and a small number are other types.[3] Diagnosis is typically by cervical screening followed by a biopsy.[1] Medical imaging is then done to determine whether or not the cancer has spread.[1]

HPV vaccines protect against between two and seven high-risk strains of this family of viruses and may prevent up to 90% of cervical cancers.[8][14][15] As a risk of cancer still exists, guidelines recommend continuing regular Pap tests.[8] Other methods of prevention include: having few or no sexual partners and the use of condoms.[7] Cervical cancer screening using the Pap test or acetic acid can identify precancerous changes which when treated can prevent the development of cancer.[16] Treatment of cervical cancer may consist of some combination of surgery, chemotherapy, and radiation therapy.[1] Five-year survival rates in the United States are 68%.[17] Outcomes, however, depend very much on how early the cancer is detected.[3]

Worldwide, cervical cancer is both the fourth-most common cause of cancer and the fourth-most common cause of death from cancer in women.[2] In 2012, an estimated 528,000 cases of cervical cancer occurred, with 266,000 deaths.[2] This is about 8% of the total cases and total deaths from cancer.[18] About 70% of cervical cancers occur in developing countries and 90% of the deaths.[2][19] In low-income countries, it is one of the most common causes of cancer death.[16] In developed countries, the widespread use of cervical screening programs has dramatically reduced rates of cervical cancer.[20] In medical research, the most famous immortalised cell line, known as HeLa, was developed from cervical cancer cells of a woman named Henrietta Lacks.[21]

Cervical cancer
Blausen 0221 CervicalDysplasia
Location of cervical cancer and an example of normal and abnormal cells
SpecialtyOncology
SymptomsEarly: none[1]
Later: vaginal bleeding, pelvic pain, pain during sexual intercourse[1]
Usual onsetOver 10 to 20 years[2]
TypesSquamous cell carcinoma, adenocarcinoma, others[3]
CausesHuman papillomavirus infection (HPV)[4][5]
Risk factorsSmoking, weak immune system, birth control pills, starting sex at a young age, many sexual partners or a partner with many sexual partners[1][3][6]
Diagnostic methodCervical screening followed by a biopsy[1]
PreventionRegular cervical screening, HPV vaccines, condoms[7][8]
TreatmentSurgery, chemotherapy, radiation therapy[1]
PrognosisFive-year survival rate:
68% (US)
46% (India)[9]
Frequency570,000 new cases (2018)[10]
Deaths311,000 (2018)[10]

Signs and symptoms

The early stages of cervical cancer may be completely free of symptoms.[4][20] Vaginal bleeding, contact bleeding (one most common form being bleeding after sexual intercourse), 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.[22] 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 vaginal bleeding, bone fractures, and (rarely) leakage of urine or feces from the vagina.[23] Bleeding after douching or after a pelvic exam is a common symptom of cervical cancer.[24]

Causes

Figure 28 02 08
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.
Figure 28 02 06
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 HPV is the greatest risk factor for cervical cancer, followed by smoking.[25] HIV infection is also a risk factor.[25] Not all of the causes of cervical cancer are known, however, and several other contributing factors have been implicated.[26][27]

Human papillomavirus

Human papillomavirus types 16 and 18 are the cause of 75% of cervical cancer cases globally, while 31 and 45 are the causes of another 10%.[28]

Women who have sex with men who have many other sexual partners or women who have many sexual partners have a greater risk.[29][30]

Of the 150-200 types of HPV known,[31][32] 15 are classified as high-risk types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, and 82), three 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).[33]

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.

Infection with HPV is generally believed to be required for cervical cancer to occur.[34]

Smoking

Cigarette smoking, both active and passive, increases the risk of cervical cancer. Among HPV-infected women, current and former smokers have roughly two to three times the incidence of invasive cancer. Passive smoking is also associated with increased risk, but to a lesser extent.[35]

Smoking has also been linked to the development of cervical cancer.[36][37][38] Smoking can increase the risk in women a few different ways, which can be by direct and indirect methods of inducing cervical cancer.[36][38][39] A direct way of contracting this cancer is a smoker has a higher chance of CIN3 occurring which has the potential of forming cervical cancer.[36] 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.[39] 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.[40] 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.[38] Also, not only does it aid in the development of HPV, but also if the woman is already HPV-positive, she is at an even greater likelihood of contracting cervical cancer.[40]

Oral contraceptives

Long-term use of oral contraceptives is associated with increased risk of cervical cancer. Women who have used oral contraceptives for 5 to 9 years have about three times the incidence of invasive cancer, and those who used them for 10 years or longer have about four times the risk.[35]

Multiple pregnancies

Having many pregnancies is associated with an increased risk of cervical cancer. Among HPV-infected women, those who have had seven or more full-term pregnancies have around four times the risk of cancer compared with women with no pregnancies, and two to three times the risk of women who have had one or two full-term pregnancies.[35]

Diagnosis

Ca cervicis uteri T2 SAG
Cervical cancer seen on a T2-weighted sagittal MR image of the pelvis

Biopsy

The Pap test can be used as a screening test, but produces a false negative in up to 50% of cases of cervical cancer.[41][42] Other concerns is the cost of doing pap tests which make it unaffordable in many areas of the world.[43]

Confirmation of the diagnosis of cervical cancer or precancer 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,[4] with visual contrast provided by staining the normal tissues a mahogany brown with Lugol's iodine.[44] Medical devices used for biopsy of the cervix include punch forceps among others.

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 and cervical 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.

Squamous carcinoma of the cervix
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.

Often before the biopsy, the doctor asks for medical imaging to rule out other causes of woman's symptoms. Imaging modalities such as ultrasound, CT scan and MRI have been used to look for alternating disease, spread of tumor and effect on adjacent structures. Typically, they appear as heterogeneous mass in the cervix.[45]

Precancerous lesions

Ca in situ, cervix 2
Histopathologic image (H&E stain) of carcinoma in situ (also called CIN III), stage 0: The normal architecture of stratified squamous epithelium is replaced by irregular cells that extend throughout its full thickness. Normal columnar epithelium is also seen.

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

The naming and histologic classification of cervical carcinoma precursor lesions has changed many times over the 20th century. The World Health Organization classification[46][47] 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.[47] 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 test (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,[47] however, they are results of different tests, and the Pap test results need not match the histologic findings.

Cancer subtypes

Uterine leiomyoma with cancer cervix
Cervical cancer with uterine leiomyoma

Histologic subtypes of invasive cervical carcinoma include the following:[48][49] 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.[4]

Noncarcinoma malignancies which can rarely occur in the cervix include melanoma and lymphoma. 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

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 these 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.

Diagram showing stage 1A cervical cancer CRUK 200

Stage 1A cervical cancer

Diagram showing stage 1B cervical cancer CRUK 203

Stage 1B cervical cancer

Diagram showing stage 2A cervical cancer CRUK 212

Stage 2A cervical cancer

Diagram showing stage 2B cervical cancer CRUK 216

Stage 2B cervical cancer

Diagram showing stage 3B cervical cancer CRUK 226

Stage 3B cervical cancer

Diagram showing stage 4A cervical cancer CRUK 236

Stage 4A cervical cancer

Diagram showing stage 4B cervical cancer CRUK 239

Stage 4B cervical cancer

Prevention

Screening

Cervical screening Test Vehicle in Minsheng Community 20120421
Cervical screening test vehicle in Taiwan
VIANeg
Negative visual inspection with acetic acid of the cervix
VIAPosCIN1
Positive visual inspection with acetic acid of the cervix for CIN-1

Checking the cervix by the Papanicolaou test (Pap test), for cervical cancer has dramatically reduced the number of cases of and mortality from cervical cancer in developed countries.[20] Pap test screening every three to five years with appropriate follow-up can reduce cervical cancer incidence up to 80%.[52] Abnormal results may suggest the presence of precancerous changes, allowing examination and possible preventive treatment. The treatment of low-grade lesions may adversely affect subsequent fertility and pregnancy.[35] 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.[53]

According to the 2010 European guidelines, the age at which to start screening ranges between 20 and 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.[54]

In the United States, screening is recommended to begin at age 21, regardless of age at which a woman began having sex or other risk factors.[55] Pap tests should be done every three years between the ages of 21 and 65.[55] In women over the age of 65, screening may be discontinued if no abnormal screening results were seen within the previous 10 years and no history of CIN 2 or higher exists.[55][56][57] HPV vaccination status does not change screening rates.[56]

There are a number of recommended options for screening those 30 to 65.[58] This includes cervical cytology every 3 years, HPV testing every 5 years, or HPV testing together with cytology every 5 years.[58][56] Screening is not beneficial before age 25 as the rate of disease is low. Screening is not beneficial in women older than 60 years if they have a history of negative results.[35] The American Society of Clinical Oncology (ASCO) guideline has recommend for different levels of resource availability.[59]

Liquid-based cytology is another potential screening method.[60][61] 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%.[62] 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.[63]

Pap tests have not been as effective in developing countries.[64] This is in part because many of these countries have an impoverished health care infrastructure, too few trained and skilled professionals to obtain and interpret Pap tests, uninformed women who get lost to follow-up, and a lengthy turn-around time to get results.[64] These realities have resulted in the investigation of cervical screening approaches that use fewer resources and offer rapid results such as visual inspection with acetic acid or HPV DNA testing.[64]

Barrier protection

Barrier protection and/or spermicidal gel use during sexual intercourse decreases cancer risk.[35] Condoms offer protection against cervical cancer.[65] Evidence on whether condoms protect against HPV infection is mixed, but they may protect against genital warts and the precursors to cervical cancer.[65] They also provide protection against other STIs, 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.[66] One study suggests that prostaglandin in semen may fuel the growth of cervical and uterine tumors and that affected women may benefit from the use of condoms.[67]

Abstinence also prevents HPV infection.[35]

Vaccination

Two HPV vaccines (Gardasil and Cervarix) reduce the risk of cancerous or precancerous changes of the cervix and perineum by about 93% and 62%, respectively.[68] The vaccines are between 92% and 100% effective against HPV 16 and 18 up to at least 8 years.[35]

HPV vaccines are typically given to 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 four[69] to six[70] years, and they are believed to be effective for longer;[71] 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.

Since 2010, young women in Japan have been eligible to receive the cervical cancer vaccination for free.[72] In June 2013, the Japanese Ministry of Health, Labor and Welfare mandated that, before administering the vaccine, medical institutions must inform women that the Ministry does not recommend it.[72] However, the vaccine is still available at no cost to Japanese women who choose to accept the vaccination.[72]

Nutrition

Vitamin A is associated with a lower risk[73] as are vitamin B12, vitamin C, vitamin E, and beta-Carotene.[74]

Treatment

Cervical Cryotherapy
Cervical cryotherapy

The treatment of cervical cancer varies worldwide, largely due to 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. Surgical intervention may have better outcomes than radiological approaches.[75] In addition, chemotherapy can be used to treat cervical cancer, and has been found to be more effective than radiation alone.[76]

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 or cone biopsy.[77][78]

If a cone biopsy does not produce clear margins[79] (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 women who want to preserve their fertility is a trachelectomy.[80] 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,[81] 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 woman 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 woman 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[82] or vaginally[83] and opinions are conflicting as to which is better.[84] A radical abdominal trachelectomy with lymphadenectomy usually only requires a two- to three-day hospital stay, and most women recover very quickly (about six weeks). Complications are uncommon, although women who are able to conceive after surgery are susceptible to preterm labor and possible late miscarriage.[85] A wait of at least one year is generally recommended before attempting to become pregnant after surgery.[86] Recurrence in the residual cervix is very rare if the cancer has been cleared with the trachelectomy.[81] Yet, women are recommended 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). Women treated with surgery who have high-risk features found on pathologic examination are given radiation therapy with or without chemotherapy to reduce the risk of relapse.

Diagram showing the position of the applicators for internal radiotherapy for cervical cancer CRUK 344
Brachytherapy for cervical cancer

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.[87] Such addition of platinum-based chemotherapy to chemoradiation seems not only to improve survival but also reduces risk of recurrence in women with early stage cervical cancer (IA2-IIA).[88]

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.[89] Combination treatment has significant risk of neutropenia, anemia, and thrombocytopenia side effects.

For surgery to be curative, the entire cancer must be removed with no cancer found at the margins of the removed tissue on examination under a microscope.[90] This procedure is known as exenteration.[90]

Diagram showing the area removed with a posterior exenteration for cancer of the cervix CRUK 288

Diagram showing the area removed with a posterior surgery

Diagram showing the area removed with a total exenteration operation for cancer of the cervix CRUK 289

Diagram showing the area removed with a total operation

Diagram showing the area removed with an anterior exenteration operation for cancer of the cervix CRUK 290

Diagram showing the area removed with an anterior operation

Prognosis

Stage

Prognosis depends on the stage of the cancer. The chance of a survival rate is nearly 100% for women with microscopic forms of cervical cancer.[91] With treatment, the five-year relative survival rate for the earliest stage of invasive cervical cancer is 92%, and the overall (all stages combined) five-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.[92]

With treatment, 80-90% of women with stage I cancer and 60-75% of those with stage II cancer are alive 5 years after diagnosis. Survival rates decrease to 30-40% for women with stage III cancer and 15% or fewer of those with stage IV cancer five years after diagnosis.[93] Recurrent cervical cancer detected at its earliest stages might be successfully treated with surgery, radiation, chemotherapy, or a combination of the three. About 35% of women with invasive cervical cancer have persistent or recurrent disease after treatment.[94]

By country

Five year survival in the United States for White women is 69% and for Black women is 57%.[95]

Regular screening has meant that precancerous 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.[96] About 1,000 women per year die of cervical cancer in the UK. All of the Nordic countries have cervical cancer-screening programs in place.[97] The Pap test was integrated into clinical practice in the Nordic countries in the 1960s.[97]

In Africa outcomes are often worse as diagnosis is frequently at a latter stage of disease.[98]

Epidemiology

Cervix uteri cancer world map - Death - WHO2004
Age-standardized death from cervical cancer per 100,000 inhabitants in 2004[99]

Worldwide, cervical cancer is both the fourth-most common cause of cancer and deaths from cancer in women.[2] In 2012, 528,000 cases of cervical cancer were estimated to have occurred, with 266,000 deaths.[2] 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.[18] About 80% of cervical cancers occur in developing countries.[100] It is the most frequently detected cancer during pregnancy, with an occurrence of 1.5 to 12 for every 100,000 pregnancies.[101]

Australia

Australia had 734 cases of cervical cancer in 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).[102] Regular twice-yearly Pap tests can reduce the incidence of cervical cancer up to 90% in Australia, and save 1,200 Australian women from dying from the disease each year.[103] It is predicted that because of the success of the primary HPV testing programme there will be fewer than four new cases per 100 000 women annually by 2028.[104]

Canada

In Canada, an estimated 1,300 women will have been diagnosed with cervical cancer in 2008 and 380 will have died.[105]

India

In India, the number of people with cervical cancer is rising, but overall the age-adjusted rates are decreasing.[106] Usage of condoms in the female population has improved the survival of women with cancers of the cervix.[107]

European Union

In the European Union, about 34,000 new cases per year and over 16,000 deaths due to cervical cancer occurred in 2004.[52]

United Kingdom

Cervical cancer is the 12th-most common cancer in women in the UK (around 3,100 women were diagnosed with the disease in 2011), and accounts for 1% of cancer deaths (around 920 died in 2012).[108] 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.

United States

An estimated 12,900 new cervical cancers and 4,100 cervical cancer deaths will occur in the United States in 2015.[35] In the United States, it is the eighth-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.[17] In 1998, about 12,800 women were diagnosed in the US and about 4,800 died.[20] In 2014, an estimated 12,360 new cases were expected to be diagnosed, and about 4,020 were expected to die of cervical cancer.[17] Among cancers of the female reproductive tract it is less common than endometrial cancer and ovarian cancer. The rates of new cases in the United States was 7 per 100,000 women in 2004.[109] Cervical cancer deaths decreased by approximately 74% in the last 50 years, largely due to widespread Pap test screening.[110] The annual direct medical cost of cervical cancer prevention and treatment prior to introduction of the HPV vaccine was estimated at $6 billion.[110]

History

  • 400 BCE — Hippocrates noted that cervical cancer was incurable
  • 1925 — Hinselmann invented the colposcope
  • 1928 — Papanicolaou developed the Papanicolaou technique
  • 1941 — Papanicolaou and Traut: Pap test screening began
  • 1946 — Aylesbury spatula was developed to scrape the cervix, collecting the sample for the Pap test
  • 1951 — First successful in-vitro cell line, HeLa, derived from biopsy of cervical cancer of Henrietta Lacks
  • 1976 — Harald zur Hausen and Gisam found HPV DNA in cervical cancer and genital warts; Hausen later won the Nobel Prize for his work[111]
  • 1988 — Bethesda System for reporting Pap results was developed
  • 2006 — First HPV vaccine was approved by the FDA

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

  1. Cervical cancer was noted to be 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.[112]
  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)

These historical observations suggested that cervical cancer could be caused by a sexually transmitted agent. Initial research in the 1940s and 1950s attributed cervical cancer to smegma (e.g. Heins et al. 1958).[113] 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 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.[114] 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.[115] It was not until the 1980s that HPV was identified in cervical cancer tissue.[116] It has since been demonstrated that HPV is implicated in virtually all cervical cancers.[117] 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.[118] 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

Australia

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.[119] 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.[120] Difficulty in accessing screening services (for example, transport difficulties) and a lack of female GPs, trained Pap test providers and trained female Aboriginal Health Workers are also issues.[120]

The Australian Cervical Cancer Foundation (ACCF), founded in 2008, promotes '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.'[121] Ian Frazer, one of the developers of the Gardasil cervical cancer vaccine, is the scientific advisor to ACCF.[122] 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.[123]

United States

A 2007 survey of American women found 40% had heard of HPV infection and less than half of those knew it causes cervical cancer.[124] Over a longitudinal study from 1975-2000, it was found that people of lower socioeconomic census brackets had higher rates of late-stage cancer diagnosis and higher morbidity rates. After controlling for stage, there still existed differences in survival rates.[125]

References

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Ann Christy (singer)

Ann Christy (born Christianne Leenaerts, 22 September 1945 in Antwerp – 7 August 1984 in Meise) was a Belgian singer who enjoyed success in her native country and is best known internationally for her participation in the 1975 Eurovision Song Contest.

Cervarix

Cervarix is a vaccine against certain types of cancer-causing human papillomavirus (HPV).

Cervarix is designed to prevent infection from HPV types 16 and 18, that cause about 70% of cervical cancer cases. These types also cause most HPV-induced genital and head and neck cancers. Additionally, some cross-reactive protection against virus strains 45 and 31 were shown in clinical trials. Cervarix also contains AS04, a proprietary adjuvant that has been found to boost the immune system response for a longer period of time.Cervarix is manufactured by GlaxoSmithKline. An alternative product, from Merck & Co., is known as Gardasil.

Cervical intraepithelial neoplasia

Cervical intraepithelial neoplasia (CIN), also known as cervical dysplasia, is the abnormal growth of cells on the surface of the cervix that could potentially lead to cervical cancer. More specifically, CIN refers to the potentially precancerous transformation of cells of the cervix.

CIN most commonly occurs at the squamocolumnar junction of the cervix, a transitional area between the squamous epithelium of the vagina and the columnar epithelium of the endocervix. It can also occur in vaginal walls and vulvar epithelium. CIN is graded on a 1-3 scale, with 3 being the most abnormal (see classification section below).

Human papilloma virus (HPV) infection is necessary for the development of CIN, but not all with this infection develop cervical cancer. A large number of women with HPV infection never develop CIN or cervical cancer. Typically, HPV resolves on its own. However, those with an HPV infection that lasts more than 1 or 2 years have a higher risk of developing a higher grade of CIN.Like other intraepithelial neoplasias, CIN is not cancer and is usually curable. Most cases of CIN either remain stable or are eliminated by the person's immune system without need for intervention. However, a small percentage of cases progress to cervical cancer, typically cervical squamous cell carcinoma (SCC), if left untreated.

Cervical screening

Cervical screening is the process of detecting and removing abnormal tissue or cells in the cervix before cervical cancer develops. By aiming to detect and treat cervical neoplasia early on, cervical screening aims at secondary prevention of cervical cancer. Several screening methods for cervical cancer are the Pap test (also known as Pap smear or conventional cytology), liquid-based cytology, the HPV DNA testing and the visual inspection with acetic acid. Pap test and liquid-based cytology have been effective in diminishing incidence and mortality rates of cervical cancer in developed countries but not in developing countries. Prospective screening methods that can be used in low-resource areas in the developing countries are the HPV DNA testing and the visual inspection.

Cervicectomy

In gynecologic oncology, trachelectomy, also cervicectomy, is a surgical removal of the uterine cervix. As the uterine body is preserved, this type of surgery is a fertility preserving surgical alternative to a radical hysterectomy and applicable in selected younger women with early cervical cancer.

Cervix

The cervix or cervix uteri (Latin: neck of the uterus) is the lower part of the uterus in the human female reproductive system. The cervix is usually 2 to 3 cm long (~1 inch) and roughly cylindrical in shape, which changes during pregnancy. The narrow, central cervical canal runs along its entire length, connecting the uterine cavity and the lumen of the vagina. The opening into the uterus is called the internal os, and the opening into the vagina is called the external os. The lower part of the cervix, known as the vaginal portion of the cervix (or ectocervix), bulges into the top of the vagina. The cervix has been documented anatomically since at least the time of Hippocrates, over 2,000 years ago.

The cervical canal is a passage through which sperm must travel to fertilize an egg cell after sexual intercourse. Several methods of contraception, including cervical caps and cervical diaphragms, aim to block or prevent the passage of sperm through the cervical canal. Cervical mucus is used in several methods of fertility awareness, such as the Creighton model and Billings method, due to its changes in consistency throughout the menstrual period. During vaginal childbirth, the cervix must flatten and dilate to allow the fetus to progress along the birth canal. Midwives and doctors use the extent of the dilation of the cervix to assist decision-making during childbirth.

The cervical canal is lined with a single layer of column-shaped cells, while the ectocervix is covered with multiple layers of cells topped with flat cells. The two types of epithelia meet the squamocolumnar junction. Infection with the human papillomavirus (HPV) can cause changes in the epithelium, which can lead to cancer of the cervix. Cervical cytology tests can often detect cervical cancer and its precursors, and enable early successful treatment. Ways to avoid HPV include avoiding sex, using condoms, and HPV vaccination. HPV vaccines, developed in the early 21st century, reduce the risk of cervical cancer by preventing infections from the main cancer-causing strains of HPV.

Colposcopy

Not to be confused with colonoscopy.Colposcopy (Ancient Greek: κόλπος, translit. kolpos, lit. 'hollow, womb, vagina' + skopos "look at") is a medical diagnostic procedure to examine an illuminated, magnified view of the cervix and the tissues of the vagina and vulva. Many premalignant lesions and malignant lesions in these areas have discernible characteristics that can be detected through the examination. It is done using a colposcope, which provides an enlarged view of the areas, allowing the colposcopist to visually distinguish normal from abnormal appearing tissue and take directed biopsies for further pathological examination. The main goal of colposcopy is to prevent cervical cancer by detecting and treating precancerous lesions early. The procedure was developed by the German physician Hans Hinselmann, with help from Eduard Wirths. The development of colposcopy involved experimentation on Jewish inmates from Auschwitz.A specialized colposcope equipped with a camera is used in examining and collecting evidence for victims of rape and sexual assault.

Erin Andrews

Erin Jill Andrews (born May 4, 1978) is an American sportscaster and television personality. She hosts Dancing with the Stars for ABC and is a sideline reporter for Fox NFL.Andrews was previously a co-host of College GameDay on ESPN and a contributor for Good Morning America on the ABC network. She also has an on-air presence at many major sporting events, including the Super Bowl and the World Series.

Gardasil

Gardasil, also known as Gardisil or Silgard or recombinant human papillomavirus vaccine [types 6, 11, 16, 18], is a vaccine for use in the prevention of certain strains of human papillomavirus (HPV), specifically HPV types 6, 11, 16 and 18. HPV types 16 and 18 cause an estimated 70% of cervical cancers, and are responsible for most HPV-induced anal, vulvar, vaginal, and penile cancer cases. HPV types 6 and 11 cause an estimated 90% of genital warts cases. In addition, high-risk human papilloma virus (hr-HPV) genital infection is the most common sexually transmitted infection among women. Though Gardasil does not treat existing infection, vaccination is still recommended for HPV positive individuals, as it may protect against one or more different strains of the disease. The HPV strains that Gardasil protects against are sexually transmitted.

The vaccine was approved in the US in June 2006 by the U.S. Food and Drug Administration (FDA). The FDA approved the use of Gardasil for use in girls and women aged 9–26 In 2011, the Gardasil vaccine has also been approved in 120 other countries. The FDA recommends vaccination before adolescence and potential sexual activity.In 2007, the Advisory Committee on Immunization Practices (ACIP) recommended gardasil for routine vaccination of girls aged 11 and 12 yearsIn December 2014, the FDA approved a nine-valent Gardasil-based vaccine, Gardasil 9, to protect against infection with the strains covered by the first generation of Gardasil as well as five other HPV strains responsible for 20% of cervical cancers (HPV-31, HPV-33, HPV-45, HPV-52, and HPV-58). In October 2018, the FDA approved expanded use of Gardasil 9 to include individuals 27 through 45 years old.

Gynecologic oncology

Gynecologic oncology is a specialized field of medicine that focuses on cancers of the female reproductive system, including ovarian cancer, uterine cancer, vaginal cancer, cervical cancer, and vulvar cancer. As specialists, they have extensive training in the diagnosis and treatment of these cancers.

In the United States, 82,000 women are diagnosed with gynecologic cancer annually. In 2013, an estimated 91,730 were diagnosed.The Society of Gynecologic Oncology and the European Society of Gynaecological Oncology are professional organizations for gynecologic oncologists, and the Gynecologic Oncology Group is a professional organization for gynecological oncologists as well as other medical professionals who deal with gynecologic cancers. The Foundation for Women's Cancer is the major U.S. organization that raises awareness and research funding and provides educational programs and materials about gynecologic cancers.

HPV vaccine

Human papilloma virus (HPV) vaccines are vaccines that prevent infection by certain types of human papillomavirus. Available vaccines protect against either two, four, or nine types of HPV. All vaccines protect against at least HPV type 16 and 18 that cause the greatest risk of cervical cancer. It is estimated that they may prevent 70% of cervical cancer, 80% of anal cancer, 60% of vaginal cancer, 40% of vulvar cancer, and possibly some mouth cancer. They additionally prevent some genital warts with the vaccines against 4 and 9 HPV types providing greater protection.The World Health Organization (WHO) recommends HPV vaccines as part of routine vaccinations in all countries, along with other prevention measures. The vaccines require two or three doses depending on a person's age and immune status. Vaccinating girls around the ages of nine to thirteen is typically recommended. The vaccines provide protection for at least 5 to 10 years. Cervical cancer screening is still required following vaccination. Vaccinating a large portion of the population may also benefit the unvaccinated. In those already infected the vaccines are not effective.HPV vaccines are very safe. Pain at the site of injection occurs in about 80% of people. Redness and swelling at the site and fever may also occur. No link to Guillain–Barré syndrome has been found.The first HPV vaccine became available in 2006. As of 2017, 71 countries include it in their routine vaccinations, at least for girls. They are on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system. The wholesale cost in the developing world is about US$47 a dose as of 2014. In the United States it costs more than US$200. Vaccination may be cost effective in the developing world.

Human papillomavirus infection

Human papillomavirus infection (HPV infection) is an infection by human papillomavirus (HPV). Most HPV infections cause no symptoms and resolve spontaneously. In some people, an HPV infection persists and results in warts or precancerous lesions. The precancerous lesions increase the risk of cancer of the cervix, vulva, vagina, penis, anus, mouth, or throat. Nearly all cervical cancer is due to HPV with two types, HPV16 and HPV18, accounting for 70% of cases. Between 60% and 90% of the other cancers mentioned above are also linked to HPV. HPV6 and HPV11 are common causes of genital warts and laryngeal papillomatosis.An HPV infection is caused by human papillomavirus, a DNA virus from the papillomavirus family, of which over 170 types are known. More than 40 types are transmitted through sexual contact and infect the anus and genitals. Risk factors for persistent HPV infections include early age of first sexual intercourse, multiple partners, smoking, and poor immune function. HPV is typically spread by sustained direct skin-to-skin contact, with vaginal and anal sex being the most common methods. Occasionally, it can spread from a mother to her baby during pregnancy. It does not appear to spread via common items like toilet seats. People can become infected with more than one type of HPV. HPV affects only humans.HPV vaccines can prevent the most common types of infection. To be most effective, they should be used before an infection occurs and are therefore recommended between the ages of nine and 13. Cervical cancer screening, such as with the Papanicolaou test (pap) or looking at the cervix after using acetic acid, can detect early cancer or abnormal cells that may develop into cancer. This allows for early treatment which results in better outcomes. Screening has reduced both the number of cases and the number of deaths from cervical cancer in the developed world. Warts can be removed by freezing.HPV is the most common sexually transmitted infection globally. Most people are infected at some point in their lives. In 2012, about 528,000 new cases and 266,000 deaths occurred from cervical cancer worldwide. Around 85% of these occurred in the developing world. In the United States, about 30,700 cases of cancer due to HPV occur each year. About 1% of sexually active adults have genital warts. While cases of warts have been described since the time of ancient Greece, their viral nature was not discovered until 1907.

Ian Frazer

Ian Hector Frazer (born 6 January 1953) is a Scottish-born Australian immunologist, the founding CEO and Director of Research of the Translational Research Institute (Australia). Frazer and Jian Zhou developed and patented the basic technology behind the HPV vaccine against cervical cancer at the University of Queensland. The vaccine, now marketed as Gardasil and Cervarix, was the second cancer preventing vaccine, and the first vaccine designed to prevent a cancer. Researchers at the National Cancer Institute, Georgetown University, and University of Rochester also contributed to the further development of the cervical cancer vaccine in parallel.

Jade Goody

Jade Cerisa Lorraine Goody (5 June 1981 – 22 March 2009) was an English reality-television personality. She entered the public spotlight in the third series of the then-Channel 4 programme Big Brother in 2002, an appearance which led to her own television programmes and the introduction of her products after her eviction from the show.Immediately criticised by the British press for her perceived lack of decorum and intelligence, Goody was dubbed by multiple outlets as "the most hated woman in Britain". The country's celebrity magazines were less derisive, publishing reports of her affable nature and competent school performance from those who knew her. Public opinion of Goody reached its most negative in January 2007, however, when she was the perpetrator of racial bullying towards Indian actress Shilpa Shetty while appearing as a housemate on Celebrity Big Brother 5. Following her eviction, Goody made a number of apologies, but continued to garner negative public reactions.In August 2008, Goody appeared on the Indian version of Big Brother, Bigg Boss, but left the show early and returned to the UK after learning that she had cervical cancer. By February 2009, the cancer had metastasized, and Goody was terminally ill. She married fellow Celebrity Big Brother contestant Jack Tweed on 22 February 2009, and died one month later, in the early hours of 22 March 2009, at the age of 27.Public opinion of Goody had softened by the time of her death. Sky Living broadcast five tribute shows from 2009 to 2012, documenting her life from early childhood through her rise to fame and her final months. The last episode of Big Brother on Channel 4 featured a 15-minute tribute to Goody, praising her as the ultimate Big Brother contestant. She was one of several people to appear on the front cover of the final edition of News of the World on 10 July 2011.

Little Eva

Eva Narcissus Boyd (June 29, 1943 – April 10, 2003), known by the stage name of Little Eva, was an American pop singer. Although some sources claim that her stage name was inspired by a character from the novel Uncle Tom's Cabin, she stated in an interview that she was named after her aunt, which prompted her family to call her "Little Eva."

Pap test

The Papanicolaou test (abbreviated as Pap test, also known as Pap smear, cervical smear, cervical screening or smear test) is a method of cervical screening used to detect potentially precancerous and cancerous processes in the cervix (opening of the uterus or womb). Abnormal findings are often followed up by more sensitive diagnostic procedures and if warranted, interventions that aim to prevent progression to cervical cancer. The test was independently invented by Dr. Georgios Papanikolaou and Dr. Aurel Babeș and named after Papanikolaou.

A Pap smear is performed by opening the vaginal canal with a speculum and collecting cells at the outer opening of the cervix at the transformation zone (where the outer squamous cervical cells meet the inner glandular endocervical cells). The collected cells are examined under a microscope to look for abnormalities. The test aims to detect potentially precancerous changes (called cervical intraepithelial neoplasia (CIN) or cervical dysplasia; the squamous intraepithelial lesion system (SIL) is also used to describe abnormalities) caused by human papillomavirus, a sexually transmitted DNA virus. The test remains an effective, widely used method for early detection of precancer and cervical cancer. While the test may also detect infections and abnormalities in the endocervix and endometrium, it is not designed to do so.

In the United States, Pap smear screening is recommended starting around 21 years of age until the age of 65. However, other countries do not recommend pap testing in non-sexually active females. Guidelines on frequency vary from every three to five years. If results are abnormal, and depending on the nature of the abnormality, the test may need to be repeated in six to twelve months. If the abnormality requires closer scrutiny, the patient may be referred for detailed inspection of the cervix by colposcopy. The person may also be referred for HPV DNA testing, which can serve as an adjunct to Pap testing. Additional biomarkers that may be applied as ancillary tests with the Pap test are evolving.

Sarah Tait

Sarah Anne Tait (née Outhwaite; 23 January 1983 – 3 March 2016) was an Australian rower - a national and world champion, three-time Olympian and Olympic-medal winner. She was the first mother to represent Australia in rowing at Olympic level, having returned to international competition following the birth of her daughter.

Tanya Branning

Tanya Cross (also Branning and Jessop) is a fictional character from the BBC soap opera EastEnders, played by Jo Joyner. She made her first appearance on 27 June 2006. Tanya's storylines have included opening her own salon, giving birth to her third child, discovering that her husband Max Branning (Jake Wood) had an affair with Stacey Slater (Lacey Turner) before divorcing and then burying him alive with the help from her new partner Sean Slater (Robert Kazinsky), marrying Greg Jessop (Stefan Booth), starting an affair with Max on her wedding day to Greg, dealing with her eldest daughter, Lauren Branning (Madeline Duggan/Jacqueline Jossa)’s alcoholism, battling cervical cancer, discovering that Max has a secret wife, Kirsty Branning (Kierston Wareing) on their second wedding day, witnessing her daughters Lauren and Abi Branning (Lorna Fitzgerald) fall from the roof of The Queen Victoria pub which leads to her mental breakdown.

Joyner left the show temporarily on 25 December 2009 for maternity leave and returned for one episode on 23 June 2010. She made her full-time return on 27 September 2010. On 1 May 2012, it was announced Joyner would take another break from the series in 2013, however, on 1 April 2013, it was announced her departure would be indefinite. On 15 May 2013, Joyner filmed her final scenes and departed on 28 June 2013. Tanya returned in February 2015 for two episodes as part of the show's 30th anniversary celebrations. Joyner reprised the role in 2017 for four episodes, appearing between 25 December 2017 and 16 February 2018.

Timeline of cervical cancer

This is a timeline of cervical cancer, describing especially major discoveries and advances in treatment of the disease.

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