Cervical cancer

HPV types 16 and 18 are the cause of 75% of cervical cancer cases globally, while 31 and 45 are the causes of another 10%.[34]

Women who have multiple sexual partners, or have partners who have multiple sexual partners, regardless of sex are at higher risk of cervical cancer .[35][36]

Of the 150-200 types of HPV known,[37][38] 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).[39]

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. Having multiple strains at the same time is common, 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.[40]

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.[41]

Smoking has also been linked to the development of cervical cancer.[42][43][31] Smoking can increase the risk in women a few different ways, which can be by direct and indirect methods of inducing cervical cancer.[42][31][44] A direct way of contracting this cancer is a smoker has a higher chance of cervical intraepithelial neoplasia (CIN3) occurring, which has the potential of forming cervical cancer.[42] 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.[44] 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.[45] 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.[31] 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.[45]

Long-term use of oral contraceptives is associated with increased risk of cervical cancer in women who have had HPV. 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.[41]

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.[41]

The Pap test can be used as a screening test, but produces a false negative in up to 50% of cases of cervical cancer.[46][47] Other concerns is the cost of doing Pap tests, which make them unaffordable in many areas of the world.[48]

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,[5] with visual contrast provided by staining the normal tissues a mahogany brown with Lugol's iodine.[49] Medical devices used for biopsy of the cervix include punch forceps. 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.

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 the tumor, and effect on adjacent structures. Typically, they appear as heterogeneous mass on the cervix.[50]

Interventions such as playing music during the procedure and viewing the procedure on a monitor can reduce the anxiety associated with the examination.[51]

Histopathologic image (H&E stain) of carcinoma in situ (also called CIN3), 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[52][53] 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 standardize treatment.[53] 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,[53] but they are results of different tests, and the Pap test results need not match the histologic findings.

Histologic subtypes of invasive cervical carcinoma include:[54][55]

• Squamous cell carcinoma (about 80–85%[56][57])
• adenocarcinoma (about 15% of cervical cancers in the UK[52])
• Adenosquamous carcinoma
• Small cell carcinoma
• Neuroendocrine tumour
• Glassy cell carcinoma
• Villoglandular adenocarcinoma

• 
  Invasive squamous cell carcinoma of the cervix is characterized by infiltration as irregular anastomosing nests or single cells.[58] This case is poorly differentiated. H&E stain.
• 
  The location of cervical cancer can be described in terms of quadrants, or corresponding to a clock face when the subject is in supine position.

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.[5] Endocervical adenocarcinoma represents 20–25% of the histological types of cervical carcinoma. Gastric-type mucinous adenocarcinoma of the cervix is a rare type of cancer with aggressive behavior. This type of malignancy is not related to high-risk human papillomavirus (HPV).[59] Noncarcinoma malignancies which can rarely occur in the cervix include melanoma and lymphoma. The International Federation of Gynecology and Obstetrics (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.

Cervical cancer is staged by the FIGO system, which is based on clinical examination rather than surgical findings. Prior to the 2018 revisions to FIGO staging, the system allowed 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. However, the current system allows use of any imaging or pathological methods for staging.[60]

• 
  Stage 1A cervical cancer
• 
  Stage 1B cervical cancer
• 
  Stage 2A cervical cancer
• 
  Stage 2B cervical cancer
• 
  Stage 3B cervical cancer
• 
  Stage 4A cervical cancer
• 
  Stage 4B cervical cancer

Cervical screening test vehicle in Taiwan

Negative visual inspection with acetic acid of the cervix

Positive visual inspection with acetic acid of the cervix for CIN-1

Checking cervical cells with the Papanicolaou test (Pap test) for cervical pre-cancer has dramatically reduced the number of cases of, and mortality from, cervical cancer.[24] Liquid-based cytology may reduce the number of inadequate samples.[61][62][63] Pap test screening every three to five years with appropriate follow-up can reduce cervical cancer incidence up to 80%.[64] Abnormal results may suggest the presence of precancerous changes, allowing examination and possible preventive treatment, known as colposcopy. The treatment of low-grade lesions may adversely affect subsequent fertility and pregnancy.[41] 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.[65]

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.[64]

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.[66] Pap tests should be done every three years between the ages of 21 and 65.[66] 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 CIN2 or higher exists.[66][67][68] HPV vaccination status does not change screening rates.[67]

A number of recommended options exist for screening those 30 to 65.[69] This includes cervical cytology every 3 years, HPV testing every 5 years, or HPV testing together with cytology every 5 years.[69][67] 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.[41] The American Society of Clinical Oncology guideline has recommend for different levels of resource availability.[70]

Pap tests have not been as effective in developing countries.[71] 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.[71] Visual inspection with acetic acid and HPV DNA testing have been tried, though with mixed success.[71]

Barrier protection or spermicidal gel use during sexual intercourse decreases, but does not eliminate risk of transmitting the infection,[41] though condoms may protect against genital warts.[72] They also provide protection against other sexually transmitted infections, such as HIV and Chlamydia, which are associated with greater risks of developing cervical cancer.

Three HPV vaccines (Gardasil, Gardasil 9, and Cervarix) reduce the risk of cancerous or precancerous changes of the cervix and perineum by about 93% and 62%, respectively.[73] The vaccines are between 92% and 100% effective against HPV 16 and 18 up to at least 8 years.[41]

HPV vaccines are typically given to age 9 to 26, as the vaccine is most effective if given before infection occurs. 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. The American Society of Clinical Oncology guideline has recommendations for different levels of resource availability.[70]

Since 2010, young women in Japan have been eligible to receive the cervical cancer vaccination for free.[74] 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.[74] However, the vaccine is still available at no cost to Japanese women who choose to accept the vaccination.[74]

Vitamin A is associated with a lower risk[75] as are vitamin B12, vitamin C, vitamin E, and beta-Carotene.[76]

Prognosis depends on the stage of the cancer. For intraepithelial cervical neoplasmas the prognosis is good.[106] 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 66%. 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.[107]

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 58% for women with stage III cancer and 17% or fewer of those with stage IV cancer five years after diagnosis.[107] 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.[108]

Five-year survival in the United States for White women is 69% and for Black women is 57%.[109]

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.[110] 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.[111] The Pap test was integrated into clinical practice in the Nordic countries in the 1960s.[111]

In Africa outcomes are often worse as diagnosis is frequently at a latter stage of disease.[112] In a scoping review of publicly-available cervical cancer prevention and control plans from African countries, plans tended to emphasize survivorship rather than early HPV diagnosis and prevention.[113]

In 2022, it is estimated that 942 new cases of cervical cancer will be diagnosed in Australia. In 2022, it is estimated that a female has a 1 in 180 (or 0.56%) risk of being diagnosed with cervical cancer by the age of 85.[118]

In 2020, there were 165 women aged 25–74 who died from cervical cancer, which is a mortality rate of 2 deaths per 100,000 women in the population. Over the 5 years 2016–2020, there were 62 Aboriginal and Torres Strait Islander women aged 25–74 who died from cervical cancer, which is a mortality rate of 7 deaths per 100,000 Indigenous women in the population. Over the 5 years 2016–2020, the age-standardised mortality rate among Aboriginal and Torres Strait Islander women was 3.8 times the rate of non-Indigenous Australians.[119]

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).[120] 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.[121] 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.[122]

An estimated 1,450 Canadians will be diagnosed with cervical cancer in 2022. An estimated 380 will die from it.[123]

In India, the number of people with cervical cancer is rising, but overall the age-adjusted rates are decreasing.[124] Usage of condoms in the female population has improved the survival of women with cancers of the cervix.[125]

As of 2022, the World Health Organization announced that "each year in the WHO European Region more than 66 000 women are newly diagnosed with cervical cancer and more than 30 000 die from this preventable disease. "[126]

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).[127] With a 42% reduction from 1988 to 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.

An estimated 13,170 new cervical cancers and 4,250 cervical cancer deaths will occur in the United States in 2019.[128] The median age at diagnosis is 50. The rates of new cases in the United States was 7.3 per 100,000 women, based on rates from 2012 to 2016. Cervical cancer deaths decreased by approximately 74% in the last 50 years, largely due to widespread Pap test screening.[129] The annual direct medical cost of cervical cancer prevention and treatment prior to introduction of the HPV vaccine was estimated at $6 billion.[129]

The Nigerian Institute of Medical Research (NIMR) reports that 28 Nigerian women lose their lives daily due to this disease. This alarming statistic underscores the pressing need for better awareness, prevention, and treatment efforts across the country. Numerous Nigerian women lack access to these preventive measures. In many regions of the country, screening tests such as Pap tests and HPV tests are not easily accessible or affordable[130][131]

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.[143] 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.[144] 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.[144]

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.'[145] Ian Frazer, one of the developers of the Gardasil cervical cancer vaccine, is the scientific advisor to ACCF.[146] Janette Howard, the wife of the then-Prime Minister of Australia, John Howard, was diagnosed with cervical cancer in 1996, and first spoke publicly about the disease in 2006.[147]

A Centers for Disease Control and Prevention public service announcement about cervical cancer health disparities in the 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.[148] Over a longitudinal study from 1975 to 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.[149]

Transgender men and gender-diverse people who have a cervix (even if partially intact) or have a prior history of cervical cancer or precancerous conditions, and are age 21 or older who has ever had sex with anyone need to get screened for cervical cancer.[150][151] Transmasculine people are just as likely as cisgender women to have cervical cancer, but are less likely to undergo cervical screening, because of dysphoria, gender disaffirmation or disempowerment of the individual by healthcare providers,[152] or being misinformed of HPV and cervical cancer risks[153] as well as many healthcare providers perceiving transmasculine individuals to be at low risk of cervical cancer.[154]

Transgender women who have not had bottom surgery have no risk of cervical cancer, as they do not have a cervix. Trans women who have had bottom surgery to create a vagina (vaginoplasty) and possibly a cervix, are at a very small risk to develop cancer in the tissues of their neo-vagina or neo-cervix as these tissues are made up of different cells than a cervix in a cisgender woman[155][156] Cervical cancer screening is not necessary in trans women who have undergone vaginoplasty because they do not have a cervix.[157]

Intersex people with a cervix are also able to have cervical cancer.[158]