The cervix is the neck of a woman’s uterus. It is attached to the body of her uterus and partly protrudes into her vagina. About three centimetres long, it has a central canal and an internal and external opening. The cervix plays vital roles in conception and pregnancy, making mucus that aids sperm transportation from the vagina, keeping the uterus closed throughout pregnancy, then relaxing and steadily opening during labour to allow vaginal delivery.
A woman’s cervix is exposed to sexually transmitted infection. A common cause of sexually transmitted infection is the Human Papilloma virus (HPV). Although a woman is likely to successfully fight off the vast majority of HPV infections with her own immune system, the virus can sometimes persist in the surface cells of her cervix, causing a precancerous condition called cervical intraepithelial neoplasia (CIN). HPV can also cause comparable precancerous changes to the glandular cells that line the inner surface of the cervical canal. If undetected and untreated for many years, the precancerous condition may progress to invasive cancer.
Worldwide, invasive cervical cancer is one of the 4 most common causes of death from cancer in women, along with breast, colorectal and lung cancer. About 80% of women diagnosed with this cancer live in developing countries, and it kills over 260,000 women each year. In developed countries such as Australia, the impact of this disease has markedly decreased because of widespread, regular screening with the Papanicolaou (Pap) test.
In 2019, it is estimated that 951 women will be diagnosed with cervical cancer in Australia and 256 women will die of the disease. The 5-year survival from cervical cancer between 2011 and 2015 was 74%. The incidence (ie. rate of new diagnosis) of cervical cancer for women aged 20–69 was 17.2 new cases per 100,000 women in 1991, the year the National Cervical Screening program was officially introduced. It is estimated that it will be 7.2 cases per 100,000 in 2019. Death rates have also halved, reflecting better treatment. Abnormalities discovered by regular screening are almost always either precancerous, or early invasive cancer which is very likely to be successfully treated.
Invasive cervical cancer is highly unlikely to be diagnosed in women under 20 years of age. The average age at diagnosis is about 47 years, and 70% of cancers are diagnosed in women under the age of 60. Most women diagnosed with this condition have not had regular Pap tests and their cancers are likely to be found because they have caused abnormal vaginal bleeding or discharge.
Treatment of invasive cervical cancer and the likely results of treatment depend very much on the stage and, to a lesser extent on the desire for future childbearing. Surgery is the main form of treatment for early cancers, but radiotherapy is required if the cancer has spread beyond the cervix. Chemotherapy is used to enhance the effects of such radiation.
The impact of invasive cervical cancer is expected to further decline in Australia because our national HPV vaccination program is protecting more and more women. However, cervical screening will remain important, because the HPV vaccine will not protect against all potentially cancer-causing (high-risk) viruses.
The cause of virtually all cervical cancers is persistent infection with a high-risk HPV. The HPV virus is the same one that causes harmless, self-healing childhood warts and more troublesome but non-cancerous genital and plantar warts.
There are over 200 HPV types, of which 15 are currently believed to be high-risk and capable of causing genital and anal cancer or precancer. Types 16 and 18 are responsible for 70% of cervical cancers. Types 6 and 11 are considered to be low-risk HPV viruses. They are responsible for most genital warts (condylomas) and low-grade CIN (CIN I). When HPV is associated with low grade abnormalities on Pap testing, type 16 is the most common genotype followed by 31, 51 and 53.
Genital HPV infection typically causes no symptoms or visible changes. Unless she has warts, it is not possible to know if a woman has an HPV infection without Pap testing or HPV DNA testing. There is no reliable HPV test for men.
Not surprisingly, behaviour that increases a woman’s risk of exposure to HPV increases her risk of developing cervical cancer. The risky behaviours include:
- Early age at first intercourse,
- Multiple sexual partners and
- Having a male partner who has had multiple sexual partners
The last point is important. Although a woman who has never had a sexual partner is at very low risk of cervical cancer, some women who develop cervical cancer have only ever had one or two sexual partners. HPV is very easy to transmit to a woman’s cervix by intimate physical contact, so the mode of transmission may involve heterosexual or homosexual interaction in a wide variety of forms, including oral and anal sex. Use of condoms substantially reduces the risk, but does not reliably prevent transmission.
About 8 out of 10 sexually active women in contemporary Australian society will become infected with HPV on at least one occasion in their lives. However, most HPV infections are successfully fought off by immune reactions. Relatively few become persisting cervical HPV infections and cause precancerous and cancerous changes in cervical cells.
Apart from HPV infections, other factors known to increase a woman’s risk of cervical cancer are:
- Having a weakened immune system
- Other sexually transmitted infections such as genital herpes and chlamydia
Over 70% of cervical cancers diagnosed in Australia are squamous carcinomas, which means they arise from the layer of flattened cells on the outer surface of the cervix.
Adenocarcinomas arise from the glandular cells lining the inner surface of the cervical canal. Adenocarcinomas and mixed form (adenosquamous) carcinomas presently account for about 25% of cervical cancers.
The incidence of invasive carcinoma of the cervix has been declining in developed countries for decades. In Australia, squamous cell carcinoma has shown the most dramatic change over this time, decreasing from 15.1 new cases per 100,000 women in 1982 to 6.3 per 100,000 in 2010.
The incidence of adenocarcinomas, however, has increased significantly relative to squamous carcinomas over the past 30 years. The reasons are believed to be related to better recognition of glandular cancers by pathologists, and greater difficulty diagnosing then in the precancerous stages on Pap tests, when they can be readily treated and cured.
HPV related squamous carcinoma, adenocarcinoma and adenosquamous carcinoma caused over 95% of cancers of the cervix diagnosed in Australia in 2010. Rare forms of cervical cancer include sarcomas, melanomas and lymphomas. The causes, management and results of treatment of these cancers are very different to HPV related carcinomas, to which the following information applies.
There are 15 types of high-risk human papilloma viruses that can cause cervical cancer, but the two most common are HPV types 16 and 18. In Australia, these two viruses are responsible for 70% of cervical cancers.
HPV vaccination programs (using vaccines first developed by an Australian team led by Professor Ian Frazer) have demonstrated dramatic efficiency in preventing new HPV 16 and 18 infections as well as precancerous CIN. They are expected to markedly decrease the rate of newly diagnosed invasive cervical cancer, but it will take several years to demonstrate this conclusively. Vaccination can also protect people against genital warts and some other HPV associated cancers, such as anal, vulvar, vaginal and oral cancers.
In 2007, Australia was the first country in the world to introduce a National HPV Immunisation Program for all schoolgirls. Since 2013, this program has been offered through schools to all male and female students aged 12-13 years.
Two vaccines were initially available: Gardasil, which protected against four HPV types (6, 11, 16 and 18), and Cervarix, which protected against only HPV types 16 and 18. Gardasil was the vaccine used in the National Immunisation Program. Types 6 and 11 are low risk HPV viruses which cause genital warts, but not cervical cancer.
In early 2018, a new vaccine called Gardasil 9 that protected against 9 HPV viruses was introduced into the National Immunization Program. In addition to protecting against HPV types 6, 11, 16 and 18, the new vaccine also protects against 5 other cancer-causing HPV viruses (Types 31, 33, 45, 52 and 58). This vaccine increases the protection against cervical cancer from 70% to 90%, but the protection is still not 100%.
The vaccines can be given between the ages of 9 and 45 years, but protection is greatest if they are given before the onset of sexual activity. Vaccination is still recommended after commencement of sexual activity, and even after an abnormal screening test. Gardasil 9 offers some protection against cancer caused by 7 high-risk HPV viruses, and a woman may be newly exposed to any one of these viruses in the future.
Natural immunity offers no comparable protection. Any one of the 15 high-risk HPV viruses can infect a woman who has naturally eliminated another high-risk type, or the viral infection can persist in a dormant state for many years. For either reason, she may develop cervical cancer much later in her life, even though she may be no longer sexually active. This evidence, and the fact that the seven high-risk viruses covered by Gardasil 9 are responsible for only 90% of cervical cancers, emphasise the importance of ongoing cervical cancer screening for vaccinated women.
In May 2014, the Medical Services Advisory Committee (MSAC) released its recommendation that Pap tests should be phased out and replaced with Human papilloma Virus (HPV) testing for cervical cancer screening. MSAC also recommended that the starting age for screening should be set at 25 years.
In December 2017, Australia officially changed from screening with Pap smears every 2 years from 18 to 69 years to screening with the HPV test every 5 years from 25 to 74 years.
The HPV test involves taking a sample from the cervix, just like the Pap smear. The sample is collected into a container of fixative solution for liquid cytology. In the pathology laboratory, an automated process creates a single layer of cervical cells on a slide (Figure 1).
The test looks for the presence of one of the 15 high-risk HPV virus which are responsible for cervical cancer, so the new test is diagnosing the presence or absence of the actual cause of the cancer. Most HPV viruses do not cause cancer, or even precancer, because they are eliminated by the woman’s own immune system.
The HPV test is more effective at preventing cervical cancer, because its failure to detect the virus (ie. the false negative rate) is extremely low. This allows the test to be performed every 5 years if the result is normal, instead of every 2 years.
If a high-risk virus is detected, the cells in the liquid cytology bottle will be automatically examined to determine whether there are any abnormal cells present. If so, the woman will be referred for a colposcopic examination.
All women who have ever been sexually active, including lesbian and transgender women, should have regular cervical screening. This applies even if they have received the HPV vaccine, because the vaccine does not protect against all high-risk HPV viral types.
If the HPV virus detected is Type 16 or Type 18, the patient is referred directly for a colposcopic examination. This is because these viruses carry the highest risk of there being an abnormality present.
If one of the other high-risk viruses is detected, the sample is automatically subjected to examination of the cells in the liquid cytology solution, to see if any abnormal cells are present (Figure 1).
If a high-grade abnormality is found in the cells, the woman is referred for a colposcopic examination (Figure 2). If an abnormality is found at colposcopy, a biopsy is taken, and the lesion is treated as discussed under Cervical Intraepithelial Neoplasia (CIN).
If a low-grade abnormality is detected in the cells, the HPV DNA test is repeated in 12 months.
If no abnormal cells are seen in the liquid cytology sample, the woman is advised to have another HPV test in 12 months.
A woman will need to have two consecutive negative HPV tests before returning to normal 5- yearly screening.
The colposcope is an instrument that allows an examining gynaecologist to obtain a close up, well lit, binocular, magnified view of the cervix.
During colposcopy, the examiner inserts an appropriately sized speculum into the woman’s vagina to expose her cervix. The cervix is cleared of mucus and a cotton swab soaked in weak (3%) acetic acid is applied to its surface. The acetic acid causes precancerous areas to turn white (acetowhite). The examiner identifies the acetowhite areas and looks for any abnormal blood vessel patterns within the acetowhite areas. Very unusual blood vessel patterns might suggest early invasive cancer is present.
The severity of the lesion is determined by the density of the acetowhite areas, and the degree of abnormality of the blood vessel patterns. The examiner takes small pieces of tissue (biopsies) from the most abnormal looking areas, using a special instrument such as punch biopsy forceps. Sometimes a sample is also taken from the inner cervical canal, using a small curette. Examination of these biopsies allows a pathologist to make a tissue diagnosis (histopathology report).
A cone biopsy, in which a cone shaped piece of tissue is cut out of the cervix, is a diagnostic technique that usually requires general anaesthesia but not an overnight hospital stay. It is used in the following circumstances:
- If a woman’s cytopathology report describes glandular cells showing evidence of high-grade precancerous abnormalities.
- When colposcopy and biopsy identify high-grade CIN, but the abnormal area extends into the cervical canal and is outside the viewing range.
- When one or more colposcopic biopsies shows evidence of very early (microinvasive) cancer, or if the Pap test is suspicious for invasive cancer.
If the margins are free of any disease, the cone biopsy may also be used for treatment of CIN or microinvasive cancer.
A woman with invasive cervical cancer that is not discovered as a result of screening, will usually report abnormal bleeding. The most common symptom in sexually active women is bleeding after intercourse (post-coital bleeding).
This bleeding usually occurs while the cancer is quire early, and still amenable to surgical treatment. In women who are not sexually active, spontaneous bleeding between periods or after menopause is uncommon, and usually does not occur until the cancer is more advanced.
Other symptoms of cervical cancer include pain during intercourse (dyspareunia), persistent vaginal discharge, pelvic pain, lower back pain, leg swelling and urinary frequency.
The stage of a woman’s cancer describes the extent of spread. Invasive cervical cancer spreads:
- By direct invasion, initially throughout a woman’s cervix, then into her vagina and other tissues outside her cervix (parametrium). If diagnosis is delayed, the cancer may eventually spread into her bladder and/or rectum.
- Via lymphatic vessels, initially to her pelvic lymph nodes.
- Via blood vessels, particularly to her lungs, liver and bone. Blood stream spread is uncommon, and usually occurs after spread to lymph nodes.
Staging allows standardised reporting of cases between centres. Every cancer is staged, as a basis for planning treatment and determining the likely outcome of that plan. The International Federation of Obstetricians and Gynecologists (FIGO) Staging of Invasive Carcinoma of the Cervix describes stages I to IV and several substages:
- Stage I – The cancer is found only in the cervix.
- Stage II – The tumour has spread beyond the cervix and uterus to the vagina or other tissue next to the cervix (parametrium).
- Stage III – The cancer has spread right out to the sidewall of the pelvis or has blocked a ureter (the tube carrying urine from the kidney to the bladder).
- Stage IV – The cancer has spread to the bladder or rectum, or beyond the pelvis to other organs including the lungs, liver or bones.
Treatment of a woman with invasive cervical cancer and the outcome she can expect from it (prognosis) depend substantially on the stage of her cancer. The higher the stage, the worse the prognosis and the more complex and difficult is the treatment required.
Before treatment, invasive cervical cancer will continue to spread and its stage will increase with time. Low stage (Stage I) may be called “early” and higher stages (Stage II and above) may be called “advanced”. The term “locally advanced” means cancer has spread beyond the cervix but not beyond the pelvis.
Staging incorporates the findings of physical examination, colposcopic inspection and diagnostic biopsies that show evidence of invasive cancer. In addition, imaging and blood tests are used to determine the extent of spread. A computerised tomogram (CT) of chest, abdomen and pelvis is often performed to check for any obvious spread of the cancer, e.g. to the lungs or liver, or any obstruction of the kidneys. Magnetic resonance imaging (MRI) is particularly helpful to determine the extent of local spread of cancer, including any spread into the tissues outside the cervix (parametrium), or into the bladder or rectum. Positron-emission tomography (PET) is being increasingly used to detect cancer that has spread to lymph nodes or other organs.
Imaging modalities can be combined to improve their accuracy. In locally advanced cervical cancer, positron emission tomography / computed tomography (PET/CT) has become important in the initial evaluation of disease extent. It is better than other imaging modalities in determining whether cancer has spread to lymph nodes and distant organs such as liver or lungs.
Prior to treatment, a number of blood tests must be performed. These include a Full Blood Count, to check if a woman is anaemic from blood loss, kidney function tests, which may be abnormal if urine flow from the kidney into the bladder is blocked by the cancer, and liver function tests, which will be abnormal if cancer has spread to her liver.
A woman may have very early disease (FIGO stage IA1). She will have a high grade abnormality on Pap testing. On colposcopy she will have densely acetowhite areas and highly abnormal blood vessel patterns suggesting very early cancer. Her pathology report will show invasive cancer extending less than 3 mm deep, i.e. she has microinvasive carcinoma. If this very limited invasion is confirmed by a cone biopsy with clear surgical margins and there is no evidence that her cancer has invaded the blood or lymph vessels, she needs no further immediate treatment for her cancer if she desires future childbearing. She will need regular followup HPV and/or Pap tests to ensure her cancer has not regrown. Any future pregnancy will have to be carefully managed to limit her risk of cervical incompetence and associated premature delivery, and hysterectomy should be recommended when she has completed her family. If she has no wish for childbearing, she should be offered a simple hysterectomy, to remove her entire cervix and the body of her uterus. Careful follow-up will still be necessary, particularly to check for other HPV related precancers of the vagina or vulva.
If her cancer has the above features but cone biopsy shows it to be slightly more extensive (stage IA2), the recommended treatment would be to perform a wider hysterectomy (modified radical hysterectomy) and removal of the pelvic lymph nodes (pelvic lymphadenectomy).
If she desires future childbearing, she may be offered large cone biopsy and pelvic lymphadenectomy. An alternative to a large cone biopsy is a radical trachelectomy, in which the majority of her cervix is removed, together with some surrounding tissue (parametrium) and about 1 cm of upper vagina. This operation may be performed abdominally or vaginally. Pelvic lymphadenectomy is also performed, either with the laparoscope or at open surgery. A permanent purse-string suture (cerclage) would usually be placed around her remaining cervix, to help limit the risk of future premature childbirth.
If a woman has visible features of invasive cancer (Stage IB) the recommended treatment would usually be more extensive hysterectomy (radical hysterectomy and pelvic lymphadenectomy). If her cancer is less than 2cm diameter and she desires future childbearing, she may be offered radical trachelectomy with pelvic lymphadenectomy as described above. Radiation therapy combined with chemotherapy (chemoradiation) is an alternative approach that has comparable ability to successfully treat the cancer at this stage.
Radical hysterectomy involves removal of her uterus along with some of the surrounding tissues (parametrium) and the upper 1-2 cm of her vagina. The operation takes about 3 hours and is performed under general anaesthesia. It carries the risk of all major operations including bleeding, infection and blood clots in the veins. A particularly likely complication of radical hysterectomy is bladder dysfunction, in the form of inability to empty the bladder. This is caused by injury to the nerves in the pelvis that control the bladder. Bladder function usually returns to normal within 1 to 3 weeks, but about 1-2% of patients may have permanent bladder dysfunction, and will need to be taught to catheterise themselves once or twice a day.
Pelvic lymphadenectomy exposes her to a 15-20% risk of developing some degree of swelling of one or both legs, called lymphoedema. Any lymphoedema would be likely to appear about 6-12 months after her operation, but it could first appear many years later. Scratches and cuts to the legs may rapidly lead to infection and that may precipitate the onset of lymphoedema, so a woman having this operation should take sensible precautions to avoid even minor leg wounds. Long plane flights may also precipitate lymphoedema and she should wear strong support stockings when undertaking such trips. Once lymphoedema develops, it will not spontaneously get better, so will require long term management, including lower limb massage and use of a surgical stocking.
Chemoradiation, described in detail in the treatment section, avoids the risks of major surgery, a particular advantage for a woman who has other health conditions that add to this risk. Chemoradiation has its own risks, and may cause at least some damage to her:
- Ovaries, e.g. premature failure if she had not reached menopause
- Vagina, e.g. narrowing (vaginal stenosis)
- Rectum, e.g. inflammation (proctitis)
- Bladder e.g. inflammation (cystitis)
Surgery and radiotherapy treatments are not mutually exclusive. If a woman’s cervical cancer is treated surgically, all the tissue removed is carefully examined under the microscope by a pathologist. If the cancer is found to have spread to her lymph nodes, to have invaded beyond the cervix or to extensively involve her cervix or lymphatic vessels in her cervix, it is likely she will benefit from postoperative external beam radiation.
When a woman’s cancer has spread beyond the cervix, surgery alone is no longer an option, and if she has cancer up to stage IVA she is treated with chemoradiation. Her therapy would usually begin with external beam radiation and her treatment would be completed with brachytherapy – the use of radioactive implants placed either within or close to the cancer.
If a woman’s cervical cancer has spread to distant organs or bones – stage IVB – treatment is palliative. She will be offered any treatment that could reduce pain, bleeding or any other discomfort, including local radiation therapy to affected parts of her body. She is likely to be offered chemotherapy that might prolong her life but there is no chemotherapeutic approach that is curative.
Women whose cancer is picked up on a Pap test generally have early stage disease. If the cancer is microinvasive (stages IAI or IAII), the 5 year survival is 95-100%. If the disease is stage IB, the 5-year survival is 70-85%. The overall 5-year survival for cervical cancer in Australia is about 70%.
The history of cervical cancer is one of great successes for scientific research, clinical research and population medicine. Advances of knowledge in these fields and the interventions that have followed in countries like Australia have shifted a cancer epidemic into an era when the incidence of this cancer and the deaths it causes are rapidly declining. Early intervention strategies have been optimised. Cancer screening rates have been improved with the use of registries and efficiency of screening has been improved by focussing on high quality techniques at every stage.
Australia has been proudly at the forefront of these changes and its women have benefitted immeasurably from them. Australia was the first country to introduce vaccination against high risk HPV for all schoolgirls for primary prevention. We will be among the first to introduce new primary HPV DNA testing with liquid based cytology triage protocols for national screening. Both initiatives will make a dramatic difference to our future.
Even more could be achieved by focussing on known problem areas. These include resistance to HPV vaccination by well meaning but misguided people. Also worrying are relatively low rates of cervical screening in women of non-English speaking background, Aboriginal and Torres Strait Islander women and women residing in remote areas. Women in the latter categories are still having invasive cervical cancer diagnosed at relatively high rates compared with the general population.
There is also a need to develop better therapies for women with advanced and metastatic cervical cancer, and this should be addressed through ongoing laboratory and clinical research.
CIN is a precancerous condition. Its cells cannot invade into deeper layers of a woman’s cervix or enter blood or lymphatic vessels and spread to other organs. A woman with CIN has no symptoms, so it can only be suspected by her having an abnormal Pap or HPV DNA test. Definitive diagnosis is made by colposcopically directed biopsy. CIN is virtually 100% curable.
CIN represents a spectrum of disease, ranging from CIN I (mild changes usually caused by low or high-risk HPV) to CIN III (severe changes, usually caused by high-risk HPV). Most women with CIN I will be spontaneously cured, because their bodies clear the virus with their own immune system. Most women with CIN III will not spontaneously clear the lesion, and in at least 35% of these women, the CIN III will develop into invasive cancer within 10 years if left untreated.
All women with CIN II or CIN III require active treatment. If the limits of a woman’s CIN are fully visible on colposcopy, the next step is superficial ablation using large loop excision of the transformation zone (LLETZ), carbon dioxide laser or cryosurgery.
LLETZ uses a diathermy loop to cut away superficial tissue affected by CIN. It has gained popularity in recent years because the equipment is relatively inexpensive, and most women can be treated under local anaesthesia, without the need for an overnight hospital stay. Tissue is obtained for microscopic examination, and the margins of the excised tissue can be checked to see if all the CIN has been removed. Some bleeding results, but this is rarely a problem.
Laser destruction of CIN can also be performed under local anaesthesia and rarely causes bleeding. However, laser equipment is expensive. There is some evidence that laser treatments are less harmful to the cervix in terms of future child-bearing.
Cryotherapy causes destruction of the CIN by freezing. The procedure is relatively painless and can be performed without anaesthesia. There is no bleeding and the equipment is relatively inexpensive. However, when CIN affects a large area of cervix, cryotherapy often fails, so it is only useful for small lesions.
Provided that examination of tissue removed by LLETZ or cone biopsy shows that all CIN II or CIN III has been excised, i.e. the margins of resection are clear, the likelihood of cure is as high as would be achieved by hysterectomy. LLETZ rarely has any adverse effect on subsequent pregnancy outcome.
After a cone biopsy, most women are advised to wait six months before attempting to become pregnant to allow the tissue to heal and to have a post-treatment check. Subsequent pregnancies must be closely monitored because of the increased risk of cervical incompetence and premature birth. Rarely, cone biopsy can cause complications such as cervical canal narrowing (cervical stenosis) that require other treatments to facilitate conception and childbirth.