Cervical cancer is the term for a malignant neoplasm arising from cells originating in the cervix uteri. One of the most common symptoms of cervical cancer is abnormal vaginal bleeding, but in some cases there may be no obvious symptoms until the cancer has progressed to an advanced stage.Treatment usually consists of surgery (including local excision) in early stages, and chemotherapy and/or radiotherapy in more advanced stages of the disease.The cervix is the narrow portion of the uterus where it joins with the top of the vagina. Most cervical cancers are squamous cell carcinomas, arising in the squamous (flattened) epithelial cells that line the cervix. Adenocarcinoma, arising in glandular epithelial cells is the second most common type. Very rarely, cancer can arise in other types of cells in the cervix.
Signs and symptoms
The early stages of cervical cancer may be completely asymptomatic. Vaginal bleeding, contact bleeding, or (rarely) a vaginal mass may indicate the presence of malignancy. Also, moderate pain during sexual intercourse and vaginal discharge are symptoms of cervical cancer. In advanced disease, metastases may be present in the abdomen, lungs or elsewhere.Symptoms of advanced cervical cancer may include: loss of appetite, weight loss, fatigue, pelvic pain, back pain, leg pain, swollen legs, heavy bleeding from the vagina, bone fractures, and/or (rarely) leakage of urine or faeces from the vagina (rarely).
Causes
Infection with some types of human papilloma virus (HPV) is the greatest risk factor for cervical cancer, followed by smoking.Other risk factors include human immunodeficiency virus.Not all of the causes of cervical cancer are known, however, and several other contributing factors have been implicated.Human papillomavirus
Human papillomavirus is the cause of 70% of cervical cancer globally.Women who have many sexual partners (or who have sex with men who have had many other partners) have a greater risk.
Of the 150-200 types of HPV known, 15 are classified as high-risk types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, and 82), 3 as probable high-risk (26, 53, and 66), and 12 as low-risk (6, 11, 40, 42, 43, 44, 54, 61, 70, 72, 81, and CP6108). Types 16 and 18 are generally acknowledged to cause about 70% of cervical cancer cases. Together with type 31, they are the prime risk factors for cervical cancer.
Genital warts, which are a form of benign tumor of epithelial cells, are also caused by various strains of HPV. However, these serotypes are usually not related to cervical cancer. It is common to have multiple strains at the same time, including those that can cause cervical cancer along with those that cause warts. The medically accepted paradigm, officially endorsed by the American Cancer Society and other organizations, is that a patient must have been infected with HPV to develop cervical cancer, and is hence viewed as a sexually transmitted disease (although many dispute that, technically, it is the causative agent, not the cancer, that is a sexually transmitted disease), but most women infected with high risk HPV will not develop cervical cancer.Use of condoms reduces, but does not always prevent transmission. Likewise, HPV can be transmitted by skin-to-skin-contact with infected areas. In males, there is no commercially available test for HPV, although HPV is thought to grow preferentially in the epithelium of the glans penis, and cleaning of this area may be preventative.
Diagnosis
Biopsy
While the pap smear is an effective screening test, confirmation of the diagnosis of cervical cancer or pre-cancer requires a biopsy of the cervix. This is often done through colposcopy, a magnified visual inspection of the cervix aided by using a dilute acetic acid (e.g. vinegar) solution to highlight abnormal cells on the surface of the cervix.Medical devices used for biopsy of the cervix include punch forceps or SpiraBrush CX.Colposcopic impression, the estimate of disease severity based on the visual inspection, forms part of the diagnosis.
Further diagnostic and treatment procedures are loop electrical excision procedure (LEEP) and conization, in which the inner lining of the cervix is removed to be examined pathologically. These are carried out if the biopsy confirms severe cervical intraepithelial neoplasia.
Precancerous lesions
Cervical intraepithelial neoplasia, the potential precursor to cervical cancer, is often diagnosed on examination of cervical biopsies by a pathologist. For premalignant dysplastic changes, the CIN (cervical intraepithelial neoplasia) grading is used.The naming and histologic classification of cervical carcinoma percursor lesions has changed many times over the 20th century. The World Health Organization classification 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. It classifies mild dysplasia as CIN1, moderate dysplasia as CIN2, and severe dysplasia and CIS as CIN3. More recently, CIN2 and CIN3 have been combined into CIN2/3. These results are what a pathologist might report from a biopsy.
These should not be confused with the Bethesda System terms for Pap smear (cytopathology) results. Among the Bethesda results: Low-grade Squamous Intraepithelial Lesion (LSIL) and High-grade Squamous Intraepithelial Lesion (HSIL). An LSIL Pap may correspond to CIN1, and HSIL may correspond to CIN2 and CIN3,however they are results of different tests, and the Pap smear results need not match the histologic findings.
Cancer subtypes
Histologic subtypes of invasive cervical carcinoma include the following: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.- squamous cell carcinoma (about 80-85%)
- adenocarcinoma (about 15% of cervical cancers in the UK)
- adenosquamous carcinoma
- small cell carcinoma
- neuroendocrine tumour
- glassy cell carcinoma
- villoglandular adenocarcinoma
- Non-carcinoma malignancies which can rarely occur in the cervix include
- melanoma
- lymphoma
Staging
Cervical cancer is staged by the International Federation of Gynecology and Obstetrics (FIGO) staging system, which is based on clinical examination, rather than surgical findings. It allows only the following diagnostic tests to be used in determining the stage: palpation, inspection, colposcopy, endocervical curettage, hysteroscopy, cystoscopy, proctoscopy, intravenous urography, and X-ray examination of the lungs and skeleton, and cervical conization.Prevention
Screening
The widespread introduction of cervical screening by the Papanicolaou test, or Pap smear for cervical cancer has been credited with dramatically reducing the incidence and mortality of cervical cancer in developed countries.Pap smear screening every 3–5 years with appropriate follow-up can reduce cervical cancer incidence by up to 80%.Abnormal results may suggest the presence of pre cancerous changes allowing examination and possible preventive treatment. If precancerous disease or cervical cancer is detected early, it can be monitored or treated relatively noninvasively, with little impairment of fertility.Cervical cancer screening is typically recommended starting at age 21. Recommendations for how often a Pap smear should be done vary from once a year to once every five years, in the absence of abnormal results. Guidelines vary on how long to continue screening, but well screened women who have not had abnormal smears can stop screening about age 60 to 70.
Liquid-based cytology is another potential screening method. 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%. 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.
Vaccination
There are two HPV vaccines (Gardasil and Cervarix) which reduce the risk of cancerous or precancerous changes of the cervix and perineum by about 93%.HPV vaccines are typically given to women age 9 to 26 as the vaccine is only effective if given before infection occurs. The vaccines have been shown to be effective for at least 4 to 6years, and it is believed they will be effective for longer; however, the duration of effectiveness and whether a booster will be needed is unknown. The high cost of this vaccine has been a cause for concern. Several countries have considered (or are considering) programs to fund HPV vaccination.
Condoms
Condoms are thought to offer some protection against cervical cancer. Evidence on whether condoms protect against HPV infection is mixed, but they may protect against genital warts and the precursors to cervical cancer.They also provide protection against other STDs, such as HIV and Chlamydia, which are associated with greater risks of developing cervical cancer.Condoms may also be useful in treating potentially precancerous changes in the cervix. Exposure to semen appears to increase the risk of precancerous changes (CIN 3), and use of condoms helps to cause these changes to regress and helps clear HPV. One study suggests that prostaglandin in semen may fuel the growth of cervical and uterine tumours and that affected women may benefit from the use of condoms.
Treatment
The treatment of cervical cancer varies worldwide, largely due to large variances in disease burden in developed and developing nations, access to surgeons skilled in radical pelvic surgery, and the emergence of "fertility sparing therapy" in developed nations. Because cervical cancers are radiosensitive, radiation may be used in all stages where surgical options do not exist.Microinvasive cancer (stage IA) may be treated by hysterectomy (removal of the whole uterus including part of the vagina). For stage IA2, the lymph nodes are removed as well. Alternatives include local surgical procedures such as a loop electrical excision procedure (LEEP) or cone biopsy. For 1A1 disease, a cone biopsy (aka cervical conization) is considered curative.
If a cone biopsy does not produce clear margins,one more possible treatment option for patients who want to preserve their fertility is a trachelectomy. 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,as few doctors are skilled in this procedure. Even the most experienced surgeon cannot promise that a trachelectomy can be performed until after surgical microscopic examination, as the extent of the spread of cancer is unknown. If the surgeon is not able to microscopically confirm clear margins of cervical tissue once the patient is under general anesthesia in the operating room, a hysterectomy may still be needed. This can only be done during the same operation if the patient has given prior consent. Due to the possible risk of cancer spread to the lymph nodes in stage 1b cancers and some stage 1a cancers, the surgeon may also need to remove some lymph nodes from around the uterus for pathologic evaluation.
A radical trachelectomy can be performed abdominally or vaginall] and there are conflicting opinions as to which is better. A radical abdominal trachelectomy with lymphadenectomy usually only requires a two to three day hospital stay, and most women recover very quickly (approximately six weeks). Complications are uncommon, although women who are able to conceive after surgery are susceptible to preterm labor and possible late miscarriage.It is generally recommended to wait at least one year before attempting to become pregnant after surgery. Recurrence in the residual cervix is very rare if the cancer has been cleared with the trachelectomy. Yet, it is recommended for patients to practice vigilant prevention and follow up care including pap screenings/colposcopy, with biopsies of the remaining lower uterine segment as needed (every 3–4 months for at least 5 years) to monitor for any recurrence in addition to minimizing any new exposures to HPV through safe sex practices until one is actively trying to conceive.
Early stages (IB1 and IIA less than 4 cm) can be treated with radical hysterectomy with removal of the lymph nodes or radiation therapy. Radiation therapy is given as external beam radiotherapy to the pelvis and brachytherapy (internal radiation). Patients treated with surgery who have high risk features found on pathologic examination are given radiation therapy with or without chemotherapy in order to reduce the risk of relapse.Larger early stage tumors (IB2 and IIA more than 4 cm) may be treated with radiation therapy and cisplatin-based chemotherapy, hysterectomy (which then usually requires adjuvant radiation therapy), or cisplatin chemotherapy followed by hysterectomy.
Advanced stage tumors (IIB-IVA) are treated with radiation therapy and cisplatin-based chemotherapy.On June 15, 2006, the US Food and Drug Administration approved the use of a combination of two chemotherapy drugs, hycamtin and cisplatin for women with late-stage (IVB) cervical cancer treatment.Combination treatment has significant risk of neutropenia, anemia, and thrombocytopenia side effects. Hycamtin is manufactured by GlaxoSmithKline.
Prognosis
Prognosis depends on the stage of the cancer. With treatment, the 5-year relative survival rate for the earliest stage of invasive cervical cancer is 92%, and the overall (all stages combined) 5-year survival rate is about 72%. These statistics may be improved when applied to women newly diagnosed, bearing in mind that these outcomes may be partly based on the state of treatment five years ago when the women studied were first diagnosed.
With treatment, 80 to 90% of women with stage I cancer and 50 to 65% of those with stage II cancer are alive 5 years after diagnosis. Only 25 to 35% of women with stage III cancer and 15% or fewer of those with stage IV cancer are alive after 5 years.According to the International Federation of Gynecology and Obstetrics, survival improves when radiotherapy is combined with cisplatin-based chemotherapy.
As the cancer metastasizes to other parts of the body, prognosis drops dramatically because treatment of local lesions is generally more effective than whole body treatments such as chemotherapy.
Interval evaluation of the patient after therapy is imperative. Recurrent cervical cancer detected at its earliest stages might be successfully treated with surgery, radiation, chemotherapy, or a combination of the three. Thirty-five percent of patients with invasive cervical cancer have persistent or recurrent disease after treatment.Average years of potential life lost from cervical cancer are 25.3 (SEER Cancer Statistics Review 1975-2000, National Cancer Institute (NCI)). Approximately 4,600 women were projected to die in 2001 in the US of cervical cancer (DSTD), and the annual incidence was 13,000 in 2002 in the US, as calculated by SEER. Thus the ratio of deaths to incidence is approximately 35.4%.
Regular screening has meant that pre cancerous changes and early stage cervical cancers have been detected and treated early. Figures suggest that cervical screening is saving 5,000 lives each year in the UK by preventing cervical cancer.About 1,000 women per year die of cervical cancer in the UK.
History
- 400 BCE - Hippocrates: cervical cancer incurable
- 1925 - Hinselmann: invented colposcope
- 1928 - Papanicolaou: developed Papanicolaou technique
- 1941 - Papanicolaou and Trout: Pap smear screening
- 1946 - Ayer: Aylesbury spatula to scrape the cervix, collecting sample for Pap smear
- 1951 - First successful in-vitro cell line, HeLa, derived from biopsy of cervical cancer of Henrietta Lacks
- 1976 - Zur Hausen and Gisam: found HPV DNA in cervical cancer and warts
- 1988 - Bethesda System for reporting Pap results developed
- 2006 - First HPV vaccine FDA approved
- Epidemiologists working in the early 20th century noted that cervical cancer behaved like a sexually transmitted disease. In summary:
- Cervical cancer was common in female sex workers.
- It was rare in nuns, except for those who had been sexually active before entering the convent. (Rigoni in 1841)
- It was more common in the second wives of men whose first wives had died from cervical cancer.
- It was rare in Jewish women.
- In 1935, Syverton and Berry discovered a relationship between RPV (Rabbit Papillomavirus) and skin cancer in rabbits. (HPV is species-specific and therefore cannot be transmitted to rabbits)
This led to the suspicion that cervical cancer could be caused by a sexually transmitted agent. Initial research in the 1940s and 1950s put the blame on smegma (e.g. Heins et al. 1958). 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. Herpes viruses were also implicated in other malignant diseases, including Burkitt's lymphoma, Nasopharyngeal carcinoma, Marek's disease and the Lucké renal adenocarcinoma. HSV was recovered from cervical tumour cells.A description of human papillomavirus (HPV) by electron microscopy was given in 1949, and HPV-DNA was identified in 1963. It was not until the 1980s that HPV was identified in cervical cancer tissue. It has since been demonstrated that HPV is implicated in virtually all cervical cancers.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. 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.
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