Cervical cancer
Encyclopedia
Cervical cancer is malignant
neoplasm of the cervix uteri or cervical area. One of the most common symptoms is abnormal vaginal bleeding
, but in some cases there may be no obvious symptoms until the cancer is in its advanced stages. Treatment consists of surgery
(including local excision) in early stages and chemotherapy
and radiotherapy in advanced stages of the disease.
Pap smear
screening can identify potentially precancerous changes. Treatment of high grade changes can prevent the development of cancer. In developed countries, the widespread use of cervical screening programs has reduced the incidence of invasive cervical cancer by 50% or more.
Human papillomavirus
(HPV) infection is a necessary factor in the development of almost all cases of cervical cancer. HPV vaccine
s effective against the two strains of HPV that currently cause approximately 70% of cervical cancer have been licensed in the U.S, Canada, Australia and the EU. Since the vaccines only cover some of the cancer causing ("high-risk") types of HPV, women should seek regular Pap smear screening, even after vaccination.
The cervix is the narrow portion of the uterus where it joins with the top of the vagina. Most cervical cancers are squamous cell carcinoma
s, 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.
. 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
, lung
s or elsewhere.
Symptoms of advanced cervical cancer may include: loss of appetite, weight loss, fatigue, pelvic pain, back pain, leg pain, single swollen leg, heavy bleeding from the vagina, leaking of urine or faeces from the vagina, and bone fractures.
HPV DNA may be detected in virtually all cases of cervical cancer. Not all of the causes of cervical cancer are known. Several other contributing factors have been implicated.
. The virus cancer link works by triggering alterations in the cells of the cervix, which can lead to the development of cervical intraepithelial neoplasia
, which can lead to cancer.
Women who have many sexual partners (or who have sex with men who had many other partners) have a greater risk.
More than 150 types of HPV are acknowledged to exist (some sources indicate more than 200 subtypes). Of these, 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 factor
s for cervical cancer.
Genital warts are caused by various strains of HPV which are usually not related to cervical cancer. However, it is possible 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 condom
s 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.
provides the following list of risk factors for cervical cancer: human papillomavirus
(HPV) infection, smoking
, HIV
infection, chlamydia infection, stress and stress-related disorders, dietary factors, hormonal contraception
, multiple pregnancies
, exposure to the hormonal drug diethylstilbestrol
, and family history
of cervical cancer. Early age at first intercourse and first pregnancy are also considered risk factors, magnified by early use of oral contraceptives. There is a possible genetic risk associated with HLA-B7
.
There has not been any definitive evidence to support the claim that circumcision of the male partner reduces the risk of cervical cancer, although some researchers say there is compelling epidemiological evidence that men who have been circumcised are less likely to be infected with HPV. However, in men with low-risk sexual behaviour and monogamous female partners, circumcision makes no difference to the risk of cervical cancer.
, 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
.
, 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.
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.
Non-carcinoma malignancies which can rarely occur in the cervix include
Note that the FIGO stage does not incorporate lymph node
involvement in contrast to the TNM staging for most other cancers.
For cases treated surgically, information obtained from the pathologist can be used in assigning a separate pathologic stage but is not to replace the original clinical stage.
(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.
be disregarded)
invasion <5 mm and the largest extension >7 mm
not >7.0 mm
greater than stage IA
Stage 1-A1 young women - conization wis clear margin. Parous women - hysterectomy.
Stage 1-A2 laproscopic lymphadenectomy + vaginal trechelectomy + post operative radiotherapy.
Stage 1B & 2A 1. Wertheim's hysterectomy . 2- schauta vaginal hysterectomy + laparoscopic lymphadenectomy 3: primary radiotherapy 4: combined surgery & radiotherapy.
Stage 2B, 3, 4 - chemotherapy
, is a vaccine against HPV types 6, 11, 16 & 18 which is up to 98% effective.
Cervarix
has been shown to be 92% effective in preventing HPV strains 16 and 18 and is effective for more than four years.
Together, HPV types 16 and 18 currently cause about 70% of cervical cancer cases. HPV types 6 and 11 cause about 90% of genital wart cases. HPV vaccines have also been shown to prevent precursors to some other cancers associated with HPV.
HPV vaccines are targeted at girls and women of age 9 to 26 because the vaccine only works if given before infection occurs; therefore, public health workers are targeting girls before they begin having sex. The vaccines have been shown to be effective for at least 4 to 6 years, 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 use of the vaccine in men to prevent genital warts, anal cancer
, and interrupt transmission to women or other men is initially considered only a secondary market.
The high cost of this vaccine has been a cause for concern. Several countries have or are considering programs to fund HPV vaccination.
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 condom
s.
s from tobacco
increase the risk for many cancer types, including cervical cancer, and women who smoke have about double the chance of a nonsmoker to develop cervical cancer.
Higher levels of vegetable consumption were associated with a 54% decrease risk of HPV persistence.
Vitamin A
There is weak evidence to suggest a significant deficiency of retinol
can increase chances of cervical dysplasia, independently of HPV infection.
A small (n~=500) case-control study of a narrow ethnic group (native Americans in New Mexico) assessed serum micro-nutrients as risk factors for cervical dysplasia. Subjects in the lowest serum retinol
quartile were at increased risk of CIN
I compared with women in the highest quartile.
However, the study population had low overall serum retinol, suggesting deficiency. A study of serum retinol in a well-nourished population reveals that the bottom 20% had serum retinol close to that of the highest levels in this New Mexico sub-population.
Vitamin C
Risk of type-specific, persistent HPV infection was lower among women reporting intake values of vitamin C
in the upper quartile compared with those reporting intake in the lowest quartile.
Vitamin E
HPV clearance time was significantly shorter among women with the highest compared with the lowest serum levels of tocopherol
s, but significant trends in these associations were limited to infections lasting 120 days) was not significantly associated with circulating levels of tocopherols. Results from this investigation support an association of micronutrients with the rapid clearance of incident oncogenic HPV infection of the uterine cervix.
A statistically significantly lower level of alpha-tocopherol
was observed in the blood serum of HPV-positive patients with cervical intraepithelial neoplasia. The risk of dysplasia was four times higher for an alpha-tocopherol level < 7.95 mumol/l.
Folic acid
Higher folate status was inversely associated with becoming HPV test-positive. Women with higher folate status were significantly less likely to be repeatedly HPV test-positive and more likely to become test-negative. Studies have shown that lower levels of antioxidants coexisting with low levels of folic acid increases the risk of CIN development. Improving folate status in subjects at risk of getting infected or already infected with high-risk HPV may have a beneficial impact in the prevention of cervical cancer.
However, another study showed no relationship between folate status and cervical dysplasia.
Carotenoids
The likelihood of clearing an oncogenic HPV infection is significantly higher with increasing levels of lycopene
s. A 56% reduction in HPV persistence risk was observed in women with the highest plasma [lycopene] concentrations compared with women with the lowest plasma lycopene concentrations. These data suggests that vegetable consumption and circulating lycopene may be protective against HPV persistence.
(potentially premalignant changes in the cervix) before a cancer has developed, allowing examination and possible preventive treatment. If premalignant disease or cervical cancer is detected early, it can be monitored or treated relatively noninvasively, with little impairment of fertility.
Cervical cancer screening is typically recommended starting three years or more after first sex, or starting at age 21 to 25. 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.
To take a Pap smear, the vagina is held open with a speculum
, the loose surface cells on the cervix are scraped using a specially shaped spatula and a brush, and the cells are spread on a microscope slide. At a laboratory the slide is stained, examined for abnormal cells and findings are reported
.
Until recently the Pap smear has remained the principal technology for preventing cervical cancer. However, following a rapid review of the published literature, originally commissioned by NICE, liquid based cytology has been incorporated within the UK national screening programme. 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.
Automated technologies have been developed with the aim of improving on the interpretation of smears, normally carried out by cytotechnologists. Unfortunately these on the whole have proven less useful; although the more recent reviews suggest that generally they may be no worse than human interpretation.
The HPV test is a newer technique for cervical cancer triage which detects the presence of human papillomavirus
infection in the cervix. It is more sensitive than the pap smear (less likely to produce false negative results), but less specific (more likely to produce false positive results) and its role in routine screening is still evolving. Since more than 99% of invasive cervical cancers worldwide contain HPV, some researchers recommend that HPV testing be done together with routine cervical screening. But, given the prevalence of HPV (around 80% infection history among the sexually active population) others suggest that routine HPV testing would cause undue alarm to carriers, more unnecessary follow-up testing and treatment. HPV testing along with cytology significantly increases the cost of screening.
VIA/cryo, for visualization of the cervix with acetic acid (vinegar) and treatment with cryotherapy, sometimes with special lights (speculoscopy
), or taking pictures for expert evaluation (cervicography
) have been evaluated as adjuncts to or replacements for Pap smear screening, especially in countries where Pap smear screening is prohibatively expensive. There are efforts to develop low cost HPV tests which might be used for primary screening of older women in less developed countries.
(removal of the whole uterus including part of the vagina
). For stage IA2, the lymph node
s are removed as well. An alternative for patients who desire to remain fertile is a local surgical procedure such as a loop electrical excision procedure
(LEEP) or cone biopsy
.
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 vaginally 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.
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.
In the United States
, it is only the 8th most common cancer of women. In 1998, about 12,800 women were diagnosed in the US and about 4,800 died. In 2008 in the US an estimated 11,000 new cases were expected to be diagnosed, and about 3,870 were expected to die of cervical cancer. Among gynecological cancers it ranks behind endometrial cancer
and ovarian cancer
. The incidence and mortality in the US are about half those for the rest of the world, which is due in part to the success of screening with the Pap smear
. The incidence of new cases of cervical cancer in the United States was 7 per 100,000 women in 2004. Cervical cancer deaths decreased by approximately 74% in the last 50 years, largely due to widespread Pap smear screening. The annual direct medical cost of cervical cancer prevention and treatment is prior to introduction of the HPV vaccine was estimated at $6 billion.
In the European Union, there were about 34,000 new cases per year and over 16,000 deaths due to cervical cancer in 2004.
In the United Kingdom, the age-standardised (European) incidence is 8.5/100,000 per year (2006). It is the twelfth most common cancer in women, accounting for 2% of all female cancers, and is the second most common cancer in the under 35s females, after breast cancer.
The UK's European age-standardised mortality is 2.4/100,000 per year (2007) (Cancer Research UK Cervical cancer statistics for the UK). With a 42% reduction from 1988-1997 the NHS implemented screening programme has been highly successful, screening the highest risk age group (25–49 years) every 3 years, and those ages 50–64 every 5 years.
In Canada, an estimated 1,300 women will be diagnosed with cervical cancer in 2008 and 380 will die.
In Australia, there were 734 cases of cervical cancer (2005). The number of women diagnosed with cervical cancer has dropped on average by 4.5% each year since organised screening began in 1991 (1991–2005).
Regular two-yearly Pap tests can reduce the incidence of cervical cancer by up to 90% in Australia, and save 1,200 Australian women dying from the disease each year.
Epidemiologists
working in the early 20th century noted that cervical cancer behaved like a sexually transmitted disease. In summary:
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.
Malignant
Malignancy is the tendency of a medical condition, especially tumors, to become progressively worse and to potentially result in death. Malignancy in cancers is characterized by anaplasia, invasiveness, and metastasis...
neoplasm of the cervix uteri or cervical area. One of the most common symptoms is abnormal vaginal bleeding
Vaginal bleeding
Vaginal bleeding refers to bleeding in females that is either a physiologic response during the non-conceptional menstrual cycle or caused by hormonal or organic problems of the reproductive system. Vaginal bleeding may occur at any age, but always needs investigation when encountered in female...
, but in some cases there may be no obvious symptoms until the cancer is in its advanced stages. Treatment consists of surgery
Surgery
Surgery is an ancient medical specialty that uses operative manual and instrumental techniques on a patient to investigate and/or treat a pathological condition such as disease or injury, or to help improve bodily function or appearance.An act of performing surgery may be called a surgical...
(including local excision) in early stages and chemotherapy
Chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
and radiotherapy in advanced stages of the disease.
Pap smear
Pap smear
The Papanicolaou test is a screening test used in to detect pre-cancerous and cancerous processes in the endocervical canal of the female reproductive system. Changes can be treated, thus preventing cervical cancer...
screening can identify potentially precancerous changes. Treatment of high grade changes can prevent the development of cancer. In developed countries, the widespread use of cervical screening programs has reduced the incidence of invasive cervical cancer by 50% or more.
Human papillomavirus
Human papillomavirus
Human papillomavirus is a member of the papillomavirus family of viruses that is capable of infecting humans. Like all papillomaviruses, HPVs establish productive infections only in keratinocytes of the skin or mucous membranes...
(HPV) infection is a necessary factor in the development of almost all cases of cervical cancer. HPV vaccine
HPV vaccine
The human papilloma virus vaccine prevents infection with certain species of human papillomavirus associated with the development of cervical cancer, genital warts, and some less common cancers...
s effective against the two strains of HPV that currently cause approximately 70% of cervical cancer have been licensed in the U.S, Canada, Australia and the EU. Since the vaccines only cover some of the cancer causing ("high-risk") types of HPV, women should seek regular Pap smear screening, even after vaccination.
Squamous cell carcinoma
Squamous cell carcinoma , occasionally rendered as "squamous-cell carcinoma", is a histologically distinct form of cancer. It arises from the uncontrolled multiplication of malignant cells deriving from epithelium, or showing particular cytological or tissue architectural characteristics of...
s, arising in the squamous (flattened) epithelial cells
Squamous epithelium
In anatomy, squamous epithelium is an epithelium characterised by its most superficial layer consisting of flat, scale-like cells called squamous epithelial cells...
that line the cervix. Adenocarcinoma
Adenocarcinoma
Adenocarcinoma is a cancer of an epithelium that originates in glandular tissue. Epithelial tissue includes, but is not limited to, the surface layer of skin, glands and a variety of other tissue that lines the cavities and organs of the body. Epithelium can be derived embryologically from...
, 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 asymptomaticAsymptomatic
In medicine, a disease is considered asymptomatic if a patient is a carrier for a disease or infection but experiences no symptoms. A condition might be asymptomatic if it fails to show the noticeable symptoms with which it is usually associated. Asymptomatic infections are also called subclinical...
. Vaginal bleeding
Vaginal bleeding
Vaginal bleeding refers to bleeding in females that is either a physiologic response during the non-conceptional menstrual cycle or caused by hormonal or organic problems of the reproductive system. Vaginal bleeding may occur at any age, but always needs investigation when encountered in female...
, 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
Metastasis
Metastasis, or metastatic disease , is the spread of a disease from one organ or part to another non-adjacent organ or part. It was previously thought that only malignant tumor cells and infections have the capacity to metastasize; however, this is being reconsidered due to new research...
may be present in the abdomen
Abdomen
In vertebrates such as mammals the abdomen constitutes the part of the body between the thorax and pelvis. The region enclosed by the abdomen is termed the abdominal cavity...
, lung
Human lung
The human lungs are the organs of respiration in humans. Humans have two lungs, with the left being divided into two lobes and the right into three lobes. Together, the lungs contain approximately of airways and 300 to 500 million alveoli, having a total surface area of about in...
s or elsewhere.
Symptoms of advanced cervical cancer may include: loss of appetite, weight loss, fatigue, pelvic pain, back pain, leg pain, single swollen leg, heavy bleeding from the vagina, leaking of urine or faeces from the vagina, and bone fractures.
Causes
Human papillomavirus (HPV) infection with high-risk types has been shown to be a necessary factor in the development of cervical cancer.HPV DNA may be detected in virtually all cases of cervical cancer. Not all of the causes of cervical cancer are known. Several other contributing factors have been implicated.
Human papillomavirus infection
In the United States each year there are more than 6.2 million new HPV infections in both men and women, according to the CDC, of which 10 percent will go on to develop persistent dysplasia or cervical cancer. That is why HPV is known as the "common cold" of the sexually transmitted infection world. It is very common and affects roughly 80 percent of all sexually active people, whether they have symptoms or not. The most important risk factor in the development of cervical cancer is infection with a high-risk strain of human papillomavirusHuman papillomavirus
Human papillomavirus is a member of the papillomavirus family of viruses that is capable of infecting humans. Like all papillomaviruses, HPVs establish productive infections only in keratinocytes of the skin or mucous membranes...
. The virus cancer link works by triggering alterations in the cells of the cervix, which can lead to the development of cervical intraepithelial neoplasia
Cervical intraepithelial neoplasia
Cervical intraepithelial neoplasia , also known as cervical dysplasia and cervical interstitial neoplasia, is the potentially premalignant transformation and abnormal growth of squamous cells on the surface of the cervix. CIN is not cancer, and is usually curable...
, which can lead to cancer.
Women who have many sexual partners (or who have sex with men who had many other partners) have a greater risk.
More than 150 types of HPV are acknowledged to exist (some sources indicate more than 200 subtypes). Of these, 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 factor
Risk factor
In epidemiology, a risk factor is a variable associated with an increased risk of disease or infection. Sometimes, determinant is also used, being a variable associated with either increased or decreased risk.-Correlation vs causation:...
s for cervical cancer.
Genital warts are caused by various strains of HPV which are usually not related to cervical cancer. However, it is possible 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
Sexually transmitted disease
Sexually transmitted disease , also known as a sexually transmitted infection or venereal disease , is an illness that has a significant probability of transmission between humans by means of human sexual behavior, including vaginal intercourse, oral sex, and anal sex...
(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 condom
Condom
A condom is a barrier device most commonly used during sexual intercourse to reduce the probability of pregnancy and spreading sexually transmitted diseases . It is put on a man's erect penis and physically blocks ejaculated semen from entering the body of a sexual partner...
s 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
Epithelium
Epithelium is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. Epithelial tissues line the cavities and surfaces of structures throughout the body, and also form many glands. Functions of epithelial cells include secretion, selective...
of the glans penis
Glans penis
The glans penis is the sensitive bulbous structure at the distal end of the penis. The glans penis is anatomically homologous to the clitoral glans of the female...
, and cleaning of this area may be preventative.
Cofactors
The American Cancer SocietyAmerican Cancer Society
The American Cancer Society is the "nationwide community-based voluntary health organization" dedicated, in their own words, "to eliminating cancer as a major health problem by preventing cancer, saving lives, and diminishing suffering from cancer, through research, education, advocacy, and...
provides the following list of risk factors for cervical cancer: human papillomavirus
Human papillomavirus
Human papillomavirus is a member of the papillomavirus family of viruses that is capable of infecting humans. Like all papillomaviruses, HPVs establish productive infections only in keratinocytes of the skin or mucous membranes...
(HPV) infection, smoking
Tobacco smoking
Tobacco smoking is the practice where tobacco is burned and the resulting smoke is inhaled. The practice may have begun as early as 5000–3000 BCE. Tobacco was introduced to Eurasia in the late 16th century where it followed common trade routes...
, HIV
HIV
Human immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...
infection, chlamydia infection, stress and stress-related disorders, dietary factors, hormonal contraception
Hormonal contraception
Hormonal contraception refers to birth control methods that act on the endocrine system. Almost all methods are composed of steroid hormones, although in India one selective estrogen receptor modulator is marketed as a contraceptive. The original hormonal method—the combined oral contraceptive...
, multiple pregnancies
Pregnancy
Pregnancy refers to the fertilization and development of one or more offspring, known as a fetus or embryo, in a woman's uterus. In a pregnancy, there can be multiple gestations, as in the case of twins or triplets...
, exposure to the hormonal drug diethylstilbestrol
Diethylstilbestrol
Diethylstilbestrol is a synthetic nonsteroidal estrogen that was first synthesized in 1938. Human exposure to DES occurred through diverse sources, such as dietary ingestion from supplemented cattle feed and medical treatment for certain conditions, including breast and prostate cancers...
, and family history
Family history
Family history is the systematic narrative and research of past events relating to a specific family, or specific families.- Introduction :...
of cervical cancer. Early age at first intercourse and first pregnancy are also considered risk factors, magnified by early use of oral contraceptives. There is a possible genetic risk associated with HLA-B7
HLA-B7
HLA-B7 is an HLA-B serotype. The serotype identifies the more common HLA-B*07 gene products. B7, previously HL-A7, was one of the first 'HL-A' antigens recognized, largely because of the frequency of B*0702 in Northern and Western Europe and the United States...
.
There has not been any definitive evidence to support the claim that circumcision of the male partner reduces the risk of cervical cancer, although some researchers say there is compelling epidemiological evidence that men who have been circumcised are less likely to be infected with HPV. However, in men with low-risk sexual behaviour and monogamous female partners, circumcision makes no difference to the risk of cervical cancer.
Biopsy procedures
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 colposcopyColposcopy
Colposcopy 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 which can be detected through the examination...
, a magnified visual inspection of the cervix aided by using a dilute acetic acid
Acetic acid
Acetic acid is an organic compound with the chemical formula CH3CO2H . It is a colourless liquid that when undiluted is also called glacial acetic acid. Acetic acid is the main component of vinegar , and has a distinctive sour taste and pungent smell...
(e.g. vinegar
Vinegar
Vinegar is a liquid substance consisting mainly of acetic acid and water, the acetic acid being produced through the fermentation of ethanol by acetic acid bacteria. Commercial vinegar is produced either by fast or slow fermentation processes. Slow methods generally are used with traditional...
) 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
Loop electrical excision procedure
The loop electrosurgical excision procedure is currently one of the most commonly used approaches to treat high grade cervical dysplasia discovered on colposcopic examination. In UK it is known as "large loop excision of the transformation zone" . The procedure has many advantages including low...
(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
Cervical intraepithelial neoplasia
Cervical intraepithelial neoplasia , also known as cervical dysplasia and cervical interstitial neoplasia, is the potentially premalignant transformation and abnormal growth of squamous cells on the surface of the cervix. CIN is not cancer, and is usually curable...
.
Precancerous lesions
Cervical intraepithelial neoplasiaCervical intraepithelial neoplasia
Cervical intraepithelial neoplasia , also known as cervical dysplasia and cervical interstitial neoplasia, is the potentially premalignant transformation and abnormal growth of squamous cells on the surface of the cervix. CIN is not cancer, and is usually curable...
, the potential precursor to cervical cancer, is often diagnosed on examination of cervical biopsies by a pathologist
Pathology
Pathology is the precise study and diagnosis of disease. The word pathology is from Ancient Greek , pathos, "feeling, suffering"; and , -logia, "the study of". Pathologization, to pathologize, refers to the process of defining a condition or behavior as pathological, e.g. pathological gambling....
. For premalignant dysplastic changes, the CIN (cervical intraepithelial neoplasia
Cervical intraepithelial neoplasia
Cervical intraepithelial neoplasia , also known as cervical dysplasia and cervical interstitial neoplasia, is the potentially premalignant transformation and abnormal growth of squamous cells on the surface of the cervix. CIN is not cancer, and is usually curable...
) grading is used.
The naming and histologic
Histology
Histology is the study of the microscopic anatomy of cells and tissues of plants and animals. It is performed by examining cells and tissues commonly by sectioning and staining; followed by examination under a light microscope or electron microscope...
classification of cervical carcinoma percursor lesions has changed many times over the 20th century. The World Health Organization
World Health Organization
The World Health Organization is a specialized agency of the United Nations that acts as a coordinating authority on international public health. Established on 7 April 1948, with headquarters in Geneva, Switzerland, the agency inherited the mandate and resources of its predecessor, the Health...
classification system was descriptive of the lesions, naming them mild, moderate or severe dysplasia
Dysplasia
Dysplasia , is a term used in pathology to refer to an abnormality of development. This generally consists of an expansion of immature cells, with a corresponding decrease in the number and location of mature cells. Dysplasia is often indicative of an early neoplastic process...
or carcinoma in situ
Carcinoma in situ
Carcinoma in situ is an early form of cancer that is defined by the absence of invasion of tumor cells into the surrounding tissue, usually before penetration through the basement membrane. In other words, the neoplastic cells proliferate in their normal habitat, hence the name "in situ"...
(CIS). The term, Cervical Intraepithelial Neoplasia
Cervical intraepithelial neoplasia
Cervical intraepithelial neoplasia , also known as cervical dysplasia and cervical interstitial neoplasia, is the potentially premalignant transformation and abnormal growth of squamous cells on the surface of the cervix. CIN is not cancer, and is usually curable...
(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
Bethesda System
The Bethesda System is a system for reporting cervical or vaginal cytologic diagnoses, used for reporting Pap smear results. It was introduced in 1988, and revised in 1991 and 2001...
terms for Pap smear (cytopathology
Cytopathology
Cytopathology is a branch of pathology that studies and diagnoses diseases on the cellular level. The discipline was founded by Rudolf Virchow in 1858. A common application of cytopathology is the Pap smear, used as a screening tool, to detect precancerous cervical lesions and prevent cervical...
) 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
HistologicHistopathology
Histopathology refers to the microscopic examination of tissue in order to study the manifestations of disease...
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 carcinomaSquamous cell carcinomaSquamous cell carcinoma , occasionally rendered as "squamous-cell carcinoma", is a histologically distinct form of cancer. It arises from the uncontrolled multiplication of malignant cells deriving from epithelium, or showing particular cytological or tissue architectural characteristics of...
(about 80-85%) - adenocarcinomaAdenocarcinomaAdenocarcinoma is a cancer of an epithelium that originates in glandular tissue. Epithelial tissue includes, but is not limited to, the surface layer of skin, glands and a variety of other tissue that lines the cavities and organs of the body. Epithelium can be derived embryologically from...
(about 15% of cervical cancers in the UK) - adenosquamous carcinomaAdenosquamous carcinomaAdenosquamous carcinoma is a type of cancer that contains two types of cells: squamous cells and gland-like cells.- External links :* entry in the public domain NCI Dictionary of Cancer Terms...
- small cell carcinomaSmall cell carcinomaSmall cell carcinoma is a type of highly malignant cancer that most commonly arises within the lung, although it can occasionally arise in other body sites, such as the cervix and prostate....
- neuroendocrine tumour
- glassy cell carcinomaGlassy cell carcinoma of the cervixGlassy cell carcinoma of the cervix, also glassy cell carcinoma, is a rare aggressive malignant tumour of the uterine cervix. The tumour gets its name from its microscopic appearance; it's cytoplasm has a glass-like appearance.-Signs and symptoms:...
- villoglandular adenocarcinomaVilloglandular adenocarcinoma of the cervixVilloglandular adenocarcinoma of the cervix, also villoglandular papillary adenocarcinoma, papillary villoglandular adenocarcinoma and well-differentiated villoglandular adenocarcinoma, abbreviated VGA, is a rare type of cervical cancer that, in relation to other cervical cancers, is typically...
Non-carcinoma malignancies which can rarely occur in the cervix include
- melanomaMelanomaMelanoma is a malignant tumor of melanocytes. Melanocytes are cells that produce the dark pigment, melanin, which is responsible for the color of skin. They predominantly occur in skin, but are also found in other parts of the body, including the bowel and the eye...
- lymphomaLymphomaLymphoma is a cancer in the lymphatic cells of the immune system. Typically, lymphomas present as a solid tumor of lymphoid cells. Treatment might involve chemotherapy and in some cases radiotherapy and/or bone marrow transplantation, and can be curable depending on the histology, type, and stage...
Note that the FIGO stage does not incorporate lymph node
Lymph node
A lymph node is a small ball or an oval-shaped organ of the immune system, distributed widely throughout the body including the armpit and stomach/gut and linked by lymphatic vessels. Lymph nodes are garrisons of B, T, and other immune cells. Lymph nodes are found all through the body, and act as...
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 ObstetricsInternational Federation of Gynecology and Obstetrics
The International Federation of Gynaecology and Obstetrics, usually just FIGO as the acronym of its French name Fédération Internationale de Gynécologie et d'Obstétrique, is a worldwide NGO organisation representing obstetricians and gynaecologists in over one hundred territories...
(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
Colposcopy
Colposcopy 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 which can be detected through the examination...
, endocervical curettage
Curettage
Curettage, in medical procedures, is the use of a curette to remove tissue by scraping or scooping.Curettages are also a declining method of abortion. It has been replaced by vacuum aspiration over the last decade....
, hysteroscopy
Hysteroscopy
Hysteroscopy is the inspection of the uterine cavity by endoscopy with access through the cervix. It allows for the diagnosis of intrauterine pathology and serves as a method for surgical intervention .-Method:...
, cystoscopy
Cystoscopy
Cystoscopy is endoscopy of the urinary bladder via the urethra. It is carried out with a cystoscope.Diagnostic cystoscopy is usually carried out with local anaesthesia...
, proctoscopy
Proctoscopy
Proctoscopy is a common medical procedure in which an instrument called a proctoscope is used to examine the anal cavity, rectum or sigmoid colon. A proctoscope is a short, straight, rigid, hollow metal tube, and usually has a small light bulb mounted at the end...
, intravenous urography, and X-ray
X-ray
X-radiation is a form of electromagnetic radiation. X-rays have a wavelength in the range of 0.01 to 10 nanometers, corresponding to frequencies in the range 30 petahertz to 30 exahertz and energies in the range 120 eV to 120 keV. They are shorter in wavelength than UV rays and longer than gamma...
examination of the lungs and skeleton, and cervical conization.
- Stage I The carcinoma is strictly confined to the cervix (extension to the corpus would
be disregarded)
- IA Invasive carcinoma which can be diagnosed only by microscopy, with deepest
invasion <5 mm and the largest extension >7 mm
-
- IA1 Measured stromal invasion of <3.0 mm in depth and extension of <7.0 mm
-
- IA2 Measured stromal invasion of >3.0 mm and not >5.0 mm with an extension of
not >7.0 mm
- IB Clinically visible lesions limited to the cervix uteri or pre-clinical cancers
greater than stage IA
-
- IB1 Clinically visible lesion <4.0 cm in greatest dimension
-
- IB2 Clinically visible lesion >4.0 cm in greatest dimension
- Stage II Cervical carcinoma invades beyond the uterus, but not to the pelvic wall or to the lower third of the vagina
- IIA Without parametrial invasion
- IIA1 Clinically visible lesion <4.0 cm in greatest dimension
-
- IIA2 Clinically visible lesion >4.0 cm in greatest dimension
- IIB With obvious parametrial invasion
- Stage III The tumour extends to the pelvic wall and/or involves lower third of the vagina and/or causes hydronephrosis or non-functioning kidney
- IIIA Tumour involves lower third of the vagina, with no extension to the pelvic wall
- IIIB Extension to the pelvic wall and/or hydronephrosis or non-functioning kidney
- Stage IV The carcinoma has extended beyond the true pelvis or has involved (biopsy proven) the mucosa of the bladder or rectum. A bullous oedema, as such, does not permit a case to be allotted to Stage IV
- IVA Spread of the growth to adjacent organs
- IVB Spread to distant organs
Stage 1-A1 young women - conization wis clear margin. Parous women - hysterectomy.
Stage 1-A2 laproscopic lymphadenectomy + vaginal trechelectomy + post operative radiotherapy.
Stage 1B & 2A 1. Wertheim's hysterectomy . 2- schauta vaginal hysterectomy + laparoscopic lymphadenectomy 3: primary radiotherapy 4: combined surgery & radiotherapy.
Stage 2B, 3, 4 - chemotherapy
Vaccination
GardasilGardasil
Gardasil , also known as Gardisil or Silgard, is a vaccine for use in the prevention of certain types of human papillomavirus , 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,...
, is a vaccine against HPV types 6, 11, 16 & 18 which is up to 98% effective.
Cervarix
Cervarix
Cervarix is a vaccine against certain types of cancer-causing human papillomavirus .Cervarix is designed to prevent infection from HPV types 16 and 18, that cause about 70% of cervical cancer cases. These types also cause some other genital cancers and some oropharyngeal cancers...
has been shown to be 92% effective in preventing HPV strains 16 and 18 and is effective for more than four years.
Together, HPV types 16 and 18 currently cause about 70% of cervical cancer cases. HPV types 6 and 11 cause about 90% of genital wart cases. HPV vaccines have also been shown to prevent precursors to some other cancers associated with HPV.
HPV vaccines are targeted at girls and women of age 9 to 26 because the vaccine only works if given before infection occurs; therefore, public health workers are targeting girls before they begin having sex. The vaccines have been shown to be effective for at least 4 to 6 years, 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 use of the vaccine in men to prevent genital warts, anal cancer
Anal cancer
Anal cancer is a type of cancer which arises from the anus, the distal orifice of the gastrointestinal tract. It is a distinct entity from the more common colorectal cancer. The etiology, risk factors, clinical progression, staging, and treatment are all different. Anal cancer is typically a...
, and interrupt transmission to women or other men is initially considered only a secondary market.
The high cost of this vaccine has been a cause for concern. Several countries have or are considering programs to fund HPV vaccination.
Condoms
Condoms offer some protection against cervical cancer. 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
Prostaglandin
A prostaglandin is any member of a group of lipid compounds that are derived enzymatically from fatty acids and have important functions in the animal body. Every prostaglandin contains 20 carbon atoms, including a 5-carbon ring....
in semen
Semen
Semen is an organic fluid, also known as seminal fluid, that may contain spermatozoa. It is secreted by the gonads and other sexual organs of male or hermaphroditic animals and can fertilize female ova...
may fuel the growth of cervical and uterine tumours and that affected women may benefit from the use of condom
Condom
A condom is a barrier device most commonly used during sexual intercourse to reduce the probability of pregnancy and spreading sexually transmitted diseases . It is put on a man's erect penis and physically blocks ejaculated semen from entering the body of a sexual partner...
s.
Smoking
CarcinogenCarcinogen
A carcinogen is any substance, radionuclide, or radiation that is an agent directly involved in causing cancer. This may be due to the ability to damage the genome or to the disruption of cellular metabolic processes...
s from tobacco
Tobacco
Tobacco is an agricultural product processed from the leaves of plants in the genus Nicotiana. It can be consumed, used as a pesticide and, in the form of nicotine tartrate, used in some medicines...
increase the risk for many cancer types, including cervical cancer, and women who smoke have about double the chance of a nonsmoker to develop cervical cancer.
Nutrition
Fruits and vegetablesHigher levels of vegetable consumption were associated with a 54% decrease risk of HPV persistence.
Vitamin A
There is weak evidence to suggest a significant deficiency of retinol
Retinol
Retinol is one of the animal forms of vitamin A. It is a diterpenoid and an alcohol. It is convertible to other forms of vitamin A, and the retinyl ester derivative of the alcohol serves as the storage form of the vitamin in animals....
can increase chances of cervical dysplasia, independently of HPV infection.
A small (n~=500) case-control study of a narrow ethnic group (native Americans in New Mexico) assessed serum micro-nutrients as risk factors for cervical dysplasia. Subjects in the lowest serum retinol
Retinol
Retinol is one of the animal forms of vitamin A. It is a diterpenoid and an alcohol. It is convertible to other forms of vitamin A, and the retinyl ester derivative of the alcohol serves as the storage form of the vitamin in animals....
quartile were at increased risk of CIN
Cervical intraepithelial neoplasia
Cervical intraepithelial neoplasia , also known as cervical dysplasia and cervical interstitial neoplasia, is the potentially premalignant transformation and abnormal growth of squamous cells on the surface of the cervix. CIN is not cancer, and is usually curable...
I compared with women in the highest quartile.
However, the study population had low overall serum retinol, suggesting deficiency. A study of serum retinol in a well-nourished population reveals that the bottom 20% had serum retinol close to that of the highest levels in this New Mexico sub-population.
Vitamin C
Risk of type-specific, persistent HPV infection was lower among women reporting intake values of vitamin C
Vitamin C
Vitamin C or L-ascorbic acid or L-ascorbate is an essential nutrient for humans and certain other animal species. In living organisms ascorbate acts as an antioxidant by protecting the body against oxidative stress...
in the upper quartile compared with those reporting intake in the lowest quartile.
Vitamin E
HPV clearance time was significantly shorter among women with the highest compared with the lowest serum levels of tocopherol
Tocopherol
Tocopherols are a class of chemical compounds of which many have vitamin E activity. It is a series of organic compounds consisting of various methylated phenols...
s, but significant trends in these associations were limited to infections lasting 120 days) was not significantly associated with circulating levels of tocopherols. Results from this investigation support an association of micronutrients with the rapid clearance of incident oncogenic HPV infection of the uterine cervix.
A statistically significantly lower level of alpha-tocopherol
Alpha-tocopherol
α-Tocopherol is a type of tocopherol with formula C29H50O2. It has E number "E307".α-Tocopherol is a form of vitamin E that is preferentially absorbed and accumulated in humans...
was observed in the blood serum of HPV-positive patients with cervical intraepithelial neoplasia. The risk of dysplasia was four times higher for an alpha-tocopherol level < 7.95 mumol/l.
Folic acid
Higher folate status was inversely associated with becoming HPV test-positive. Women with higher folate status were significantly less likely to be repeatedly HPV test-positive and more likely to become test-negative. Studies have shown that lower levels of antioxidants coexisting with low levels of folic acid increases the risk of CIN development. Improving folate status in subjects at risk of getting infected or already infected with high-risk HPV may have a beneficial impact in the prevention of cervical cancer.
However, another study showed no relationship between folate status and cervical dysplasia.
Carotenoids
The likelihood of clearing an oncogenic HPV infection is significantly higher with increasing levels of lycopene
Lycopene
Lycopene is a bright red carotene and carotenoid pigment and phytochemical found in tomatoes and other red fruits and vegetables, such as red carrots, watermelons and papayas...
s. A 56% reduction in HPV persistence risk was observed in women with the highest plasma [lycopene] concentrations compared with women with the lowest plasma lycopene concentrations. These data suggests that vegetable consumption and circulating lycopene may be protective against HPV persistence.
Screening
The widespread introduction of the Papanicolaou test, or Pap smear for cervical cancer screening has been credited with dramatically reducing the incidence and mortality of cervical cancer in developed countries. Pap smear screening every 3–5 years with appropriate follow-up can reduce cervical cancer incidence by up to 80%. Abnormal Pap smear results may suggest the presence of cervical intraepithelial neoplasiaCervical intraepithelial neoplasia
Cervical intraepithelial neoplasia , also known as cervical dysplasia and cervical interstitial neoplasia, is the potentially premalignant transformation and abnormal growth of squamous cells on the surface of the cervix. CIN is not cancer, and is usually curable...
(potentially premalignant changes in the cervix) before a cancer has developed, allowing examination and possible preventive treatment. If premalignant disease or cervical cancer is detected early, it can be monitored or treated relatively noninvasively, with little impairment of fertility.
Cervical cancer screening is typically recommended starting three years or more after first sex, or starting at age 21 to 25. 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.
To take a Pap smear, the vagina is held open with a speculum
Speculum (medical)
A speculum is a medical tool for investigating body cavities, with a form dependent on the body cavity for which it is designed. In old texts, the speculum may also be referred to as a diopter or dioptra...
, the loose surface cells on the cervix are scraped using a specially shaped spatula and a brush, and the cells are spread on a microscope slide. At a laboratory the slide is stained, examined for abnormal cells and findings are reported
Bethesda System
The Bethesda System is a system for reporting cervical or vaginal cytologic diagnoses, used for reporting Pap smear results. It was introduced in 1988, and revised in 1991 and 2001...
.
Until recently the Pap smear has remained the principal technology for preventing cervical cancer. However, following a rapid review of the published literature, originally commissioned by NICE, liquid based cytology has been incorporated within the UK national screening programme. 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.
Automated technologies have been developed with the aim of improving on the interpretation of smears, normally carried out by cytotechnologists. Unfortunately these on the whole have proven less useful; although the more recent reviews suggest that generally they may be no worse than human interpretation.
The HPV test is a newer technique for cervical cancer triage which detects the presence of human papillomavirus
Human papillomavirus
Human papillomavirus is a member of the papillomavirus family of viruses that is capable of infecting humans. Like all papillomaviruses, HPVs establish productive infections only in keratinocytes of the skin or mucous membranes...
infection in the cervix. It is more sensitive than the pap smear (less likely to produce false negative results), but less specific (more likely to produce false positive results) and its role in routine screening is still evolving. Since more than 99% of invasive cervical cancers worldwide contain HPV, some researchers recommend that HPV testing be done together with routine cervical screening. But, given the prevalence of HPV (around 80% infection history among the sexually active population) others suggest that routine HPV testing would cause undue alarm to carriers, more unnecessary follow-up testing and treatment. HPV testing along with cytology significantly increases the cost of screening.
VIA/cryo, for visualization of the cervix with acetic acid (vinegar) and treatment with cryotherapy, sometimes with special lights (speculoscopy
Speculoscopy
Speculoscopy is a procedure in which a special blue-white light is used to examine the cervix for cancerous or pre-cancerous lesions....
), or taking pictures for expert evaluation (cervicography
Cervicography
Cervicography is a diagnostic medical procedure in which a non-physician takes pictures of the cervix and submits them to a physician for interpretation. Other related procedures are speculoscopy and colposcopy. The procedure is considered a screening test for cervical cancer and is complementary...
) have been evaluated as adjuncts to or replacements for Pap smear screening, especially in countries where Pap smear screening is prohibatively expensive. There are efforts to develop low cost HPV tests which might be used for primary screening of older women in less developed countries.
Treatment
Microinvasive cancer (stage IA) is usually treated by hysterectomyHysterectomy
A hysterectomy is the surgical removal of the uterus, usually performed by a gynecologist. Hysterectomy may be total or partial...
(removal of the whole uterus including part of the vagina
Vagina
The vagina is a fibromuscular tubular tract leading from the uterus to the exterior of the body in female placental mammals and marsupials, or to the cloaca in female birds, monotremes, and some reptiles. Female insects and other invertebrates also have a vagina, which is the terminal part of the...
). For stage IA2, the lymph node
Lymph node
A lymph node is a small ball or an oval-shaped organ of the immune system, distributed widely throughout the body including the armpit and stomach/gut and linked by lymphatic vessels. Lymph nodes are garrisons of B, T, and other immune cells. Lymph nodes are found all through the body, and act as...
s are removed as well. An alternative for patients who desire to remain fertile is a local surgical procedure such as a loop electrical excision procedure
Loop electrical excision procedure
The loop electrosurgical excision procedure is currently one of the most commonly used approaches to treat high grade cervical dysplasia discovered on colposcopic examination. In UK it is known as "large loop excision of the transformation zone" . The procedure has many advantages including low...
(LEEP) or cone biopsy
Cervical conization
Cervical conization refers to a biopsy of the cervix in which a cone-shaped sample of tissue is removed from the mucous membrane. Conization may be used either for diagnostic purposes, or for therapeutic purposes to remove pre-cancerous cells.Types include:* cold knife conization...
.
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
Trachelectomy
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...
. 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 vaginally 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
Colposcopy
Colposcopy 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 which can be detected through the examination...
, 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
Safe sex
Safe sex is sexual activity engaged in by people who have taken precautions to protect themselves against sexually transmitted diseases such as AIDS. It is also referred to as safer sex or protected sex, while unsafe or unprotected sex is sexual activity engaged in without precautions...
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
Radiation therapy , radiation oncology, or radiotherapy , sometimes abbreviated to XRT or DXT, is the medical use of ionizing radiation, generally as part of cancer treatment to control malignant cells.Radiation therapy is commonly applied to the cancerous tumor because of its ability to control...
. Radiation therapy is given as external beam radiotherapy to the pelvis and brachytherapy
Brachytherapy
Brachytherapy , also known as internal radiotherapy, sealed source radiotherapy, curietherapy or endocurietherapy, is a form of radiotherapy where a radiation source is placed inside or next to the area requiring treatment...
(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
Cisplatin
Cisplatin, cisplatinum, or cis-diamminedichloroplatinum is a chemotherapy drug. It is used to treat various types of cancers, including sarcomas, some carcinomas , lymphomas, and germ cell tumors...
-based chemotherapy, hysterectomy (which then usually requires adjuvant
Adjuvant
An adjuvant is a pharmacological or immunological agent that modifies the effect of other agents, such as a drug or vaccine, while having few if any direct effects when given by itself...
radiation therapy), or cisplatin chemotherapy followed by hysterectomy.
Advanced stage tumors (IIB-IVA) are treated with radiation therapy and cisplatin
Cisplatin
Cisplatin, cisplatinum, or cis-diamminedichloroplatinum is a chemotherapy drug. It is used to treat various types of cancers, including sarcomas, some carcinomas , lymphomas, and germ cell tumors...
-based chemotherapy.
On June 15, 2006, the US Food and Drug Administration
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
approved the use of a combination of two chemotherapy drugs, hycamtin and cisplatin
Cisplatin
Cisplatin, cisplatinum, or cis-diamminedichloroplatinum is a chemotherapy drug. It is used to treat various types of cancers, including sarcomas, some carcinomas , lymphomas, and germ cell tumors...
for women with late-stage (IVB) cervical cancer treatment. Combination treatment has significant risk of neutropenia
Neutropenia
Neutropenia, from Latin prefix neutro- and Greek suffix -πενία , is a granulocyte disorder characterized by an abnormally low number of neutrophils, the most important type of white blood cell...
, anemia
Anemia
Anemia is a decrease in number of red blood cells or less than the normal quantity of hemoglobin in the blood. However, it can include decreased oxygen-binding ability of each hemoglobin molecule due to deformity or lack in numerical development as in some other types of hemoglobin...
, and thrombocytopenia
Thrombocytopenia
Thrombocytopenia is a relative decrease of platelets in blood.A normal human platelet count ranges from 150,000 to 450,000 platelets per microliter of blood. These limits are determined by the 2.5th lower and upper percentile, so values outside this range do not necessarily indicate disease...
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
Years of potential life lost
Years of potential life lost or potential years of life lost , is an estimate of the average years a person would have lived if he or she had not died prematurely. It is, therefore, a measure of premature mortality. As a method, it is an alternative to death rates that gives more weight to deaths...
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.
Epidemiology
Worldwide, cervical cancer is twelfth most common and the fifth most deadly cancer in women. It affects about 16 per 100,000 women per year and kills about 9 per 100,000 per year. Approximately 80% of cervical cancers occur in developing countries Worldwide, in 2008, it was estimated that there were 473,000 cases of cervical cancer, and 253,500 deaths per year.In the United States
United States
The United States of America is a federal constitutional republic comprising fifty states and a federal district...
, it is only the 8th most common cancer of women. In 1998, about 12,800 women were diagnosed in the US and about 4,800 died. In 2008 in the US an estimated 11,000 new cases were expected to be diagnosed, and about 3,870 were expected to die of cervical cancer. Among gynecological cancers it ranks behind endometrial cancer
Endometrial cancer
Endometrial cancer refers to several types of malignancies that arise from the endometrium, or lining, of the uterus. Endometrial cancers are the most common gynecologic cancers in the United States, with over 35,000 women diagnosed each year. The incidence is on a slow rise secondary to the...
and ovarian cancer
Ovarian cancer
Ovarian cancer is a cancerous growth arising from the ovary. Symptoms are frequently very subtle early on and may include: bloating, pelvic pain, difficulty eating and frequent urination, and are easily confused with other illnesses....
. The incidence and mortality in the US are about half those for the rest of the world, which is due in part to the success of screening with the Pap smear
Pap smear
The Papanicolaou test is a screening test used in to detect pre-cancerous and cancerous processes in the endocervical canal of the female reproductive system. Changes can be treated, thus preventing cervical cancer...
. The incidence of new cases of cervical cancer in the United States was 7 per 100,000 women in 2004. Cervical cancer deaths decreased by approximately 74% in the last 50 years, largely due to widespread Pap smear screening. The annual direct medical cost of cervical cancer prevention and treatment is prior to introduction of the HPV vaccine was estimated at $6 billion.
In the European Union, there were about 34,000 new cases per year and over 16,000 deaths due to cervical cancer in 2004.
In the United Kingdom, the age-standardised (European) incidence is 8.5/100,000 per year (2006). It is the twelfth most common cancer in women, accounting for 2% of all female cancers, and is the second most common cancer in the under 35s females, after breast cancer.
The UK's European age-standardised mortality is 2.4/100,000 per year (2007) (Cancer Research UK Cervical cancer statistics for the UK). With a 42% reduction from 1988-1997 the NHS implemented screening programme has been highly successful, screening the highest risk age group (25–49 years) every 3 years, and those ages 50–64 every 5 years.
In Canada, an estimated 1,300 women will be diagnosed with cervical cancer in 2008 and 380 will die.
In Australia, there were 734 cases of cervical cancer (2005). The number of women diagnosed with cervical cancer has dropped on average by 4.5% each year since organised screening began in 1991 (1991–2005).
Regular two-yearly Pap tests can reduce the incidence of cervical cancer by up to 90% in Australia, and save 1,200 Australian women dying from the disease each year.
History
- 400 BCE - HippocratesHippocratesHippocrates of Cos or Hippokrates of Kos was an ancient Greek physician of the Age of Pericles , and is considered one of the most outstanding figures in the history of medicine...
: cervical cancer incurable - 1925 - Hinselmann: invented colposcope
- 1928 - PapanicolaouGeorgios PapanikolaouGeorgios Nicholas Papanikolaou was a Greek pioneer in cytology and early cancer detection, and inventor of the "Pap smear".-Life:...
: developed Papanicolaou technique - 1941 - Papanicolaou and Trout: Pap smearPap smearThe Papanicolaou test is a screening test used in to detect pre-cancerous and cancerous processes in the endocervical canal of the female reproductive system. Changes can be treated, thus preventing cervical cancer...
screening - 1946 - Ayer: Aylesbury spatula to scrape the cervix, collecting sample for Pap smear
- 1976 - Zur HausenHarald zur HausenHarald zur Hausen is a German virologist and professor emeritus. He has done research on cancer of the cervix, where he discovered the role of papilloma viruses, for which he received the Nobel Prize in Physiology or Medicine 2008.-Biography:Zur Hausen was born in Gelsenkirchen, Germany, went to...
and Gisam: found HPV DNA in cervical cancer and warts - 1988 - Bethesda SystemBethesda SystemThe Bethesda System is a system for reporting cervical or vaginal cytologic diagnoses, used for reporting Pap smear results. It was introduced in 1988, and revised in 1991 and 2001...
for reporting Pap results developed - 2006 - First HPV vaccineHPV vaccineThe human papilloma virus vaccine prevents infection with certain species of human papillomavirus associated with the development of cervical cancer, genital warts, and some less common cancers...
FDA approved
Epidemiologists
Epidemiology
Epidemiology is the study of health-event, health-characteristic, or health-determinant patterns in a population. It is the cornerstone method of public health research, and helps inform policy decisions and evidence-based medicine by identifying risk factors for disease and targets for preventive...
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 workerSex workerA sex worker is a person who works in the sex industry. The term is usually used in reference to those in the sex industry that actually provide such sexual services, as opposed to management and staff of such industries...
s. - It was rare in nunNunA nun is a woman who has taken vows committing her to live a spiritual life. She may be an ascetic who voluntarily chooses to leave mainstream society and live her life in prayer and contemplation in a monastery or convent...
s, 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 rabbitRabbitRabbits are small mammals in the family Leporidae of the order Lagomorpha, found in several parts of the world...
s. (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
Smegma
Smegma is a combination of exfoliated epithelial cells, transudated skin oils, and moisture. It occurs in both female and male mammalian genitalia.-Human smegma:Both females and males produce smegma...
(e.g. Heins et al. 1958). During the 1960s and 1970s it was suspected that infection with herpes simplex virus
Herpes simplex virus
Herpes simplex virus 1 and 2 , also known as Human herpes virus 1 and 2 , are two members of the herpes virus family, Herpesviridae, that infect humans. Both HSV-1 and HSV-2 are ubiquitous and contagious...
was the cause of the disease. In summary, HSV
Herpes simplex virus
Herpes simplex virus 1 and 2 , also known as Human herpes virus 1 and 2 , are two members of the herpes virus family, Herpesviridae, that infect humans. Both HSV-1 and HSV-2 are ubiquitous and contagious...
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
Burkitt's lymphoma
Burkitt's lymphoma is a cancer of the lymphatic system...
, Nasopharyngeal carcinoma
Nasopharyngeal carcinoma
Nasopharyngeal carcinoma is the most common cancer originating in the nasopharynx, the uppermost region of the pharynx , behind the nose where the nasal passages and auditory tubes join the remainder of the upper respiratory tract. NPC differs significantly from other cancers of the head and neck...
, Marek's disease
Marek's disease
Marek's disease is a highly contagious viral neoplastic disease in chickens. It is named after József Marek, a Hungarian veterinarian. Occasionally misdiagnosed as an abtissue pathology it is caused by an alphaherpesvirus known as 'Marek's disease virus' or Gallid herpesvirus 2...
and the Lucké renal adenocarcinoma. HSV was recovered from cervical tumour cells.
A description of human papillomavirus
Human papillomavirus
Human papillomavirus is a member of the papillomavirus family of viruses that is capable of infecting humans. Like all papillomaviruses, HPVs establish productive infections only in keratinocytes of the skin or mucous membranes...
(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
Georgetown University
Georgetown University is a private, Jesuit, research university whose main campus is in the Georgetown neighborhood of Washington, D.C. Founded in 1789, it is the oldest Catholic university in the United States...
Medical Center, the University of Rochester
University of Rochester
The University of Rochester is a private, nonsectarian, research university in Rochester, New York, United States. The university grants undergraduate and graduate degrees, including doctoral and professional degrees. The university has six schools and various interdisciplinary programs.The...
, the University of Queensland
University of Queensland
The University of Queensland, also known as UQ, is a public university located in state of Queensland, Australia. Founded in 1909, it is the oldest and largest university in Queensland and the fifth oldest in the nation...
in Australia, and the U.S. National Cancer Institute
National Cancer Institute
The National Cancer Institute is part of the National Institutes of Health , which is one of 11 agencies that are part of the U.S. Department of Health and Human Services. The NCI coordinates the U.S...
. In 2006, the U.S. Food and Drug Administration (FDA) approved the first preventive HPV vaccine, marketed by Merck & Co.
Merck & Co.
Merck & Co., Inc. , also known as Merck Sharp & Dohme or MSD outside the United States and Canada, is one of the largest pharmaceutical companies in the world. The Merck headquarters is located in Whitehouse Station, New Jersey, an unincorporated area in Readington Township...
under the trade name Gardasil.