Cervical cancer (see the image below) is the third most common malignancy in women worldwide, and it remains a leading cause of cancer-related death for women in developing countries. In the United States, cervical cancer is relatively uncommon.
Essential update: FDA approves bevacizumab for late-stage cervical cancer
In August 2014, the US Food and Drug Administration (FDA) approved bevacizumab (Avastin) for the management of persistent, recurrent or late-stage (metastatic) carcinoma of the cervix. [1, 2] This agent is approved for combination chemotherapy with paclitaxel and cisplatin or with paclitaxel and topotecan. [1, 2]
Approval was based on the GOG-0240 study (n = 452) that assessed the efficacy and safety of bevacizumab plus chemotherapy (paclitaxel and cisplatin or paclitaxel and topotecan) in women with persistent, recurrent or metastatic carcinoma of the cervix. [1, 3] A statistically significant improvement in overall survival (OS) and an increase in the rate of tumor shrinkage was shown in women treated with bevacizumab plus chemotherapy compared with chemotherapy alone. However, hypertension, thromboembolic events, and gastrointestinal fistulas were higher in the bevacizumab group. [1, 3]
Signs and symptoms
The most common finding in patients with cervical cancer is an abnormal Papanicolaou (Pap) test result.
Physical symptoms of cervical cancer may include the following:
Abnormal vaginal bleeding
See Clinical Presentation for more detail.
Current screening recommendations for specific age groups, based on guidelines from the American Cancer Society (ACS), the American Society for Colposcopy and Cervical Pathology (ASCCP), the American Society for Clinical Pathology (ASCP), the US Preventive Services Task Force (USPSTF), and the American College of Obstetricians and Gynecologists (ACOG), are as follows [4, 5, 6, 7] :
< 21 years: No screening recommended
21-29 years: Cytology (Pap smear) alone every 3 years
30-65 years: Human papillomavirus (HPV) and cytology cotesting every 5 years (preferred) or cytology alone every 3 years (acceptable)
>65 years: No screening recommended if adequate prior screening has been negative and high risk is not present
See Workup for more detail.
Evidence suggests that HPV vaccines prevent HPV infection.  The following 2 HPV vaccines are approved by the FDA:
Gardasil (Merck, Whitehouse Station, NJ): This quadrivalent vaccine is approved for girls and women 9-26 years of age to prevent cervical cancer (and also genital warts and anal cancer) caused by HPV types 6, 11, 16, and 18; it is also approved for males 9-26 years of age 
Cervarix (GlaxoSmithKline, Research Triangle Park, NC): This bivalent vaccine is approved for girls and women 9-25 years of age to prevent cervical cancer caused by HPV types 16 and 18 
The Advisory Committee on Immunization Practices (ACIP) recommendations for vaccination are as follows:
Routine vaccination of females aged 11-12 years of age with 3 doses of either HPV2 or HPV4
Routine vaccination with HPV4 for boys aged 11-12 years of age, as well as males aged 13-21 years of age who have not been vaccinated previously
Vaccination with HPV4 in males aged 9-26 years of age for prevention of genital warts; routine use not recommended
The treatment of cervical cancer varies with the stage of the disease, as follows:
Stage 0: Carcinoma in situ (stage 0) is treated with local ablative or excisional measures such as cryosurgery, laser ablation, and loop excision; surgical removal is preferred
Stage IA1: The treatment of choice for stage IA1 disease is surgery; total hysterectomy, radical hysterectomy, and conization are accepted procedures
Stage IA2, IB, or IIA: Combined external beam radiation with brachytherapy and radical hysterectomy with bilateral pelvic lymphadenectomy for patients with stage IB or IIA disease; radical vaginal trachelectomy with pelvic lymph node dissection is appropriate for fertility preservation in women with stage IA2 disease and those with stage IB1 disease whose lesions are 2 cm or smaller
Stage IIB, III, or IVA: Cisplatin-based chemotherapy with radiation is the standard of care 
Stage IVB and recurrent cancer: Individualized therapy is used on a palliative basis; radiation therapy is used alone for control of bleeding and pain; systemic chemotherapy is used for disseminated disease 
Cervical cancer is the third most common malignancy in women worldwide, and it remains a leading cause of cancer-related death for women in developing countries. In the United States, cervical cancer is relatively uncommon. (See Epidemiology.)
The incidence of invasive cervical cancer has declined steadily in the United States over the past few decades; however, it remains at high levels in many developing countries. The change in the epidemiologic trend in the United States has been attributed to mass screening with Papanicolaou (Pap) tests, which permits detection and treatment of preinvasive disease.
Recognition of the etiologic role of human papillomavirus (HPV) infection in cervical cancer has led to the recommendation of adding HPV testing to the screening regimen in women 30-65 years of age (see Workup). However, women who have symptoms, abnormal screening test results, or a gross lesion of the cervix are best evaluated with colposcopy and biopsy.
For further recommendations concerning cervical cancer evaluation and management of abnormal Pap test results, and treatment of cervical intraepithelial neoplasia (CIN), see the American Society for Colposcopy and Cervical Pathology (ASCCP) guidelines.  (See also Presentation and Workup.)
The treatment of cervical cancer varies with the stage of the disease. For early invasive cancer, surgery is the treatment of choice. In more advanced cases, radiation combined with chemotherapy is the current standard of care. In patients with disseminated disease, chemotherapy or radiation provides symptom palliation. (See Treatment and Medication.)
Human papillomavirus (HPV) infection must be present for cervical cancer to occur. HPV infection occurs in a high percentage of sexually active women. However, approximately 90% of HPV infections clear on their own within months to a few years and with no sequelae, although cytology reports in the 2 years following infection may show a low-grade squamous intraepithelial lesion.
On average, only 5% of HPV infections will result in the development of CIN grade 2 or 3 lesions (the recognized cervical cancer precursor) within 3 years of infection. Only 20% of CIN 3 lesions progress to invasive cervical cancer within 5 years, and only 40% of CIN 3 lesions progress to invasive cervical cancer with 30 years.
Because only a small proportion of HPV infections progress to cancer, other factors must be involved in the process of carcinogenesis. The following factors have been postulated to influence the development of CIN 3 lesions:
The type and duration of viral infection, with high-risk HPV type and persistent infection predicting a higher risk for progression; low-risk HPV types do not cause cervical cancer
Host conditions that compromise immunity (eg, poor nutritional status, immunocompromise, and HIV infection)
Environmental factors (eg, smoking and vitamin deficiencies)
Lack of access to routine cytology screening
In addition, various gynecologic factors significantly increase the risk of HPV infection. These include early age of first intercourse and higher number of sexual partners.
Although use of oral contraceptives for 5 years or longer has been associated with an increased risk of cervical cancer, the increased risk may reflect a higher risk for HPV infection among sexually active women. However, a possible direct interaction between oral contraceptives and HPV infection has not been disproved. 
Genetic susceptibility to cervical cancers caused by HPV infection has been identified via studies of twins and other first-degree relatives, as well as genome-wide association studies. Women who have an affected first-degree biologic relative have a 2-fold relative risk of developing a cervical tumor compared with women who have a nonbiologic first-degree relative with a cervical tumor. [14, 15] Genetic susceptibility accounts for fewer than 1% of cervical cancers.
Genetic changes in several classes of genes have been linked to cervical cancer. Tumor necrosis factor (TNF) is involved in initiating the cell commitment to apoptosis, and the genes TNFa-8, TNFa-572, TNFa-857, TNFa-863, and TNF G-308A have been associated with a higher incidence of cervical cancer. [16, 17, 18, 19] Polymorphisms in another gene involved in apoptosis and gene repair, Tp53, have been associated with an increased rate of HPV infection progressing to cervical cancer. [20, 21, 22, 23, 24]
Human leukocyte antigen (HLA) genes are involved in various ways. Some HLA gene anomalies are associated with an increased risk of HPV infection progressing to cancer, [25, 26] others with a protective effect. [27, 28] The chemokine receptor-2 (CCR2) gene on chromosome 3p21 [29, 30] and the Fas gene on chromosome 10q24.1 [26, 31] may also influence genetic susceptibility to cervical cancer, perhaps by disrupting the immune response to HPV. The CASP8 gene (also known as FLICE or MCH5) has a polymorphism in the promoter region that has been associated with a decreased risk of cervical cancer. 
Epigenetic modifications may also be involved in cervical cancer. Methylation is the best understood and probably the most common mechanism of epigenetic DNA modeling in cancer. Aberrant DNA methylation patterns have been associated with the development of cervical cancer and may harbor important clues for developing treatment. [33, 34]
HPV comprises a heterogeneous group of viruses that contain closed circular double-stranded DNA. The viral genome encodes 6 early open reading frame proteins (ie, E1, E2, E3, E4, E6, and E7), which function as regulatory proteins, and 2 late open reading frame proteins (ie, L1 and L2), which make up the viral capsid.
To date, more than 115 different genotypes of HPV have been identified and cloned. A large multinational cervical cancer study found that more than 90% of all cervical cancers worldwide are caused by 8 HPV types: 16, 18, 31, 33, 35, 45, 52, and 58. Three types—16, 18, and 45—cause 94% of cervical adenocarcinomas.  HVP type 16 may pose a risk of cancer that is an order of magnitude higher than that posed by other high-risk HPV types. 
The World Health Organization (WHO) International Agency for Research on Cancer Monograph Working Group has grouped HPV types of the mucosotropic alpha genus according to the evidence supporting their association with cervical cancer (see Table 1, below). 
Table 1. Human Papillomavirus Types Associated With Cervical Cancer (Open Table in a new window)
|HPV Alpha Group||Types||Evidence for Cervical Cancer Causation|
|1||16||Most carcinogenic HPV type, known to cause cancer at several sites|
|18,31,33,35,39,45,51,52,56,58, 59||Sufficient evidence|
|2A||68||Limited evidence in humans and strong mechanistic evidence|
|2B||26,53,66,67,70,73,82||Limited evidence in humans|
|30,34,69,85,97||Classified by phylogenetic analogy to HPV types with sufficient or limited evidence in humans|
|3||6,11||Inadequate epidemiological evidence and absence of carcinogenic potential in mechanistic studies|
|HPV = human papillomavirus.|
The HPVs that infect the human cervix fall into 2 broad risk categories. The low-risk types (eg, HPV 6 and 11) are associated with condylomata and a very small number of low-grade squamous epithelial lesions (SILs) but are never found in invasive cancer. The high-risk types (eg, HPV 16) vary in prevalence according to the cervical disease state.
Upon integration into the human genome, the linearization of high-risk HPV DNA places the E6 and E7 genes in a position of enhanced replication. E7 binds and inactivates the Rb protein while E6 binds p53 and directs its degradation, and the functional loss of the TP53 and RB genes leads to resistance to apoptosis, causing uncensored cell growth after DNA damage. This ultimately results in progression to malignancy.
Human immunodeficiency virus
The role of HIV infection in the pathogenesis of cervical cancer is not fully understood. However, HIV infection is known to suppress the already low level of immune recognition of HPV infection, allowing HPV to cause more damage than it would in immunocompetent women.
Cervical cancer is at least 5 times more common in HIV-infected women, and this increased prevalence has remained essentially unchanged with the use of highly active antiretroviral therapy.  Studies have shown a higher prevalence of HPV infection in HIV-seropositive women than in seronegative women, and the HPV prevalence was directly proportional to the severity of immunosuppression as measured by CD4+ T-cell counts.
With rare exceptions, cervical cancer results from genital infection with HPV, which is a known human carcinogen. [36, 38, 39, 40, 41] Although HPV infections can be transmitted via nonsexual routes, the majority result from sexual contact. Consequently, major risk factors identified in epidemiologic studies are as follows:
Sex at a young age
Multiple sexual partners
Promiscuous male partners
History of sexually transmitted diseases
HIV infection is associated with a 5-fold increase in the risk of cervical cancer, presumably because of an impaired immune response to HPV infection.  Exposure to diethylstilbestrol in utero has been associated with an increased risk of CIN grade 2 or higher. 
Cervical cancer is the third most common malignancy in women worldwide. The frequency varies considerably between developed and developing countries, however: Cervical cancer is the second most common cancer in developing countries, but only the tenth most common in developed countries. Similarly, cervical cancer is the second most common cause of cancer-related deaths in women in developing countries but is not even among the top 10 causes in developed countries. 
In the United States, cervical cancer is relatively uncommon. The incidence of invasive cervical cancer has declined steadily in the US over the past few decades; for example, since 2004, rates have decreased by 2.1% per year in women younger than 50 years and by 3.1% per year in women 50 years of age and older.  This trend has been attributed to mass screening with Pap tests.  Cervical cancer rates continue to rise in many developing countries, however.
The American Cancer Society (ACS) estimated that in the United States, 12,170 new cases of cervical cancer would be diagnosed in 2012.  Internationally, more than 500,000 new cases are diagnosed each year; rates vary widely, ranging from an annual incidence of 4.5 cases per 100,000 in Western Asia to 34.5 per 100,000 women in Eastern Africa.  In industrialized countries with well-established cytology screening programs, the incidence of cervical cancer ranges from 4 to 10 per 100,000 women.
The incidence of CIN 2/3 disease in the US is about 150 per 100,000 women, with the peak incidence around 800 per 100,000 women in the 25-29 year age group. The incidence of abnormal cytology screens for all ages is an order of magnitude larger, at 7800 per 100,000 women.
Forouzanfar et al performed annual age-specific assessments of cervical cancer in 187 countries from 1980 to 2010. The global cervical cancer incidence increased from 378,000 cases per year in 1980 to 454,000 cases per year in 2010 (annual rate of increase, 0.6%). Cervical cancer death rates have been decreasing, but the disease still accounted for 200,000 deaths in 2010; in developing countries, 46,000 of these women were aged 15-49 years, and 109,000 were aged 50 years or older. 
The Centers for Disease Control and Prevention (CDC) surveillance of screening-detected cancers (colon and rectum, breast, and cervix) in the United States from 2004 to 2006 reported that the incidence of late-stage cervical cancer was highest among women aged 50-79 years.  However, cervical cancer may be diagnosed in any woman of reproductive age.
Indeed, rates of cervical adenocarcinoma have been increasing in women under 40 years of age.  These cases are less easily detected with Pap test screening, and survivorship is low because cases tend to be detected at a late stage. Moreover, the HPV types causing adenocarcinoma are different from the types causing squamous carcinoma. HPV 16, which is a stronger carcinogen than other HPV types, has been found more frequently in younger women than in older ones. [50, 51]
Racial variation in cervical cancer rates per 100,000 women in the United States, according to Surveillance Epidemiology and End Results (SEER) data from 2005-2009, was as follows:
Hispanic - 11.8
African American - 9.8
American Indian/Alaska Native - 8.1
White - 8.0
Asian/Pacific Islander - 7.2
Except for Asian/Pacific Islanders, women of other races have higher mortality from cervical cancers than their white counterparts in the United States do.  Death rates from cervical cancer have been highest among African Americans; however, death rates in African-American women decreased by 2.6% per year from 2004 to 2008 while remaining stable in white women. 
The prognosis in patients with cervical cancer depends on the disease stage. In general, the 5-year survival rates are as follows:
Stage I - Greater than 90%
Stage II - 60-80%
Stage III - Approximately 50%
Stage IV - Less than 30%
The ACS estimated that 4220 women would die of cervical cancer in the United States in 2012.  This represents 1.3% of all cancer deaths and 6.5% of deaths from gynecologic cancers.
Cervical cancer is overrepresented among underserved and minority groups in the United States. It is imperative to increase awareness about the benefit of Pap test screening for preventing cervical cancer among women in these groups. Education about the benefit of HPV vaccination is also important but must be accompanied by the information that vaccination does not substitute for regular screening.
A Cochrane review found that the best approach to encourage women to undergo cervical screening involved invitations.  These may take any of the following forms:
Appointments (fixed or open)
These findings relate to screening in developed countries, however, and their relevance to developing countries is unclear. Further studies are required to determine the effectiveness of promising interventions, such as revealing in an invitation letter the gender of the smear taker, using a health promotion nurse, employing lay outreach health workers, and carrying out intensive attempts at recruitment.
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