Cervical cancer

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Nima Nasiri, M.D.[2]

Cervical cancer was once one of the leading causes of cancer-related death in the US and worldwide before the introduction of Pap smear and screening. It currently accounts for a significant but declining portion of the US cancer burden, now ranking 14th in incidence. Cervical cancer is a malignant neoplasm of the cervix. It may present with vaginal bleeding although it may remain asymptomatic until the disease reaches advanced stages. Treatment consists of surgery in the early stages and chemotherapy and radiotherapy in advanced stages of the disease. An effective HPV vaccine against the two most common cancer-causing strains of HPV has recently been licensed in the US (2006). These two HPV strains together are responsible for approximately 70% of all cervical cancers. The high risk HPV E6 and E7 gene products, which are involved in viral replication and oncogenesis bind to p53 and prevent its normal activities which are G1 arrest, apoptosis, and DNA repair. The USPSTF recommends screening for cervical cancer every 3 years with cervical cytology alone in women aged 21 to 29 years and for women aged 30 to 65 years, every 3 years with cervical cytology alone, every 5 years with high-risk human papillomavirus (hrHPV) testing alone, or every 5 years with hrHPV testing in combination with cytology (cotesting). The most important risk factors associated with the infection by HPV are young age at coitarche (first sexual intercourse), having multiple sexual partners throughout life, or women being with men having multiple sexual partners. Male circumcision and use of condoms are factors that can reduce, but do not eliminate the transmission of human papilloma virus. Treatment of cervical neoplasia depends upon stage of cancer at the time of presentation. It consists of surgical procedure like hysterectomy, and/or radiation and chemotherapy.

In 400 BC, Hippocrates referred to cervical cancer as cancer of the uterus, little was known about cervical cancer until the Renaissance era. In 1842, an Italian physician named Mario Rigoni Stern noticed that cancer of the cervix prevalence was high among married and widowed women and low or rare among the unmarried women and absent in Italian nuns.

Cervical cancer may be classified into many subtypes based on FIGO classification. In stage I, carcinoma is strictly confined to the cervix, in stage II, the carcinoma invades beyond the uterus, but has not extended onto the lower third of the vagina or to the pelvic wall.

Persistent infection with high-risk HPV genotypes is the primary driver of cervical oncogenesis and is widely related to disrupting cell cycle growth and regulations. A summary of these mechanisms include: The high risk HPV E6 and E7 gene products which are involved in viral replication and oncogenesis bind to p53 and prevent its normal activities which are G1 arrest, apoptosis, and DNA repair. HPV enters the host cells which are squamous cells of epithelium in cervix, mainly in junctional zone, between the columnar epithelium of the endocervix and the squamous epithelium of the ectocervix and that is how viral transcription and replication begins. HPV infection of the basal layer of epithelium takes place by attachment via a different mechanism of entry, this happens by cell surface heparan sulfate, stabilizing proteoglycans and Integrin.

Cervical cancer must be differentiated from other diseases that cause abnormal vaginal bleeding, such as cervical polyp, cervical leiomyoma, invasion of the cervix from primary uterine malignancy, vaginal cancer, cervical lymphoma, metastases to cervix, and cervical ectopic pregnancy.

In terms of frequency, cervical cancer currently accounts for a significant but declining portion of the US cancer burden, now ranking 14th in incidence (while still being very common in the least developed countries). In The United States, cervical cancer is more common among Hispanics, African-Americans, Asians and Pacific Islanders, and followed by whites. Alaska Natives and American Indians have the lowest rate of incidence. The median age at diagnosis is approximately 50 years, with the disease predominantly affecting women in mid-adulthood. As of the last major statistical update in 2015, the annual incidence and mortality rates in the U.S. were 7.4 and 2.3 per 100,000 women, respectively.

The most potent risk factor in the development of cervical cancer is Human papillomavirus (HPV) infection. Other risk factors include smoking, increased number of sexual partners, and young age at time of first sexual intercourse, high parity, use of oral contraceptives, immunodeficiency.

According to the American Cancer Society (ACS), American Society for Colposcopy and Cervical Pathology (ASCCP), and American Society for Clinical Pathology, screening for cervical cancer by pap smear is recommended every 3 years among women age 21 to 29 years and for women aged 30 to 65 years, every 3 years with cervical cytology alone, every 5 years with high-risk human papillomavirus (hrHPV) testing alone, or every 5 years with hrHPV testing in combination with cytology (cotesting).

Infection by high risk strain of oncogenic HPV types is an established cause of neoplastic lesions of the cervix, vagina and vulva, anus, penis and oropharynx. HPV 16 and 18 are the most common cause of approximately 70% of all cervical cancers worldwide. HPV is highly transmissible through direct skin to skin contact and intercourse, women with persistent high-risk HPV infections are at greatest risk for developing cervical cancer. Common complications of cervical cancer include vaginal bleeding, fistula and renal failure. Prognosis is generally good, and the 5-year survival rate of patients with cervical cancer is approximately 67.9%.

Cervical cancer is staged by the International Federation of Gynecology and Obstetrics (FIGO) staging system, which is based on clinical examination, imaging studies and procedures such as hysteroscopy, cystoscopy, proctoscopy, intravenous urography, and cervical conization.

Physical examination of patients with advanced cervical cancer is typically notable for a palpable cervical lesion, pallor and pedal edema. Most women with cervical cancer are asymptomatic at the early stage of disease, those patients in advanced stages of cancer may have symptoms like abnormal vaginal bleeding, vaginal discharge, abdominal and pelvic pain, urinary hesitancy.

Chest radiography (CXR) is the initial imaging modality used in the detection of suspected pulmonary metastasis. It has limited value in initial workup for cervical cancer, unless there is a metastasis to the lungs which typically happens in advanced stage of cancer.

Computerised tomography (CT) is used for clinical staging of cervical carcinoma, it improves the accuracy of staging based on FIGO guidelines. CT scan is useful in evaluating the followings:Tumor size, parametrial invasion, Lymph node and distant metastasis, Ureteral involvement and the functional status of kidneys.

Pelvic MRI is helpful in the diagnosis of cervical cancer. In patients with advanced disease, there are several findings on MRI studies which may help early prediction of the therapeutic outcome, tumor size reduction, myometrial invasion, lymph node invasion more accurately.

Transvaginal color doppler ultrasound can be used in predicting response to chemotherapy in women with cervical cancer. Doppler ultrasound can predict tumor volume based on angiogenesis, intramural vascularization and hemodynamic flow. Transvaginal ultrasound also is helpful in detecting small size tumor and invasion to lymph nodes.

Cervical biopsy is the confirmatory test for the diagnosis of cervical cancer or pre-cancer. Most women have tissue removed in the doctor’s office with local anesthesia. A pathologist checks the tissue under a microscope for abnormal cells. In Punch biopsy, a specialized forceps is utilized to obtain small samples of cervical tissue. In Loop electrosurgical excision procedure (LEEP), an electric wire loop is used to slice off a thin, round piece of cervical tissue. This method allows deep excision of the transformation zone. In endocervical curettage, a curette (a small, spoon-shaped instrument) is used to scrape a small sample of tissue from the cervix. Some doctors may use a thin, soft brush instead of a curette. A conization, or cold knife cone biopsy, cone-shaped samples are removed from cervix and allows for accurate examination of biopsy specimens by pathologists. This can be done in doctor’s office or in the hospital under general anesthesia. Most significant complication of this method is hemorrhage. There is a relative contraindication for pregnant women and also conization increase the risk of preterm birth.

The optimal therapy for cervical cancer depends on the stage at diagnosis, treatment of cervical neoplasia is mainly a combination of radiation therapy and use of chemotherapeutic agents.

The feasibility of surgery depends on the stage of cervical cancer at diagnosis, the mainstay of surgical management for cervical carcinoma is radical hysterectomy with pelvic lymphadenectomy. Surgery can be done by cold knife conization, loop electrosurgical excision procedure, total hysterectomy.

During pregnancy, no therapy is warranted for preinvasive lesions of the cervix, including carcinoma in situ, although expert colposcopy is recommended to exclude invasive cancer. Patients with early stage (IA) disease may safely undergo fertility-sparing treatments. For patients with advanced disease, waiting for viability is generally not acceptable.The standard of care for locally advanced disease consists of definitive platinum-based concurrent chemoradiotherapy.

Prevention of cervical cancer includes a comprehensive approach involving awareness, screening, and preventative vaccinations.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Nima Nasiri, M.D.[2]

In 400 BC, Hippocrates referred to cervical cancer as cancer of the uterus, it was little known about cervical cancer until the Rennaissance era. In 1842, an Italian physician named Rigoni-stern noticed that cancer of the cervix prevalence was high among married and widowed women and low or rare among the unmarried women and absent in Italian nuns.

• In 400 BC, Hippocrates referred to cervical cancer as cancer of the uterus which should be left untreated since there is no cure for it.^[1][2]
• In 1842, an Italian physician named Rigoni-stern noticed that cancer of the cervix prevalence was high among married and widowed women and low or rare among the unmarried women and absent in Italian nuns.^[3]
• In 1941, The Papanicolaou smear, a routine screening test for cervical cancer, proved by George Nicholaus Papanicolaou.^[4][5]
• In 1970s, Harold zur Hausen, a German physician, first discovered that infection with papillomavirus is cause of cervical cancer, his research included HPV types 16 and 18 as main cause of increased risk for cervical neoplasia.^[6][7]
• In 2006, first HPV vaccine was approved by FDA . ^[8]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Nima Nasiri, M.D.[2]

Cervical cancer may be classified into many subtypes based on FIGO classification.

Newly revised FIGO staging for cervical cancer, included pathological and imaging findings as well as clinical manifestations.^[1][2][3]

FIGO staging of cancer of the cervix uteri (2018)

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Nima Nasiri, M.D.[2], Aida Javanbakht, M.D.

It is established that human papillomavirus (HPV) is the main cause of development of cervical neoplasia, only high risk strain of HPV can cause cervical cancer among women who are affected. This is because of HPV produced proteins E7 which alters epithelium of cervix mainly at junctional zone between the columnar epithelium of the endocervix and the squamous epithelium of the ectocervix.

High risk strains of HPV, mainly HPV types 16 and 18 had been identified as a potent cause of cancer of cervix. HPV plays main role in pathogenesis of cervical cancer and it is widely related to disrupting cell cycle growth and regulations, summary of these include:^[1]

• The high risk HPV E6 and E7 gene products which are involved in viral replication and oncogenesis bind to p53 and prevents its normal activities which is G1 arrest, apoptosis, and DNA repair.

• HPV enters the host cell which are squamous cells of epithelium in cervix, mainly in the junctional zone, between the columnar epithelium of the endocervix and the squamous epithelium of the ectocervix and that is how viral transcription and replication begins.
• HPV infection of the basal layer of epithelium takes place by attachment via different mechanism of entry, this happens by cell surface heparan sulfate, stabilizing proteoglycans and Integrin.

There are other cofactors that cause progression of cervical neoplasia, some of these include:^[2][3][4]

• HLA type
• Immunosuppression, since response to HPV infection is cell mediated.
• Use of oral contraceptives had been identified to play an important role in
• Smoking which disrupts immune response.
• History of promiscuous sexual activity in male partner
• Early age sexual activities
• Co-infection with herpes simplex virus type 2, cytomegalovirus (CMV), human herpesvirus 6 (HHV-6), and HHV-7, which cause promotion of infection with HPV and plays an initiation role.

• IL-1β, encoded by the IL–1B gene, is an inflammatory cytokine and part of the innate immune system.^[5][6]
• TNF-α, encoded by the TNFA gene, is another potent pro-inflammatory cytokine that has been implicated in the control of HPV infection.
• Polymorphisms within HLA plays a role in pathogenesis of cervical neoplasia.
• Interleukin-12 A and B gene (IL12A and IL12B)
• IFN-γ, encoded by the IFNG gene has defensive role against viruses and induces immune mediated inflammatory responses.
• Interleukin-10: the risk and the progression of cervical cancer have been associated with increased IL-10 serum levels.
• Cytotoxic T-lymphocyte antigen-4
• HPV E6/E7 oncogenes, proteins that interfere with cell cycle growth and tumor supressor genes.
• Primary microRNA-218 (pri–miR–218) and laminin-5 β3 (LAMB3).

Conditions associated with cervical cancer include:^[7]

• Enterovaginal, rectovaginal, and vesico- or ureterovaginal fistulas
• Renal failure and/or uremia
• Stress incontinence
• Loss of libido
• Vaginal atrophy and dryness
• Early menopause
• Malnutrition
• Osteoprosis
• Anemia
• depression

Gross pathological changes can be visualized by colposcopy and biopsy and application of a 3% acetic acid solution on biopsy speciemen and inspection under bright filtered light microscopy with 10 to 15 fold magnification. Findings in gross pathology of patients with cervical cancer include:^[8]

• Acetowhitening
• Characteristic vascular pattern of dysplasia or carcinoma

Microscopic morphology of low‐grade squamous intraepithelial lesions (CIN 1) include:^[9]

• Presence of koilocytosis (perinuclear cytoplasmic clearing with peripheral condensation of the cytoplasm)
• Irregular nuclear contours, either binucleation or/and multinucleation
• Hyperchromasia and/or cellular pleomorphism
• Mild dysplasia

High‐grade dysplasia (CIN 2 and 3) is characterized by the following features:

• Loss of maturation
• Nuclear crowding
• Loss of nuclear polarity
• Prominent cytonuclear atypia, increase in nuclear‐to‐cytoplasmic ratios
• Irregular nuclear contours and coarse chromatin.
• Increased proliferation and mitotic changes in the upper part of the epithelium.
• In CIN2, most cytonuclear abnormalities are seen in the lower and middle third of the epithelium.
• CIN3 characteristic features include:
  • Full‐thickness cytonuclear atypia
  • Minimal to absent maturation
  • Numerous mitotic activities

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Nima Nasiri, M.D.[2], Monalisa Dmello, M.B,B.S., M.D. [3], Daniel Adamec[4]

Cervical cancer is primarily caused by persistent infection with oncogenic (high risk) Human papillomavirus (HPV). While a necessary etiological factor, the majority of infections are transient and resolve without progressing to malignancy. HPV is transmitted through mucosal and cutaneous contact, most commonly via sexual activity.^[1] In 2024, approximately 13,820 new cases and 4,360 related deaths were expected in the United States.^[2] Key risk factors for acquiring HPV include early age at first intercourse and a high number of lifetime sexual partners.^[3]

• Human papillomavirus is the main cause of cervical cancer. High-risk HPV types infect the basal layer of the cervical epithelium, particularly at the transformation zone, leading to malignant transformation.^[4]
• HPV is a small, non-enveloped, double-stranded circular DNA virus of approximately 8 kb, encoding eight genes, with a virion diameter of approximately 45-55 nm.^[5] It is transmitted primarily through skin-to-skin contact, in particular via sexual activity.^[6]
• Oncogenic high-risk strains include types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and 68.^[7]
• The viral oncogenes E6 and E7 interfere with cell cycle control by inactivating the tumor suppressor proteins p53 and pRb, respectively. E6 promotes p53 degradation by recruiting the cellular E3 ubiquitin ligase E6-AP (UBE3A; facilitating ubiquitin-mediated proteasomal degradation), whereas E7 inactivates pRb primarily through direct binding (disrupting E2F, enabling constitutive cell cycle entry).^[8] This disruption leads to genomic instability and the abnormal proliferation of squamous and glandular cells. ^[6]
• Previously the association between HPV infection and glandular type of cervical neoplasia was considered not as strong as that of squamous carcinoma of the cervix. However, current evidence establishes high-risk HPV (particularly HPV 18) as the causative agent in the majority of endocervical adenocarcinomas.^[9]

1. ↑ International Agency for Research on Cancer. (2007). Human papillomaviruses (IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, Vol. 90). Lyon: IARC.
2. ↑ Siegel, R. L., Giaquinto, A. N., & Jemal, A. (2024). Cancer statistics, 2024. CA: A Cancer Journal for Clinicians, 74(1), 12–49. https://doi.org/10.3322/caac.21820
3. ↑ Kjaer, S. K., Chackerian, B., van den Brule, A. J. C., Svare, E. I., Paull, G., Walbomers, J. M. M., … Meijer, C. J. L. M. (2001). High-risk human papillomavirus is sexually transmitted: Evidence from a follow-up study of virgins starting sexual activity (intercourse). Cancer Epidemiology, Biomarkers & Prevention, 10(2), 101–106.
4. ↑ Doorbar, J. (2006). Molecular biology of human papillomavirus infection and cervical cancer. Clinical Science, 110(5), 525–541. https://doi.org/10.1042/CS20050369
5. ↑ Bernard, H.‑U., Burk, R. D., Chen, Z., van Doorslaer, K., Zur Hausen, H., & de Villiers, E.‑M. (2010). Classification of papillomaviruses (PVs) based on 189 PV types and proposal of taxonomic amendments. Virology, 401(1), 70–79. https://doi.org/10.1016/j.virol.2010.02.002
6. ↑ ^{6.0 6.1} Burd EM (January 2003). “Human papillomavirus and cervical cancer”. Clin. Microbiol. Rev. 16 (1): 1–17. PMID 12525422.
7. ↑ Muñoz, N., Bosch, F. X., de Sanjosé, S., Herrero, R., Castellsagué, X., Shah, K. V., … Meijer, C. J. L. M. (2003). Epidemiologic classification of human papillomavirus types associated with cervical cancer. New England Journal of Medicine, 348(6), 518–527. https://doi.org/10.1056/NEJMoa021641
8. ↑ Huibregtse, J. M., Scheffner, M., & Howley, P. M. (1993). Cloning and expression of the cDNA for E6-AP, a protein that mediates the interaction of the human papillomavirus E6 oncoprotein with p53. Molecular and Cellular Biology, 13(2), 775–784. https://doi.org/10.1128/mcb.13.2.775
9. ↑ Andersson, S., Rylander, E., Larsson, B., Strand, A., Silfverswärd, C., & Wilander, E. (2001). The role of human papillomavirus in cervical adenocarcinoma carcinogenesis. European Journal of Cancer, 37(2), 246–250. https://doi.org/10.1016/S0959-8049(00)00376-6

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Nima Nasiri, M.D.[2]

Cervical cancer must be differentiated from other diseases that cause abnormal vaginal bleeding, such as cervical polyp, cervical leiomyoma, invasion of the cervix from primary uterine malignancy, vaginal cancer, cervical lymphoma, metastases to cervix, and cervical ectopic pregnancy.

• Cervical cancer must be differentiated from a mass involving the cervix, and causing abnormal vaginal bleeding:^[1][2][3]

• Cervical polyp
• Cervical leiomyoma
• Cervical lymphoma
• Cervical sarcoma
• Metastases to the cervix
• Cervical ectopic pregnancy
• Cervicitis
• Cervical erosion ( Ectropion )
• IUD use
• Pelvic inflammatory disease
• Endometriosis
• Adenomyosis
• Nabothian cyst

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Nima Nasiri, M.D.[2]

According to the Centers for disease control and prevention (CDC) , cancer is the second leading cause of death in the United States after heart disease. One of every four deaths in the United States is due to cancer. Cervical cancer once was one of leading cause of mortality and cancer related death in women worldwide and in US, over the past 50 years, regular Pap smear screening caused significant drop in incidence and mortality rate of cervical cancer. Cervical neoplasia still is very common in developing countries, studies shown there is an association between age and socoeconomic status of women and incidence of infection with human papilloma virus.

• According to Centers for disease control and prevention (CDC) , cancer is the second leading cause of death in the United States after heart disease. One of every four deaths in the United States is due to cancer. ^[1]
• Cervical cancer once was one of leading cause of mortality and cancer related death in women worldwide and in US, over the past 50 years, regular Pap smear screening caused significant drop in incidence and mortality rate of cervical cancer. In terms of frequency, it is ranked 14th now in the US but still is very common in least developed countries. ^[2]
• In the United States, cervical cancer is more common among Hispanics, African-Americans, Asians and pascific islanders, and followed by whites. Native Alaskans and Indians have the lowest rate. Age of diagnosis is usually above 30 years old, in their midlife. Number of new cases of cervical cancer was 7.4 per 100,000 women per year and number of deaths was 2.3 per 100,000 women per year based on statistical datas collected on 2015. ^[3]
• According to the American Cancer Society, estimates for cervical cancer in the United States for 2018 are: About 13,240 new cases of invasive cervical cancer will be diagnosed and about 4,170 women will die from cervical cancer. Based on recent CDC datas, States with highest rates of cervical cancers are Arkansas(10.4%), Louisiana(9.8%), Alabama(9.4%), Kentucky(9.4%), Texas(9.1%), Mississippi(9.1%), Kansas(9.0%), D.C(8.9%), Florida(8.7%), Nevada(8.7%).^[3]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Nima Nasiri, M.D.[2]

The most common risk factor in development of cervical cancer is Human papillomavirus (HPV) infection. Other risk factors include smoking, increased number of sexual partners, and young age at time of first sexual intercourse, immunodeficiency, high parity.

Common risk factors associated with cervical cancer include:^[1][2]

• Infection with high-risk HPV, mainly subtypes 16 and 18.
• Multiple sexual partners or a male partner with multiple previous or current sexual partners
• Young age at first intercourse
• Smoking
• High parity
• Immunosuppression
• HLA subtypes
• Use of oral contraceptives

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Assistant Editor-in-Chief: Nima Nasiri, M.D.[2]Monalisa Dmello, M.B,B.S., M.D. [3]

According to the American Cancer Society (ACS) (the American Society for Colposcopy and Cervical Pathology (ASCCP), and American Society for Clinical Pathology participated in the 2021 update^[1] but did not participate in this update):

“individuals with a cervix initiate cervical cancer screening at age 25 years and undergo primary human papillomavirus (HPV) testing every 5 years through age 65 years (preferred); if primary HPV testing is not available, then individuals aged 25 to 65 years should be screened with cotesting (HPV testing in combination with cytology) every 5 years or cytology alone every 3 years (acceptable) (strong recommendation)..”^[2]

Importantly, self-sampling HPV testing is not yet approved by the FDA although this is a priority of the “Last Mile” initiative of the National Cancer Institute^[3]

The Pap test screening detects and prevents the progression of HPV-induced cervical cancer and other abnormalities in the female genital tract by sampling cells from the outer opening of the cervix of the uterus and the endocervix. It is generally recommended that sexually active females seek pap smear testing annually, although guidelines may vary from country to country. ^{[4][5][6][7][8][9]}

HPV = human papillomavirus; CIN = cervical intraepithelial neoplasia; AIS=adenocarcinoma in situ; hrHPV = high-risk HPV.

Colposcopy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Nima Nasiri, M.D.[2]

Cervical cancer is one of the leading causes of cancer-related morbidity and mortality among women in low- and middle-income countries (LMICs), and remains the most frequent cancer in specific high-burden regions, such as sub-Saharan Africa. There is an estimate of almost 260,000 deaths annually (2001), about 80% of which occurred in developing countries. Common complications of cervical cancer include pain, vaginal bleeding, fistula and renal failure. Prognosis is generally good, and the 5-year survival rate of patients with cervical cancer is approximately 70%. Studies have demonstrated that there is an association between age of the patients and socioeconomic status of women with higher incidence of infection with high risk HPV in underserved population in the US.

• Cervical cancer is one of the leading causes of cancer-related morbidity and mortality among women in low- and middle-income countries (LMICs), and remains the most frequent cancer in specific high-burden regions, such as sub-Saharan Africa. There is an estimate of almost 260,000 deaths annually, about 80% of which occurred in developing countries.^[1]
• Infection by high risk strain of oncogenic HPV types is an established cause of neoplastic lesions of the cervix, vagina and vulva, anus, penis and oropharynx. HPV genotypes 16 and 18 are responsible for approximately 70% of cervical cancer cases worldwide. HPV is highly transmissible through direct skin-to-skin contact and intercourse, women with persistent high-risk HPV infections are at greatest risk for developing cervical cancer.
• Since the identification of HPV as main cause of cervical cancer, prevention strategies have been developed by the introduction of HPV testing and cytology screening and utilizing HPV vaccines in preadolescent girls and young women who are at greater risk.^[2]
• The most important risk factors associated with the infection by HPV are young age at time of first sexual intercourse, increased number of sexual partners throughout life, or women being with men having multiple sexual partners. Male circumcision and use of condoms are factors that can reduce, but do not eliminate the transmission of human papilloma virus.^[3]
• There is an association between age and socioeconomic status of women in underserved areas of the US and higher incidence of infection with HPV. ^[4]

Advanced stage of cervical cancer can cause varieties of complications, some of which include:^[5]

• Pain
• Vaginal hemorrhage
• Enterovaginal, rectovaginal, and vesico- or ureterovaginal fistulas
• Renal failure and/or uremia
• Malnutrition
• Anemia
• Depression

• The prognosis for patients with cervical cancer can vary significantly by stage at diagnosis, with an aggregate 5-year relative survival rate of 67.9%. This progress is largely attributable to annual screenings with Pap smears and the introduction of new preventive methods such as the HPV vaccination to decrease the mortality and incidence rates.
• The majority of all cervical cancer cases can be detected early through the use of screening by Pap test and HPV DNA testing.

• Prognosis of cervical cancer depends upon the clinical stage of the disease and distant metastasis.^[6][7][8]

• These prognostic factors affecting survival rate include:^[9]

• Patient age
• Maximum tumor diameter of ≥6 cm
• Pelvic lymph node enlargement, and distant metastasis
• Pretreatment hemoglobin level
• Concurrent chemoradiotherapy, increases survival rate significantly in patients with advanced stage of cervical cancer in comparison with those receiving radiation therapy alone
• Overall treatment period
• Clinical stage

• Other prognostic factors include:^[10][11][12]

• Human immunodeficiency virus (HIV) status: Women with HIV have more aggressive and advanced disease and a poorer prognosis.
• C-myc overexpression: A study of patients with known invasive squamous carcinoma of the cervix found that overexpression of the C-myc oncogene was associated with a poorer prognosis.
• HPV-18 DNA has been found to be an independent adverse molecular prognostic factor, studies have demonstrated a worse outcome when HPV-18 was identified in cervical cancers of patients undergoing radical hysterectomy and pelvic lymphadenectomy.