Cervical cancer overview

# Overview
Cervical cancer once was one of the leading cause of cancer-related death in the US and worldwide before the introduction of Pap smear and screening, now ranked 14th in terms of frequency in US. Cervical cancer is malignant cancer of cervix. It may present with vaginal bleeding but symptoms may be absent until cancer is in its 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. 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 prevents its normal activities which is 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 sexual intercourse at early age at the start of the first sexual relationships, having high 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 not preventing the transmission of human papilloma virus.Treatment of cervical neoplasia depends upon stage of cancer at the time of presentation, it is consisit of surgical procedure like hysterectomy, or/and radiation and chemotherapy.

# Historical Perspective
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.

# Classification
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.

# Pathophysiology
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: 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 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.

# Differential diagnosis
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.

# Epidemiology and Demographics
In terms of frequency, cervical cancer is ranked 14th now in the US but still is very common in the least developed countries.In The United State, cervical cancer is more common among Hispanics, African-Americans, Asians and Pacific Islanders, and followed by whites. Native Alaskans and Indians have the lowest rate. Age of diagnosis is usually above 30 years old, women in their midlife. Number of new cases of cervical cancer was 7.4 per 100,000 women per year and the number of deaths was 2.3 per 100,000 women per year based on statistical data collected in 2015.

# Risk Factors
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.

# Screening
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).

# Natural History, Complications and Prognosis
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%.

# Diagnosis

## Staging
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 cervicalconization.

## History and Symptoms
Physical examination of patients with late cervical cancer is usually remarkable for cervical mass, pallor, and pedal edema.Most women with cervical cancer are asymptomatic at the early stage of disease, those patients in advance stage of cancer may have symptoms like abnormal vaginal bleeding, vaginal discharge, abdominal and pelvic pain, urinary hesitancy.

## Chest Xray
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 and that usually happens in advances stage of cancer.

## CT
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.

## MRI
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.

## Ultrasound
Transvaginal color doppler ultrasound can be used in predicting response to chemotherapy in women with cervical cancer.
Doppler ultrasound can pedict 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.

## Other Diagnostic Studies
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, doctor uses a sharp tool to pinch off 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.

# Treatment

## Medical therapy
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.

## Surgery
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.

## Cervical cancer during pregnancy
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 is curative intent chemotherapy and radiation therapy.

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