Cervical cancer is the third most common type of gynecological cancer in the US after endometrial and ovarian cancer. The mortality and incidence of cervical cancer have significantly declined since the introduction of routine Papanicolaou-test screening (Pap smear) and human papillomavirus (HPV) vaccination. The most common histological type of cervical cancer is squamous cell carcinoma. In most cases, it arises from infection with high-risk HPV. Consequently, the risk factors for cervical cancer are, for the most part, identical to those for HPV (e.g., early onset of sexual activity, multiple sexual partners, history of STDs, and immunosuppression). Affected individuals are typically asymptomatic during early stages of the disease. Advanced cervical cancer typically manifests with vaginal bleeding, pelvic pain, and/or lower back pain. The development of cervical carcinoma is preceded by a premalignant epithelial dysplasia called “cervical intraepithelial neoplasia” (CIN), a type of premalignant epithelial dysplasia. The premalignant stages are screened with HPV tests (HPV DNA tests) and cytological investigation (Pap smear). Pap smears detect atypical squamous or glandular cells and, in some cases, also permit grading underlying intraepithelial lesions as low-grade (CIN I) or high-grade (CIN II/CIN III), based on the degree of atypia. Recommendations for colposcopy, treatment, and surveillance are based on a patient's risk of developing CIN III or higher. This risk is determined by current screening results and past medical history (including unknown history). High-grade intraepithelial lesions warrant colposcopy with cervical biopsy to determine the grade of CIN and diagnose invasive cervical cancer. Lesions consisting of a high-grade CIN may be excised using conization. The treatment of invasive cervical cancer involves a combination of surgery, radiation therapy, and/or chemotherapy, depending on the stage of the disease. Given that most patients are asymptomatic at early stages, primary (i.e., vaccination) and secondary (i.e., screening) prevention are particularly important. In the US, primary HPV testing is recommended for individuals between the ages of 25–65 years every 5 years. If this type of testing is not available, individuals should be screened with co-testing (HPV testing combined with a Pap smear) every 5 years or with a Pap smear every 3 years. Vaccination against HPV is currently approved for individuals aged 9–26 years.
- Pap smear (Papanicolaou test): a test used to assess for cellular abnormalities in a cervical sample using a microscope
- Primary HPV test: a test used to detect the DNA of high‐risk types of HPV using a cervical sample (only certain tests are approved by the US-FDA for primary HPV testing)
- Co-test: a test that combines a Pap smear test and an HPV DNA test from the same cervical sample
- Reflex HPV test (triage HPV test)
- Average-risk patients: refers to asymptomatic, immunocompetent, individuals with a normal cervical cancer screening history
- High-risk patients: individuals with HIV, immunosuppression, or exposure to diethylstilbestrol (DES)
- Screening test: cervical cancer screening tests (primary HPV test, Pap smear, or co-test) performed to identify individuals in the population who require a further workup for cervical cancer
- Routine screening
- Surveillance: a repeat test using primary HPV testing, Pap smear alone, or co-testing, performed at a shorter interval than the recommended routine screening interval
- Incidence: 7.4:100,000 
- Peak incidence: 35–44 years of age 
- Mortality: 2.2:100,000 women per year 
One in 161 female individuals in the US (∼ 0.6%) will develop cervical cancer during their lifetime. 
Epidemiological data refers to the US, unless otherwise specified.
Human papillomavirus virus (HPV) infection
- Infection with high-risk HPV types is the main cause of cervical cancer (DNA of HPV 16 and/or 18 is found in 70% of all patients with cervical carcinoma) 
- The major high-risk HPV types are HPV 16 (most common in squamous cell carcinoma) and HPV 18 (most common in adenocarcinoma)
- Associated with HPV infection
- Environmental risk factors
Patients are usually asymptomatic in the early stages and develop symptoms later in the course of the disease.
- Early symptoms
- Late symptoms: hydronephrosis, lymphedema, fistula formation
- Cervical examination: ulceration, induration, or an exophytic tumor
Always consider cervical cancer as a cause of postcoital bleeding.
Cervical cancer screening
- Cervical cancer screening tests are performed regularly to identify individuals who require further workup for cervical cancer (see “Secondary prevention” under “Prevention” below).
- There are three screening strategies: Pap smear alone, co-testing (Pap smear with HPV DNA testing), and primary HPV screening.
- Screening intervals depend on the type of test.
- New screening guidelines were introduced by the American Society of Colposcopy and Cervical Pathology (ASCCP) in 2019. 
- New guidelines apply to all individuals with a cervix, including individuals of the female sex, transgender men, and individuals who have had a supracervical hysterectomy.
- Age of initial screening has been raised to 25 years from the previous recommendation of 21 years of age.
- Preferred screening strategy: FDA-approved primary HPV tests every 5 years instead of Pap smear or co-testing.
- Routine screening intervals: apply to asymptomatic individuals who do not require surveillance (see “Screening interval” for Pap Smear” and “HPV DNA Testing”)
- A follow-up test, performed at a shorter interval than for routine screening either using HPV primary testing or co-testing.
- Done in individuals with prior abnormal results.
- The frequency of surveillance will depend on the individual's screening results and calculated risk for developing cervical cancer.
- Patients at risk of CIN III or higher but lower than the risk at which colposcopy is recommended (e.g., HPV-negative ASC-US)
- Retesting is done at intervals of 12 months to less than 5 years
- The recommendations of previous guidelines (Pap smear for average-risk patients starting at 21 years of age) still apply if the primary HPV tests, required for screening, are not available.
If FDA-approved primary HPV testing is not available:
- Age of initial screening is 21 years of age
- Screening is performed with Pap smear
- Screening performed with both Pap smear and HPV DNA (co-testing) can be used for individuals ≥ 30 years of age
- Patients with invasive disease detected during screening, further workup including pelvic examination and pelvic, abdominal, and thoracic imaging is done to determine the disease stage.
Cervical cancer screening tests
Papanicolaou test (Pap smear/cervical cytology)
- Description: a cytological screening test for cervical cancer in which a cell sample taken from the cervix is examined for cellular abnormalities that may be indicative of cervical cancer
Pap smear technique: A proper technique is essential for obtaining highly specific test results. 
- To obtain the specimen, use a sterile speculum to visualize the cervix
- Cleanse the cervix using a cotton pledget.
- Visualize the transformation zone and, if possible, the squamocolumnar junction.
- The specimen must be collected using a spatula or brush that is rotated by 360 degrees.
- A thin layer of the specimen is uniformly applied to the labeled glass slide.
- Immediate fixation
- Using 95% ethyl alcohol (or spray fixative) to avoid drying
- Hold the fixative spray 15–20 cm away from the slide and spray evenly.
- Stain using Papanicolaou dye.
- Immediate fixation
- Indications: screening for cervical intraepithelial neoplasia and invasive cervical cancer in individuals 25–65 years of age
- Perform every 3 years if done alone
- Perform every 5 years as co-testing
- Findings: Pap smear results the (see above)
- Advantages: detects early cellular changes indicating a risk for the development of cervical cancer
- Contraindications 
HPV DNA testing 
- Description: a screening test for cervical cancer in which cells collected from the cervix are tested for infection with high-risk HPV types
- Primary HPV test (done without concurrent Pap smear)
- Co-test (with concurrent Pap smear)
- Indications: screening for cervical intraepithelial neoplasia and invasive cervical cancer in individuals 25–65 years of age
- Screening interval: perform every 5 years with HPV primary test and co-test
- Findings (dependent on the primary HPV test used)
- Description: a procedure using a colposcope to examine the cervix, vagina, vulva, and anus for precancerous lesions or abnormalities
- Abnormal findings on gross cervical, vulvar, vaginal examination
- Abnormal results (past or current) of cervical screening test indicating a high risk for CIN III, adenocarcinoma in situ, or invasive cervical cancer
- ASC-H result in Pap smear
- Positive primary HPV tests for subtypes 16 or 18, if reflex HPV testing is not possible
- Two consecutive inconclusive cytology results in HPV-positive individuals > 25 years of age.
- Cervical leukoplakia: a collection of atypical cells that form a white membrane on the cervix that cannot be scraped off
- Acetowhite epithelium: an area of the cervical epithelium that appears white after the application of acetic acid 
- Findings suspicious for invasive cervical cancer include:
- Possibility to defer colposcopy (according to new guidelines): patients with a low risk for CIN III, adenocarcinoma in situ, or cancer 
- Advantages: identification and early treatment of precancerous or cancerous lesions
- Description: A cervical biopsy is usually done when abnormalities are found during a pelvic exam, Pap smear, and/or HPV test. It is often performed as part of a colposcopy.
- Punch biopsy
- Cone biopsy: See “Conization” below.
Endocervical curettage (ECC) 
- The mucous membrane of the endocervical canal is scraped by a curette.
- Nonpregnant patients in whom colposcopy is inconclusive
- Upper limit of the transformation zone cannot be visualized on colposcopy
- Positive screening test (primary HPV test, Pap smear, co-testing) without visible lesion on the ectocervix
- Visible HSIL or ASC-H
- Suspicion of glandular abnormalities on cytology (e.g., adenocarcinoma)
- Findings: See “Pathology” section below.
Classification of cervical pathology results
|Overview of pathology results|
|Report description||Bethesda system||CIN grading|
|Squamous atypia||ASC-US||Squamous atypia/benign with inflammation|
|Mild dysplasia||LSIL||CIN I (including HPV)|
|Moderate dysplasia||HSIL||CIN II|
|Severe dysplasia||CIN III|
|Carcinoma in situ|
|Invasive cancer||Squamous cell carcinoma (SCC)||Invasive cancer|
|Atypical glandular cells||AGC||CIN I/CIN II/CIN III|
Bethesda system for reporting cervical cytology report
The Bethesda system is a classification system used to report the results of cytological screening of cervical cancer. 
No epithelial cell abnormalities
Negative for intraepithelial lesion or malignancy (NILM): normal cytology
- The sample is adequate for evaluation
- Cells show no evidence of abnormalities
- Nonneoplastic findings (optional)
- Organisms (e.g., T. vaginalis, Candida spp.)
- Negative for intraepithelial lesion or malignancy (NILM): normal cytology
Epithelial cell abnormalities
- Atypical squamous cells of undetermined significance (ASC-US): cells feature abnormalities more marked than inflammatory or reactive, but do not qualify for LSIL
- Atypical squamous cells likely to contain HSIL cells (ASC-H): unequivocal classification not possible due to confounding factors
- Low-grade squamous intraepithelial lesion (LSIL)
- High-grade squamous intraepithelial lesion (HSIL)
- Squamous cell carcinoma (SCC)
- Atypical glandular cells (AGC)
Cervical intraepithelial neoplasia (noninvasive disease) 
Classification: classified as ClN I–III
- CIN I: mild dysplasia, involves ∼ ⅓ of the basal epithelium
- CIN II: moderate dysplasia, involves ⅓–⅔ of basal epithelium
- CIN III: severe, irreversible dysplasia or carcinoma in situ, involves > ⅔ of basal epithelium
Invasive cervical cancer
Cervical carcinoma most commonly arises from metaplastic squamous cell epithelium in the transformation zone (see “Microscopic anatomy of the cervix” in “” for more information on the histology of the cervix).
- Description: characterized by invasion beyond the basement membrane of the cervical epithelium
- Squamous cell carcinoma: ∼ 80% of cases 
Adenocarcinoma: ∼ 20% of cases 
- Subtypes include mucinous, endometrioid, clear-cell, and serous adenocarcinoma
- The most common is the endocervical mucinous subtype
- Clear-cell carcinoma of the cervix; (CCC) is a rare form of cervical cancer (∼ 4% of all cervical adenocarcinomas) that is frequently associated with exposure to diethylstilbestrol (DES). 
- Atypical columnar epithelium with elongated nuclei
- Small-cell carcinoma: ∼ 2% of cases 
Staging of invasive cervical cancer
Pretreatment staging is the most accurate way of determining the extent of the disease.
- Laboratory studies
- Tumor markers 
- Evaluation of invasion
Evaluation of metastasis
- Common areas of metastasis
|FIGO staging of cervical cancer |
|FIGO staging||Tumor location and spread|| |
Frequency at presentation
|0 (Tis)|| |
|III|| || |
Management of abnormal cervical cancer screening tests and cancer precursors
- New management guidelines for the US have been introduced in 2019 by the American Society of Colposcopy and Cervical Pathology (ASCCP). 
- Recommendations are based on HPV-based screening results and personal medical history (e.g., age, precancer treatment, immunosuppression, previous screening and biopsy results)
- Newly defined risk thresholds have been introduced to guide appropriate management.
- Recommendations for colposcopy, treatment, and surveillance are now based on a patient's immediate and 5-year risk of developing CIN III or higher-grade CIN (adenocarcinoma in situ or invasive cervical cancer) and not solely on screening results.
- The primary goal of treatment is to prevent the development of invasive cancer through the excision of precancerous lesions (CIN III, AIS).
- Abnormal screening results: updated management for abnormal primary HPV screening
- Positive primary HPV screening test result: should be followed up by a reflex HPV test from the same sample regardless of HPV genotype (to identify high-risk types of HPV)
- Negative primary HPV screening test result: resume the routine screening schedule.
- See “Management according to previous guidelines” below.
Management according to 2019 ASCCP risk guidelines 
- Management guidelines recommend different clinical actions depending on the patient's immediate risk of CIN III, AIS, or invasive cervical cancer based on current and past screening results:
|Management according to the immediate risk of CIN III or higher |
|Immediate risk of CIN III or higher is ≥ 60%|
|Immediate risk of CIN III or higher is 25–59%|
|Immediate risk of CIN III or higher is 4–24%|
|Immediate risk of CIN III or higher is < 4%|| |
Management according to abnormal screening results
|ASCCP management guidelines according to abnormal screening results|
|Results||Age of patient: < 25 years||Age of patient: ≥ 25 years|
|Specimen unsatisfactory for evaluation (no HPV/unknown result) or HPV-negative |
Follow-up of abnormal results
- Long-term follow-up after HPV-positive NILM, ASC-US, LSIL, or LSIL (CIN I) without high-grade abnormalities (HSIL, CIN II/III, AIS): HPV testing or co-testing according to risk estimation guidelines
- Short-term surveillance after HSIL treatment
- Long-term follow-up after HSIL, CIN II, CIN III, or AIS: HPV testing after 6 months
Management according to previous guidelines 
Previous guidelines were based on screening results (Pap smear or co-testing). The recommendations still apply if primary HPV testing required for screening according to the new guidelines is not available.
If positive Pap smear or co-testing results are positive, colposcopy and biopsy should be performed (punch biopsy or endocervical curettage).
- If the biopsy results are positive for CIN, manage according to the grade.
- In the case of an unsatisfactory cytology specimen, repeat the test in 2–4 months.
- In the case of inadequate colposcopy, manage according to the results of screening (e.g., cervical conization in HSIL).
- If the biopsy results are positive for cervical cancer, further workup including pelvic examination and pelvic, abdominal, and thoracic imaging is performed to determine the disease stage
- If the Pap smear or co-testing result is negative, resume the routine screening schedule.
Age 21–24 years
- If positive for ASC-US, LSIL, or HPV: repeat Pap smear at 12 months.
- If positive for ASC-H or HSIL: cytology at 12 and 24 months
Age ≥ 25 years
- After ASC-US, LSIL, or HPV positivity
- After ASC-H or HSIL: perform any of the following
Treatment of invasive cervical cancer 
- Indicated for early-stage cancer (FIGO stages IA1, IA2, IB1, IB2, IIA)
|Overview of surgical procedures|
|Type of procedure||Description||Indications||Complications|
|Diagnostic excision procedures (excisional therapy)||Cold-knife conization and loop electrosurgical excision procedure (LEEP)|| || |
|Trachelectomy|| || |
|Pelvic exenteration || |
|Hysterectomy|| || |
|Types of hysterectomy |
|Simple extrafascial hysterectomy||Modified radical hysterectomy||Radical hysterectomy|
|Vaginal margin|| || || |
|Mobilized structures|| |
- Can be used as primary therapy, in conjunction with chemotherapy, or as adjuvant therapy post cervical cancer surgery.
- Types of radiotherapy used: intracavitary and external beam therapy
- Early-stage disease (IA, IB1, IB2, IIA1) in patients for whom surgery is not an option
- In stages IB2 and IIA1: can be used as primary treatment
- Concurrent chemoradiation
Overview of treatment according to FIGO staging system
|Treatment of invasive cervical cancer according to FIGO staging system |
Direct complications of invasive cervical cancer
- Local infiltration of organs
- Fistula formation in locally advanced disease (e.g., rectovaginal, vesicovaginal, urethrovaginal fistula)
- Compression of veins or lymphatic vessels in the lesser pelvis → lymphedema of the lower extremities
- Metastasis 
- CACS) ( 
Complications of radiation therapy 
- Vaginal stenosis
- Postirradiation vaginitis (e.g., vaginal dryness, dyspareunia)
- Radiogenic cystitis/proctitis
- Radiation may increase the risk of cancer complications such as fistula formation 
We list the most important complications. The selection is not exhaustive.
- Cervical cancer has the best prognosis out of the three main gynecological cancers (ovarian, endometrial, and cervical cancer).
The survival rates decrease with increasing FIGO stage 
- Stage 0: > 93%
- Stage I: 93%
- Stage II: 63%
- Stage III: 35%
- Stage IV: 16%
- Patients without lymph node involvement have a very good prognosis, regardless of FIGO stage.
- Main cause of death: uremia, often occurs secondary to bilateral ureteral obstruction.
Primary prevention 
Principal measures: HPV immunization, preferably before first sexual intercourse, and barrier protection (condoms) during sexual intercourse.
Current vaccination guidelines
Administration of 2 doses of nine-valent HPV vaccine to all individuals (male and female) between 11–12 years of age
- Immunization can be started as early as 9 years of age.
- The 2nd dose should be administered 6–12 months after the 1st dose.
- Administration of 3 doses of nine-valent HPV vaccine to all unvaccinated individuals between 15–26 years of age
- Administration of 2 doses of nine-valent HPV vaccine to all individuals (male and female) between 11–12 years of age
FDA-approved vaccines 
- Bivalent vaccine: protection against high-risk HPV types 16 and 18
- Tetravalent vaccine: protection against low-risk types 6 and 11 (most common cause of genital warts) as well as high-risk HPV types 16 and 18
- Nine-valent vaccine: protection against low-risk types 6 and 11 as well as high-risk HPV types 16, 18, 31, 33, 45, 52, and 58
- The FDA has approved a supplemental application of the nine-valent vaccine for all individuals between 27–45 years of age. 
- Individuals with a cervix, including transgender and gender nonconforming individuals, aged 25–65 years should undergo screening for cervical cancer and management of precancerous lesions. (See “Cervical cancer screening” above)
currently recommends the following screening for women: 
- < 25 years: no screening required
- 25–65 years
- > 65 years: no more testing required if the previous testing was negative
Special patient groups
Diagnosis of cervical cancer in pregnant patients
- Screening: Pap smear or co-testing should be done in all pregnant individuals.
- Confirmation: Colposcopy and cervical biopsy are not contraindicated in pregnancy, but can be deferred until 6 weeks postpartum.
Treatment of cervical cancer in pregnant patients 
Treatment of cervical intraepithelial lesions during pregnancy
- LSIL/CIN I: can be postponed up to 6 weeks postpartum for review
HSIL/CIN II/CIN III
- Should be reviewed every 12 weeks after exclusion of invasive cervical cancer
- Treatment during pregnancy is not recommended
- Repeat Pap smear until 6 weeks postpartum
- Colposcopy is recommended after 4 weeks postpartum
Treatment of invasive cervical cancer
- Termination of pregnancy is generally recommended in early-stage cervical cancer or advanced cervical cancer unless the patient wishes to carry the child to term (see table below).
- Appropriate treatment should be initiated after delivery (6–8 weeks postpartum) in patients whose pregnancy was maintained.
|Treatment of cervical cancer in pregnant patients according to FIGO stage|
|FIGO stage||Early pregnancy (< 22–25 weeks of gestation)||Late pregnancy (≥ 22–25 weeks of gestation)|
|Stage IA1|| || |
|Stage IB2, IB3, or II|