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Cervical cancer

Last updated: April 18, 2021

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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.

One in 161 female individuals in the US (∼ 0.6%) will develop cervical cancer during their lifetime. [1]

Cervical intraepithelial neoplasia (CIN), a precursor of cervical cancer, typically occurs in young adults (25–35 years).

Epidemiological data refers to the US, unless otherwise specified.

Human papillomavirus virus (HPV) infection

Risk factors

Patients are usually asymptomatic in the early stages and develop symptoms later in the course of the disease.

Always consider cervical cancer as a cause of postcoital bleeding.

Cervical cancer screening tests consisting of Pap smear and/or HPV DNA testing are performed regularly to identify cancer precursors and early-stage cervical cancer. Further workup for cervical cancer may include expedited treatment and colposcopy with biopsy. (See “Management of abnormal cervical cancer screening tests and cancer precursors” below.)

Cervical cancer screening

  • The U.S. Preventative Services Task Force (USPSTF) guidelines were last updated in 2018 and differ from other associations' guidelines. For average-risk patients (asymptomatic, immunocompetent, and normal cervical cancer screening history), they include two screening strategies depending on age:
    1. Pap smear for 21–29 years of age every 3 years
    2. Pap smear with HPV DNA testing for 30–65 years of age every 5 years
  • New screening guidelines were introduced by the American Society of Colposcopy and Cervical Pathology (ASCCP), American Cancer Society (ACS), and the American College of Obstetricians and Gynecologists (ACOG) in 2020. For average-risk patients, they include three screening strategies: [6]
  • Routine screening intervals for asymptomatic individuals who do not require surveillance:
Overview of cervical cancer screening guidelines [6][7][8][9]
USPTF ASCCP/ACS/ACOG
Pap smear 21–29 years of age every 3 years 25–65 years of age every 3 years
Pap smear with high-risk HPV testing (co-testing) 30–65 years of age every 5 years 25–65 years of age every 5 years
Primary HPV testing Does not apply 25–65 years of age every 5 years (preferred)
  • If > 65 years: no more testing required if the previous testing was negative
  • If high-risk (immunocompromised, HIV, or DES exposure) but average life-expectancy: continue screening
  • HIV diagnosis: pap smear twice in the first year after HIV diagnosis and annually thereafter
  • Cervical cancer surveillance: Follow-up testing performed at a shorter interval than for routine screening either using HPV primary testing or co-testing.
    • Indicated for individuals with abnormal results:
    • Frequency of retesting depends on the individual's screening results and calculated risk for developing cervical cancer: 12 months< 5 years
  • For patients with invasive disease detected during screening, further workup is recommended for staging, including:
    • Pelvic examination
    • Pelvic, abdominal, and thoracic imaging

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. [10]
    • 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.
  • Indications: screening for cervical intraepithelial neoplasia and invasive cervical cancer in individuals 25–65 years of age
  • Screening interval
    • Perform every 3 years if done alone
    • Perform every 5 years as co-testing
  • Findings: Pap smear results the Bethesda system (see above)
  • Advantages: detects early cellular changes indicating a risk for the development of cervical cancer
  • Contraindications [11]

HPV DNA testing [12][13]

  • Description: a screening test for cervical cancer in which cells collected from the cervix are tested for infection with high-risk HPV types
    • The viral DNA or RNA is detected using PCR-based assays.
    • Assays can detect HPV through:
      • Direct genome detection
      • Amplification of HPV fragments
      • Amplification and genotyping of HPV 16 and HPV 18
  • Types
  • 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)
    • Pool detection of cancer-associated HPV subtypes (e.g., 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68)
    • Specific report of presence or absence of HPV subtypes (e.g., 16, 18)

Colposcopy [14][15][16]

  • Description: a procedure using a colposcope to examine the cervix, vagina, vulva, and anus for precancerous lesions or abnormalities
    • The procedure allows magnified visualization of the epithelium to guide biopsy sampling for histologic diagnosis.
    • In case of referral due to previous abnormal cytology and HPV results, testing can be repeated during this procedure.
  • Indications [6]
  • Findings
  • Possibility to defer colposcopy (according to new guidelines): patients with a low risk for CIN III, adenocarcinoma in situ, or cancer [6]
    • Patients with minor screening abnormalities (e.g., positive HPV, but not high-risk subtypes, low-grade cytologic abnormalities after a negative HPV test or co-test)
    • Patients who have their colposcopy deferred should return after 12 months for a repeat HPV test or co-test.
  • Advantages: identification and early treatment of precancerous or cancerous lesions
    • Allows for closer visualization of cervical lesions (the squamocolumnar junction and all lesions must be completely visualized)
    • Allows for identification of precancerous and cancerous lesions using acetic acid
    • Allows for biopsy or excision of suspicious lesions

Cervical biopsy

Classification of cervical pathology results

Overview of pathology results
Report description Bethesda system CIN grading
Squamous cells
Normal NILM Normal/benign
Squamous atypia ASC-US Squamous atypia/benign with inflammation
ASC-H
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
Glandular cells
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. [21]

Cervical biopsy report (CIN grading)

Cervical intraepithelial neoplasia (noninvasive disease) [22]

Invasive cervical cancer

Cervical carcinoma most commonly arises from metaplastic squamous cell epithelium in the transformation zone (see “Microscopic anatomy of the cervix” in “Female reproductive organs” for more information on the histology of the cervix).

Staging of invasive cervical cancer

Pretreatment staging is the most accurate way of determining the extent of the disease.

FIGO staging of cervical cancer [29]
FIGO staging Tumor location and spread

Frequency at presentation

0 (Tis)
  • < 1%
I
  • Tumor strictly confined to the cervix
  • IA: deepest invasion ≤ 5 mm
    • IA1: stromal invasion ≤ 3 mm
    • IA2: > 3 mm, deepest invasion ≤ 5 mm
  • IB: > 5 mm depth
    • IB1: visible lesion > 5 mm deep, ≤ 2 cm maximum diameter
    • IB2: visible lesion > 2 cm and ≤ 4 cm maximum diameter
    • IB3: > 4 cm maximum diameter
  • 47%
II
  • Tumor invades beyond the uterus, but not into the pelvic wall or lower third of the vagina
  • IIA: upper two-thirds of the vagina, no parametrial invasion
    • IIA1: visible lesion ≤ 4 cm in greatest dimension
    • IIA2: visible lesion > 4 cm in greatest dimension
  • IIB: with parametrial invasion
  • 28%
III
  • 21%
IV
  • Tumor extends beyond the true pelvis or (biopsy-proven) involvement of the vesical or rectal mucosa
  • IVA: tumor spread to adjacent organs
  • IVB: tumor spread to distant organs
  • 4%

Overview [6]

  • New management guidelines for the US have been introduced in 2019 by the American Society of Colposcopy and Cervical Pathology (ASCCP). [6]
    • 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.
      • Patients with a high risk of developing cervical cancer will need more frequent surveillance, colposcopy, and/or treatment.
      • Patients with a lower risk of developing cervical cancer can defer colposcopy and have longer surveillance interval follow-ups.
    • The primary goal of treatment is to prevent the development of invasive cancer through the excision of precancerous lesions (CIN III, AIS).
      • Treatment is generally recommended as soon as a precancerous lesion is identified, the risk for CIN III was used as the treatment threshold.
      • Observation is preferred for CIN I rather than treatment
      • Excisional treatment is the preferred option
    • Abnormal screening results: updated management for abnormal primary HPV screening
    • Surveillance
  • See “Management according to previous guidelines” below.

Management according to 2019 ASCCP risk guidelines [6]

  • 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 [6]
Classification Indications Management
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%
  • Patients with unknown screening history and one of the following
Immediate risk of CIN III or higher is < 4%
  • Surveillance frequency depends on the 5-year risk for developing CIN III, adenocarcinoma in situ, or invasive cervical cancer.
  • Risk ≥ 0.55%: surveillance screening in 12 months
  • Risk ≥ 0.15–0.54%: surveillance screening in 3 years
    • HPV-negative with ASC-US and unknown screening results
    • HPV-negative and unknown history
  • Risk < 0.15%: surveillance screening in 5 years

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
NILM
  • Routine screening
Specimen unsatisfactory for evaluation (no HPV/unknown result) or HPV-negative [6][13]

ASC-US

LSIL
  • CIN I or less preceded by ASC-H or HSIL
    • Colposcopy and HPV-based testing every 6 months for up to 2 years
      • If positive: colposcopy
      • If negative: HPV-based testing in 12 months
      • If negative twice: HPV-based testing in 3 years
    • If CIN II or higher is not found after ASC-H or HSIL: review of pathology and colposcopic findings
  • CIN I diagnosed consecutively for a minimum of 2 years
    • Colposcopy and HPV-based testing every 6 months for up to 2 years
    • Excisional treatment
ASC-H

HSIL

AGC

Follow-up of abnormal results

Management according to previous guidelines [30][31]

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.

CIN I

CIN II/CIN III

Treatment of invasive cervical cancer [32][33][34][35]

Treatment of invasive cervical carcinoma may involve surgery, chemotherapy, and/or radiation.

Surgical procedures

  • 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)
  • Patients with stage IA cervical cancer with negative tumor margins and without lymphovascular involvement [36][37]
  • Carcinoma in situ
  • As a therapeutic option for HSIL (CIN II/CIN III)
  • Suspicion of invasive cervical cancer
  • Inconsistency between cytological screening test and biopsy results
  • Large cervical lesion (covers > 75% of cervix)
  • Lesion extending into the endocervical canal
  • If the entire lesion or squamocolumnar junction cannot be completely visualized on colposcopy
Expedited treatment
  • Treatment without previous colposcopic biopsy, typically performed with excision treatment (LEEP) for nonpregnant patients ≥ 25 years of age
Trachelectomy
  • Patients with stage IA2–IB cervical cancer who wish to conceive
  • After a prior supracervical hysterectomy
Pelvic exenteration [40]
  • Palliative alternative for patients with stage IVA cervical cancer, although the prognosis is poor
  • Persistent or recurrent cervical cancer limited to the pelvis
Hysterectomy
  • Surgical removal of the uterus
  • Types of hysterectomy (see table below)
    • Subtotal (supracervical excision)
    • Total/simple (excision of uterus and cervix)
    • Radical (en bloc excision with parametrium and upper vagina)
  • Patients with stage IA1– IIA cervical cancer
  • Hemorrhage
  • Bladder and intestinal damage
  • Infection
Types of hysterectomy [41]
Simple extrafascial hysterectomy Modified radical hysterectomy Radical hysterectomy
Removed structures
Vaginal margin
  • None
  • 1–2 cm
  • Upper ¼–⅓
Mobilized structures
Separated structures

Pharmacological treatment

  • Chemotherapy
  • Radiotherapy
    • 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
    • Indications
      • 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
    • Administration of chemotherapy and radiotherapy in one session
    • Indications: standard treatment for locally advanced-stage cancer (stages IB3, II, III, IVA)
      • Preferred treatment option in stages IB3 and IIA2
      • Stage IVA or recurrence

Overview of treatment according to FIGO staging system

Treatment of invasive cervical cancer according to FIGO staging system [35][42]
FIGO stage Surgery Radiation/Chemotherapy
0
  • Primary radiotherapy in patients for whom surgery is not an option (e.g., severe cardiac, pulmonary, or renal disease)
IA1
IA2
IB–IIA
  • Modified radical hysterectomy with bilateral pelvic lymphadenectomy
    OR
  • Radical trachelectomy with bilateral pelvic lymphadenectomy in patients who wish to conceive
IIB–III
IVA
IVB

Direct complications of invasive cervical cancer

Complications of radiation therapy [45]

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 [47]
    • 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 [48][49][50]

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
      • The 2nd dose should be given 1–2 months after the 1st dose and the 3rd dose 6 months after the first dose.
      • Also preferred regimen for vaccination of immunocompromised individuals (e.g., HIV) [51]
  • FDA-approved vaccines [52]
    • 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, ACOG, and ASCCP have approved a supplemental application of the nine-valent vaccine for all individuals between 27–45 years of age. [48][53][54]

Pregnancy

Diagnosis of cervical cancer in pregnant patients

Avoid endocervical curettage in pregnant patients, as it increases the risk for preterm delivery, heavy bleeding, and trauma to the gestational sac. [56]

Treatment of cervical cancer in pregnant patients [55][57]

Treatment depends on the patient's wish to conceive in the future and carry pregnancy to term, stage of pregnancy, and stage of cancer.

  • 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
  • Tumor diameter < 2 cm: postpone treatment until after delivery
Stage IA2–IB1
Stage IB2, IB3, or II
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