Cervical cancer

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)
  • A test used to detect the DNA of high-risk HPV types
  • Performed after an abnormal Pap smear, typically using the same Pap smear sample showing abnormal cells
• 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
  • Primary HPV testing and co-testing every 5 years
  • Pap smear every 3 years
• 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 ^[1]
  • Cervical cancer is the 3^rd most common gynecological malignancy in the US after endometrial and ovarian cancer.
  • Incidence is higher in countries without screening programs and HPV vaccination.
  • Incidence has declined over the past 40 years due to screening and HPV vaccination.
• Peak incidence: 35–44 years of age ^[2][3]
• Mortality: 2.2:100,000 women per year ^[1]
  • Cervical cancer is the third most common cause of death due to a gynecological malignancy after endometrial and ovarian cancer.
  • Mortality is highest in individuals aged 55–64 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

• 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) ^[4]
• The major high-risk HPV types are HPV 16 (most common in squamous cell carcinoma) and HPV 18 (most common in adenocarcinoma)

Risk factors

• Associated with HPV infection
  • Multiple sexual partners (strongest risk factor)
  • Early-onset of sexual activity
  • Multiparity
  • Immunosuppression (e.g., HIV infection, post-transplantation)
  • History of sexually transmitted infections (e.g., herpes simplex, chlamydia)
• Environmental risk factors
  • Cigarette smoking and/or exposure to second-hand smoke (for squamous cell cancer types only)
  • In-utero exposure to diethylstilbestrol (DES)
  • Low socioeconomic status ^[5]

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

• Early symptoms
  • Abnormal vaginal bleeding: irregular vaginal bleeding, heavy, irregular menstrual bleeding, postcoital spotting
  • Abnormal vaginal discharge: blood-stained or purulent malodorous discharge (not necessarily accompanied by pruritus)
  • Dyspareunia
  • Pelvic pain
• Late symptoms: hydronephrosis, lymphedema, fistula formation
• Cervical examination: ulceration, induration, or an exophytic tumor

Always consider cervical cancer as a cause of postcoital bleeding.

Overview

• 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. ^[6]
  • 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”)
  • Surveillance
    • 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. ^[7]
  • 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.
    • Scraping of ectocervix
    • Scraping of endocervix
  • 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 ^[8]
  • History of hysterectomy for nonmalignant disease
  • History of endometrial cancer

HPV DNA testing ^[9][10]

• 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
  • Primary HPV test (done without concurrent Pap smear)
    • Preferred cervical cancer screening test
    • Only certain FDA-approved HPV tests can be used for primary HPV testing (i.e., Cobas HPV test, Onclarity HPV assay, APTIMA HPV assay, Hybrid Capture 2).
  • Co-test (with concurrent Pap smear)
    • Used when primary HPV tests are not available
    • The sample obtained for the Pap smear can also be used for DNA testing.
• 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 ^[11][12][13]

• 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]
  • 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.
• Findings
  • Cervical leukoplakia: a collection of atypical cells that form a white membrane on the cervix that cannot be scraped off
    • May indicate hyperkeratosis, parakeratosis, or CIN
    • Leukoplakia can arise at or near the transformation zone
    • Biopsy required for further evaluation
  • Acetowhite epithelium: an area of the cervical epithelium that appears white after the application of acetic acid ^[14]
    • Suggests atypical changes of the epithelium
    • Requires further evaluation with 2–4 targeted biopsies
  • Findings suspicious for invasive cervical cancer include:
    • Gross exophytic or endophytic neoplasm
    • Ulceration
    • Necrosis
    • Erosions
    • Atypical growth of the vessels (e.g., corkscrew or comma-like shape)
• 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

• 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.
• Types
  • Punch biopsy
    • A small piece of cervical tissue (diameter < 5 mm) is removed by a circular blade.
    • More than one punch biopsies (2–4 targeted biopsies) may be performed on different areas of the cervix. ^[15]
    • Indication: acetowhite area seen during colposcopy
  • Cone biopsy: See “Conization” below.
  • Endocervical curettage (ECC) ^[16][17]
    • The mucous membrane of the endocervical canal is scraped by a curette.
    • Indications
      • 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

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. ^[18]

• 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)
    • Nonneoplastic cellular variations (e.g., squamous metaplasia)
    • Reactive cellular changes (e.g., due to inflammation, radiation, IUDs)
  • Organisms (e.g., T. vaginalis, Candida spp.)
• 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)
    • Correlates with CIN I/HPV16-negative CIN II
    • May progress to HSIL
  • High-grade squamous intraepithelial lesion (HSIL)
    • Correlates with HPV16-positive CIN II/CIN III
    • May progress to squamous cell carcinoma
  • Squamous cell carcinoma (SCC)
  • Atypical glandular cells (AGC)
    • May progresses to carcinoma (endocervical adenocarcinoma in situ, adenocarcinoma)
    • Originate from the glandular epithelium of the endocervix or endometrium

Cervical biopsy report (CIN grading)

Cervical intraepithelial neoplasia (noninvasive disease) ^[19]

• Description
  • Precursor lesion characterized by epithelial dysplasia that begins at the basal layer of the squamocolumnar junction and extends outward
  • May progress to invasive carcinoma if left untreated
• Classification: classified as ClN I–III
  • CIN I: mild dysplasia, involves ∼ ⅓ of the basal epithelium
    • Epithelial architecture mostly intact
    • Loss of polarity and mitotic figures in the lower third of the epithelium
    • Koilocytes may be present
      • Epithelial cells with perinuclear halos
      • Pathognomonic for HPV infection
  • CIN II: moderate dysplasia, involves ⅓–⅔ of basal epithelium
    • Loss of epithelial architecture into as far as the middle third of the epithelium
    • Koilocytes may be present.
  • CIN III: severe, irreversible dysplasia or carcinoma in situ, involves > ⅔ of basal epithelium
    • Loss of organized epithelial architecture
    • Irregular nuclei and mitotic figures can be found throughout all epithelial layers.
    • The basement membrane is still intact.
    • Koilocytes may be present.

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).

• Description: characterized by invasion beyond the basement membrane of the cervical epithelium
• Classification
  • Squamous cell carcinoma: ∼ 80% of cases ^[20]
    • Subtypes include large cell keratinizing, large cell nonkeratinizing, and papillary squamous cell carcinoma.
    • Irregular cell morphology
    • Hyperchromatic cells with nonspherical nuclei, mitotic activity, and prominent nucleoli
    • Loss of basal membrane
  • Adenocarcinoma: ∼ 20% of cases ^[21]
    • 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). ^[22]
    • Atypical columnar epithelium with elongated nuclei
  • Small-cell carcinoma: ∼ 2% of cases ^[23][24]
    • Neuroendocrine tumor
    • Infiltration of monotonous round atypical cells, arranged in a nesting pattern
    • Nuclei with salt-and-pepper chromatin

Staging of invasive cervical cancer

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

• Workup
  • Laboratory studies
    • Complete blood count
    • Liver function tests
    • Kidney function tests
  • Tumor markers ^[25]
    • The value of tumor markers in monitoring cervical cancer has not yet been sufficiently studied; they should, therefore, not be used for screening purposes.
    • SCC antigen: squamous cell carcinoma
    • CEA, CA19-9, or CA-125: adenocarcinoma
• Evaluation of invasion
  • Pelvic examination: with a speculum, bimanual vaginal, and rectovaginal palpation
  • Cervical biopsy: obtained by colposcopy, curettage, or conization
  • Endoscopic procedures: cystoscopy, hysteroscopy, or rectoscopy (evaluate areas of possible infiltration by the tumor)
• Evaluation of metastasis
  • Common areas of metastasis
    • Lymph nodes (paraaortic or inguinal nodes)
    • Distant organs (e.g., lung, liver, bone, brain)
  • Imaging
    • Chest x-ray
    • Ultrasound
    • Thoracic/abdominal/pelvic CT
    • Cystoscopy
    • MRI: determine tumor size and extension
    • PET: determine lymph node dissemination
    • Intravenous pyelography (IVP): used for urinary tract imaging (if MRI or CT are not available)

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
    • 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)
      • If positive for HPV 16 or HPV 18 and reflex testing was not performed: Pap smear should be repeated at colposcopy
      • If positive for HPV 16 or HPV 18 and reflex testing from the same sample is not possible: colposcopy with biopsy
    • Negative primary HPV screening test result: resume the routine screening schedule.
  • Surveillance
    • HPV DNA testing or co-testing should be performed every 3 years, for at least 25 years, after treatment of HSIL, CIN II, CIN III, or AIS.
    • Pap smear alone is only acceptable if HPV DNA testing or co-testing is not possible.
• 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:
  • Expedited treatment
  • Colposcopy with biopsy
  • 12-month surveillance
  • 3-year surveillance
  • 5-year routine screening

Management according to abnormal screening results

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
  • Positive HPV testing after 6 months: colposcopy with biopsies
  • If positive excision margins for HSIL
    • Excisional treatment
    • If HSIL recurs: hysterectomy
• Long-term follow-up after HSIL, CIN II, CIN III, or AIS: HPV testing after 6 months
  • If positive for HSIL: yearly HPV primary test or co-test until three consecutive negative results
  • HPV testing or co-testing should be performed every 3 years for at least 25 years after treatment

Management according to previous guidelines ^[27][28]

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

• Age 21–24 years
  • If positive for ASC-US, LSIL, or HPV: repeat Pap smear at 12 months.
    • If results show < ASC-H/HSIL: repeat Pap smear at 12 months.
    • If results show ≥ ASC-H or higher or HPV infection: perform colposcopy.
    • If results are negative twice: resume routine screening.
  • If positive for ASC-H or HSIL: cytology at 12 and 24 months
    • If results show HSIL: perform diagnostic excision procedure (LEEP or conization)
    • If results show HPV infection or abnormal Pap smear other than HSIL: perform colposcopy
    • If negative: resume routine screening
• Age ≥ 25 years
  • After ASC-US, LSIL, or HPV positivity
    • Only follow-up with Pap smear is necessary
    • Co-testing at 12 months
      • If ≥ ASC or HPV positivity: perform colposcopy
      • If negative twice: resume routine screening
  • After ASC-H or HSIL: perform any of the following
    • Co-testing at 12 and 24 months
      • If negative: resume routine screening
      • If HPV-positive or abnormal cytology other than HSIL: perform colposcopy
      • If HSIL: perform diagnostic excision procedure (LEEP or conization)
    • Diagnostic excision procedure

CIN II/CIN III

• Treatment options
  • Excision
    • LEEP or conization
    • Preferred method
  • Ablation: cryotherapy or laser ablation
  • Young individuals who wish to bear children may opt for observation with Pap smear and colposcopy at 6 and 12 months.

Treatment of invasive cervical cancer ^{[29][30][31][32]}

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)

Pharmacological treatment

• Chemotherapy
  • Evidence on which chemotherapeutic regimen is the most effective remains a matter of debate. However, the current standard of treatment is cisplatin-based chemotherapy.
  • In the treatment of cervical cancer, chemotherapy is typically used concomitantly with radiotherapy.
• 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

Direct complications of invasive cervical cancer

• Local infiltration of organs
  • Infiltration and compression of ureter → urinary obstruction → hydronephrosis → kidney failure (bilateral obstruction is a potentially fatal complication)
  • Other organs often affected by the spread of cervical cancer include the rectum, bladder, and vagina.
• 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 ^[40]
  • Bone metastasis: bone pain, pathologic fractures, spinal compression, hypercalcemia
  • Liver metastasis: abdominal pain, abdominal distention, nausea, jaundice
  • Lung metastasis: cough, hemoptysis, dyspnea, chest pain
  • Brain metastasis: headaches, seizures, cognitive deficits, focal neurological deficits
• Cancer anorexia-cachexia syndrome (CACS) ^[41]

Complications of radiation therapy ^[42]

• Vaginal stenosis
• Postirradiation vaginitis (e.g., vaginal dryness, dyspareunia)
• Radiogenic cystitis/proctitis
• Radiation may increase the risk of cancer complications such as fistula formation ^[43]

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 ^[44]
  • 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 ^[45]

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 2^nd dose should be administered 6–12 months after the 1^st dose.
  • Administration of 3 doses of nine-valent HPV vaccine to all unvaccinated individuals between 15–26 years of age
    • The 2^nd dose should be given 1–2 months after the 1^st dose and the 3^rd dose 6 months after the first dose.
    • Also preferred regimen for vaccination of immunocompromised individuals (e.g., HIV) ^[46]
• FDA-approved vaccines ^[47]
  • 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. ^[45][48][49]

Secondary prevention

• 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)
• The ACS currently recommends the following screening for women: ^[50]
  • < 25 years: no screening required
  • 25–65 years
    • Preferred: primary HPV testing every 5 years
    • Alternative: co-testing (Pap smear with HPV test) every 5 years or Pap smear every 3 years
  • > 65 years: no more testing required if the previous testing was negative
    • Immunocompromised individuals (e.g., HIV) and those with DES exposure but average life-expectancy should continue screening.
    • Screening for women with HIV: Pap smear twice in the first year after HIV diagnosis and annually thereafter

Pregnancy

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.
  • Colposcopy: should be performed within the first and second trimesters of pregnancy
  • Cervical biopsy: depth of biopsy should be ideally < 1 cm ^[51]
• Staging
  • Chest x-ray with abdominal protection
  • Ultrasound (evaluation of the urinary tract)
  • MRI (evaluation of urinary tract, liver, and pelvis)

Avoid endocervical curettage in pregnant patients, as it increases the risk for preterm delivery, heavy bleeding, and trauma to the gestational sac. ^[52]

Treatment of cervical cancer in pregnant patients ^[51][53]

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.

1. National Cancer Institute - Annual report to the nation (rates are age-adjusted and based on 2013–2017 cases and 2014–2018 deaths). https://seer.cancer.gov/statfacts/html/cervix.html. . Accessed: October 8, 2020.
2. Key Statistics for Cervical Cancer. https://www.cancer.org/cancer/cervical-cancer/about/key-statistics.html. Updated: January 8, 2019. Accessed: September 24, 2019.
3. Gao Y, Ma J, Gao F, Song L. The evaluation of older patients with cervical cancer. Clin Interv Aging. 2013 : p.783. doi: 10.2147/cia.s45613 . | Open in Read by QxMD
4. Human papillomavirus (HPV) and cervical cancer. https://www.who.int/news-room/fact-sheets/detail/human-papillomavirus-(hpv)-and-cervical-cancer#:~:text=Cervical%20cancer%20is%20caused%20by,and%20pre%2Dcancerous%20cervical%20lesions.. Updated: November 11, 2020. Accessed: November 12, 2020.
5. Tomi Akinyemiju, Kemi Ogunsina, Swati Sakhuja, Valentine Ogbhodo, and Dejana Braithwaite. Life-course socioeconomic status and breast and cervical cancer screening: analysis of the WHO's Study on Global Ageing and Adult Health (SAGE). BMJ Open. 2016 .
6. Cervical Cancer Treatment (PDQ®)–Patient Version. https://www.cancer.gov/types/cervical/patient/cervical-treatment-pdq. Updated: February 6, 2019. Accessed: November 4, 2019.
7. FIGO Cancer Committee Guidelines for Early Invasive Cervical Cancer Management.
8. World Health Organization. Comprehensive Cervical Cancer Control: A Guide to Essential Practice.. World Health Organization ; 2016
9. Bhatla N, Aoki D, Sharma DN, Sankaranarayanan R. Cancer of the cervix uteri. International Journal of Gynecology & Obstetrics. 2018; 143 : p.22-36. doi: 10.1002/ijgo.12611 . | Open in Read by QxMD
10. Mauricio Maza, Celina M. Schocken, Katherine L. Bergman, Thomas C. Randall, and Miriam L. Cremer. Cervical Precancer Treatment in Low- and Middle-Income Countries: A Technology Overview. Journal of Global Oncology. 2017 .
11. Danielle B. Cooper; Gary W. Menefee. Conization Of Cervix. StatPearls. 2019 .
12. Angela Cho, Sunwha Park, Soyun Park, Hye Sim Kang, Soon Sup Shim, Chul Min Park, and Sung Yob Kim. Hemoperitoneum: a complication of loop electrosurgical excision procedure. Obstetrics & Gynecology Science. 2019 .
13. Surgical Procedures: Radical Cervical Trachelectomy. https://www.oncolink.org/cancers/gynecologic/treatments/surgical-procedures-radical-cervical-trachelectomy. Updated: December 2, 2015. Accessed: November 5, 2019.
14. Surgery for Cervical Cancer. https://www.cancer.org/cancer/cervical-cancer/treating/surgery.html. Updated: November 16, 2016. Accessed: November 5, 2019.
15. Neerja Bhatla1, Daisuke Aoki, Daya Nand Sharma, Rengaswamy Sankaranarayanan4. Cancer of the cervix uteri. International Journal of Gynecology & Obstetrics. 2018 .
16. Cervical Cancer Treatment. https://www.cancer.gov/types/cervical/hp/cervical-treatment-pdq#link/_778. . Accessed: January 25, 2021.
17. Li H, Wu X, Cheng X. Advances in diagnosis and treatment of metastatic cervical cancer. J Gynecol Oncol. 2016; 27 (4): p.e43. doi: 10.3802/jgo.2016.27.e43 . | Open in Read by QxMD
18. WebMD. Cancer-related anorexia/cachexia an ongoing challenge despite an increasing range of drug choices. Drug Ther Perspect. 2001; 17 (22).
19. Radiation Therapy for Cervical Cancer. https://www.cancer.org/cancer/cervical-cancer/treating/radiation.html. Updated: December 5, 2016. Accessed: October 21, 2019.
20. Masaharu Hata,Izumi Koike, Etsuko Miyagi, Reiko Numazaki, Mikiko Asai-Sato, Hisashi Kaizu, Yuki Mukai, Shoko Takano, Eiko Ito, Madoka Sugiura, and Tomio Inoue. Radiation therapy for stage IVA uterine cervical cancer: treatment outcomes including prognostic factors and risk of vesicovaginal and rectovaginal fistulas. Oncotarget. 2017 .
21. Cervical Cancer - Survival rates. https://www.medicinenet.com/cervical_cancer/article.htm. Updated: October 17, 2019. Accessed: October 21, 2019.
22. Saslow D, Andrews KS, Manassaram‐Baptiste D, Smith RA, Fontham ETH. Human papillomavirus vaccination 2020 guideline update: American Cancer Society guideline adaptation. CA Cancer J Clin. 2020; 70 (4): p.274-280. doi: 10.3322/caac.21616 . | Open in Read by QxMD
23. HPV Vaccine Schedule and Dosing. https://www.cdc.gov/hpv/hcp/schedules-recommendations.html. Updated: August 15, 2019. Accessed: October 29, 2019.
24. Human Papillomavirus Vaccine. http://www.fda.gov/BiologicsBloodVaccines/Vaccines/ApprovedProducts/ucm172678.htm. Updated: September 12, 2016. Accessed: February 17, 2017.
25. FDA Approves Expanded Use of Gardasil 9 to Include Individuals 27 Through 45 Years Old. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/UCM622715.htm?utm_campaign=10052018. Updated: October 9, 2018. Accessed: February 1, 2019.
26. Meites E, Szilagyi PG, Chesson HW, Unger ER, Romero JR, Markowitz LE. Human Papillomavirus Vaccination for Adults: Updated Recommendations of the Advisory Committee on Immunization Practices. MMWR Morb Mortal Wkly Rep. 2019; 68 (32): p.698-702. doi: 10.15585/mmwr.mm6832a3 . | Open in Read by QxMD
27. Fontham ETH, Wolf AMD, Church TR, et al. Cervical cancer screening for individuals at average risk: 2020 guideline update from the American Cancer Society. CA Cancer J Clin. 2020; 70 (5): p.321-346. doi: 10.3322/caac.21628 . | Open in Read by QxMD
28. Nitish Beharee, Zhujun Shi, Dongchen Wu, and Jinhua Wang. Diagnosis and treatment of cervical cancer in pregnant women. Cancer Medicine. 2019 .
29. Jason Wright. Cervical cancer in pregnancy. Obstetrics and Gynecology. 2017 .
30. Beharee N, Shi Z, Wu D, Wang J. Diagnosis and treatment of cervical cancer in pregnant women. Cancer Medicine. 2019; 8 (12): p.5425-5430. doi: 10.1002/cam4.2435 . | Open in Read by QxMD
31. Perkins RB, Guido RS, Castle PE, et al. 2019 ASCCP Risk-Based Management Consensus Guidelines for Abnormal Cervical Cancer Screening Tests and Cancer Precursors. J Low Genit Tract Dis. 2020; 24 (2): p.102-131. doi: 10.1097/lgt.0000000000000525 . | Open in Read by QxMD
32. Updated Consensus Guidelines for Managing Abnormal Cervical Cancer -- Screening Tests and Cancer Precursors.
33. PDQ Adult Treatment Editorial Board. Cervical Cancer Treatment (PDQ®): Patient Version. PDQ Cancer information. 2002 .
34. NCCN clinical Practice Guidelines in Oncology: Cervical Cancer, Version 1.2016 . https://www.tri-kobe.org/nccn/guideline/gynecological/english/cervical.pdf. Updated: November 25, 2015. Accessed: January 17, 2017.
35. Kripke et al.. Pap Smear vs. HPV Screening Tests for Cervical Cancer. American Family Physician. 2008; 12 .
36. Cervical Cancer Screening Among Women by Hysterectomy Status and Among Women Aged ≥65 Years — United States, 2000–2010. https://www.cdc.gov/mmwr/preview/mmwrhtml/mm6151a3.htm?s_cid=mm6151a3_w. Updated: January 4, 2013. Accessed: March 9, 2021.
37. New recommendation for cervical cancer screening, using HPV test alone. https://medicalxpress.com/news/2015-01-cervical-cancer-screening-hpv.html. Updated: January 8, 2015. Accessed: October 18, 2019.
38. Wright TC. The New ASCCP Colposcopy Standards. J Low Genit Tract Dis. 2017; 21 (4): p.215. doi: 10.1097/lgt.0000000000000337 . | Open in Read by QxMD
39. THE CERVIX: Colposcopy of the Uterine Cervix. https://hscj.ufl.edu/obgyn/docs/colposcopy-course.pdf. . Accessed: October 12, 2020.
40. Colposcopy and treatment of cervical intraepithelial neoplasia. https://screening.iarc.fr/colpochap.php?lang=1&chap=5. . Accessed: January 27, 2021.
41. Marina OC. Effects of acetic acid on light scattering from cells. J Biomed Opt. 2012; 17 (8): p.085002. doi: 10.1117/1.jbo.17.8.085002 . | Open in Read by QxMD
42. Underwood M, Arbyn M, Parry-Smith W, De Bellis-Ayres S, Todd R, Redman CW, Moss EL.. Accuracy of colposcopy‐directed punch biopsies: a systematic review and meta‐analysis. BJOG: An International Journal of Obstetrics and Gynaecology. 2012 .
43. Tests for Cervical Cancer. https://www.cancer.org/cancer/cervical-cancer/detection-diagnosis-staging/how-diagnosed.html. Updated: November 16, 2016. Accessed: November 5, 2019.
44. Apgar BS, Kaufman AJ, Bettcher C, Parker-Featherstone E.. Gynecologic Procedures: Colposcopy, Treatment of Cervical Intraepithelial Neoplasia, and Endometrial Assessment. American Family Physician. 2013 .
45. Mello V, Sundstrom RK. Cervical Intraepithelial Neoplasia (CIN). StatPearls. 2020 .
46. Jun Gu, Chit Yaw Fu, Beng Koon Ng, Lin Bo Liu, Soo Kim Lim-Tan, and Caroline Guat Lay Lee. Enhancement of Early Cervical Cancer Diagnosis with Epithelial Layer Analysis of Fluorescence Lifetime Images. PLOS One. 2015 .
47. Cervix Carcinoma - Squamous Cell Carcinoma. http://www.pathologyoutlines.com/topic/cervixSCC.html. Updated: November 4, 2017. Accessed: February 21, 2018.
48. Zaino RJ. Glandular Lesions of the Uterine Cervix. Mod Pathol. 2000; 13 (3): p.261-274.
49. Subrata Pal, Sritanu Jana, and Kingshuk Bose. Clear cell carcinoma of cervix in a postmenopausal woman: A case report. Journal of Mid-life Health. 2015 .
50. Mario M Leitao, Jr, MD, Oliver Zivanovic, MD. Small cell neuroendocrine carcinoma of the cervix. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate. https://www.uptodate.com/contents/small-cell-neuroendocrine-carcinoma-of-the-cervix.Last updated: July 1, 2019. Accessed: October 15, 2019.
51. V P. Small Cell Neuroendocrine Carcinoma of the Cervix: A Rare Entity. JOURNAL OF CLINICAL AND DIAGNOSTIC RESEARCH. 2014 . doi: 10.7860/jcdr/2014/6811.4036 . | Open in Read by QxMD
52. Kaiser Jamil, Javeed Ahmad, Hajira Fatima and G. Suryanarayana Raju. Significance of CA 125 and CEA as Biomarkers in Assessing Progress of Treatment for Cervical Cancer. International Journal of Pharmaceutical Sciences and Research. 2014 .
53. Bhatla N, Berek JS, Cuello Fredes M, et al. Revised FIGO staging for carcinoma of the cervix uteri. International Journal of Gynecology & Obstetrics. 2019; 145 (1): p.129-135. doi: 10.1002/ijgo.12749 . | Open in Read by QxMD
54. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016.. AC Cancer J Clin. 2016; 66 (1): p.7-30. doi: 10.3322/caac.21332 . | Open in Read by QxMD
55. Cancer Facts & Figures 2017. https://onlinelibrary.wiley.com/doi/full/10.3322/caac.21387. Updated: January 5, 2017. Accessed: August 23, 2019.
56. Iversen L, Sivasubramaniam S, Lee AJ, Fielding S, Hannaford PC. Lifetime cancer risk and combined oral contraceptives: the Royal College of General Practitioners' Oral Contraception Study.. American Journal of Obstetrics and Gynecology. 2017 .
57. Mangal Mahajan, Rajesh Kuber, KR Chaudhari, Prashant Chaudhari, Pravin Ghadage, Rushikesh Naik. MR imaging of carcinoma cervix. Indian Journal of Radiology and Imaging. 2013 .
58. Han Deng, Eric Hillpot, Sumona Mondal, Kamal K. Khurana & Craig D. Woodworth. HPV16-Immortalized Cells from Human Transformation Zone and Endocervix are More Dysplastic than Ectocervical Cells in Organotypic Culture. Scientific Reports. 2018 .
59. Murat Öz, Nilüfer Çetinkaya, Elmas Korkmaz, Kerem Doğa Seçkin, Mehmet Mutlu Meydanlı, and Tayfun Güngör. Optimal cone size to predict positive surgical margins after cold knife conization (CKC) and the risk factors for residual disease. Journal Of The Turkish-German Gynecological Association. 2016 .
60. Vishuda Laengsri, Chotiros Plabplueng, Lertyot Treeratanapiboon. Cervical Cancer Markers: Epigenetics and microRNAs. Laboratory Medicine. 2018 .
61. Loop Electrosurgical Excision Procedure (LEEP) and Cold Knife Conization.
62. Atlas of Colposcopy: Principles and Practice.
63. Walter Prendiville, Rengaswamy Sankaranarayanan. Colposcopy and Treatment of Cervical Precancer. World Health Organization ; 2017
64. Noller KL, Wagner AL. Colposcopy. The Global Library of Women's Medicine. 2009 . doi: 10.3843/glowm.10019 . | Open in Read by QxMD
65. Wentzensen N, Massad LS, Mayeaux EJ, et al. Evidence-Based Consensus Recommendations for Colposcopy Practice for Cervical Cancer Prevention in the United States. J Low Genit Tract Dis. 2017; 21 (4): p.216-222. doi: 10.1097/lgt.0000000000000322 . | Open in Read by QxMD