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Cervical cancer

Last updated: July 7, 2020

Summary

Cervical cancer is the third most common type of cancer amongst US women. In the United States, its incidence and mortality is well below that of breast, lung, endometrial, colon, and ovarian cancer. The mortality and incidence of cervical cancer have significantly declined after the introduction of routine Papanicolaou (Pap) smear screening. Cervical cancers are most often squamous cell carcinomas that arise from infection with a high-risk human papillomavirus (HPV) serotype. Consequently, the risk factors for cervical cancer are the same as those for HPV (e.g., early onset of sexual activity, multiple sexual partners, history of STDs, and immunosuppression). Growth of cervical carcinoma is preceded by cervical intraepithelial neoplasia (CIN), which can be detected via Pap smear. In the US, Pap smears are recommended for women between the ages of 21 and 64 and are subsidized for uninsured patients. Another method of prevention is vaccination against HPV. Currently, the HPV vaccine is recommended for individuals aged 9–45. Primary (i.e., vaccination) and secondary (i.e., screening) prevention are particularly important given that most patients are asymptomatic during early stages. Advanced cervical cancer typically presents with vaginal bleeding, pelvic pain, and/or lower back pain. Colposcopy, which allows for a cervical biopsy to be obtained, is a valuable diagnostic procedure. Lesions consisting of a high-grade CIN may be excised using conization. The treatment of invasive cervical cancer includes a combination of surgery, radiation therapy, and/or chemotherapy, depending on the stage of disease.

Epidemiology

References:[1][2]

Epidemiological data refers to the US, unless otherwise specified.

Etiology

Almost all malignant lesions of the cervix are preceded by HPV infection.

References:[3][3][4][5]

Clinical features

Patients are usually asymptomatic in early stages. Symptoms commonly first appear in advanced disease.

Always consider cervical cancer as a cause of postcoital bleeding!

References:[3][6][7]

Diagnostics

Pap smear (cervical smear)

The proper technique is essential for obtaining highly specific test results.

  1. The specimen is collected using a spatula or brush:
  2. A thin layer is uniformly applied to a glass slide.
    • Immediate fixation using 95% ethyl alcohol (or spray fixative). Avoid air-drying!
    • Stain with Papanicolaou dye
  3. Interpretation of cytologic smear according to the Bethesda system

Bethesda system

The Bethesda system is used for classifying cytological results. Management guidelines exist for each determined subtype.

Classification of cervical lesions according to cytology results Abbreviation Follow-up
Specimen unsatisfactory for evaluation
  • < 30 years: Repeat after 2–4 months if HPV status is unknown
  • ≥ 30 years: Repeat after 2–4 months or perform colposcopy if HPV positive
Negative for intraepithelial lesion or malignancy Including non-neoplastic cellular changes, inflammation, or glandular cell status posthysterectomy
  • Continue routine screening
Negative for intraepithelial lesion or malignancy but positive for high-risk HPV type

Atypical squamous cells of undetermined significance

ASC-US
  • 21–24 years
    • Repeat cytology at 12 months
    • Alternatively, perform HPV test
      • If positive → repeat algorithm above
      • If negative → routine screening
  • > 24 years
    • Perform HPV test
      • Positive → colposcopy
      • Negative → repeat smear and HPV test in three years
    • Alternatively, repeat smear at 12 months
Atypical squamous cells (cannot exclude HSIL)

ASC-H
Low-grade squamous intraepithelial lesion

LSIL
  • 21–24 years
    • Repeat cytology at 12 months
    • Alternatively, test for high-risk HPV
      • If positive → repeat smear and HPV test in three years
      • If negative → routine screening
  • 25–29 years: colposcopy
  • ≥ 30 years
    • HPV status negative → repeat smear and HPV test in 12 months
      • If negative → repeat smear and HPV test in 3 years
      • If positive → colposcopy
    • HPV status positive or unknown → colposcopy
Atypical glandular cells AGC
High-grade squamous intraepithelial lesion

HSIL

Immediate conization of ASC-H and CIN-I lesions is no longer recommended!

Cervical intraepithelial neoplasia (CIN) classification

CIN, noninvasive disease, is a precursor of invasive cervical cancer. Evaluation of cervical cytology (via Pap smear or cervical biopsy) is used to classify CIN lesions.

Cervical intraepithelial neoplasia Histology Corresponding Bethesda classification
CIN I

LSIL
CIN II

p16-negative = LSIL

p16-positive = HSIL
CIN III HSIL

Cervical intraepithelial neoplasia (CIN) typically occurs in young adults (25–35 years)!

HPV testing

Pap smear testing and HPV testing (co-testing) are routine once patients reach the age of 30!

Colposcopy

Conization

References:[3][8][9][10][11][12][13][14][15][16][17][18][19]

Pathology

Cervical carcinoma most commonly arises from metaplastic squamous cell epithelium in the transformation zone.

References:[20][21]

Treatment

Treatment depends on whether disease is invasive or noninvasive.

Noninvasive disease

Cervical intraepithelial neoplasia Management Definitive treatment Follow-up
CIN I
CIN II
  • Treatment recommended
  • Young women who wish to bear children may opt for observation with cytology and colposcopy at 6 and 12 months.
  • During pregnancy, treatment is postponed until after delivery, unless invasive disease requires prompt excision.
CIN III

Invasive disease

Anatomic location Recommendations for therapy
Surgery Radiation / Chemotherapy
Identified only by microscopy (and width < 7 mm) Depth ≤ 3 mm
  • Indications: Patient does not have intermediate or high-risk features.*
  • Procedure
    • Clear margins → extrafascial hysterectomy or – if inoperable or patient wish → observation
    • If prior conization without clear margins → perform second conization, or extrafascial or modified radical hysterectomy
  • Conization or extrafascial hysterectomy

Depth > 3 mm and < 5 mm
  • Indications: early-stage cervical cancer (stages IA2 to IB1)
  • Procedure
  • Preoperative evaluation of lymph nodes by CT imaging studies → CT-guided biopsy or PET if nodes look suspicious
  • Modified radical hysterectomy with pelvic lymphadenectomy
  • There is no international consensus on when to abort surgery if frozen section analysis reveals lymph node metastases. Some experts might continue with dissection of lymph nodes, while others might discontinue the procedure in order to proceed with radiation.
  • Women with childbearing wish → conization or trachelectomy
  • Once treatment is completed → follow up with periodic Hx/PE and Pap smears
Clinical lesions confined to cervix or lesions greater than IA

Clinical lesion of < 4 cm in size

Clinical lesion of > 4 cm in size
  • Indications: patients with locally advanced cervical cancer (stages IB2 to IVA)
  • Procedure: if patient cannot undergo primary chemoradiation → modified radical hysterectomy
Involvement of the upper two-thirds of the vagina, without parametrial invasion Clinically visible lesion ≤ 4 cm
Clinically visible lesion > 4 cm
Parametrial invasion but not onto pelvic sidewall
Involvement of lower third of vagina
Invasion of pelvic sidewall or hydronephrosis
Spread to adjacent organs
Spread to distant organs
  • Indications: patients with local recurrent disease or isolated metastases in distant organ (stage IVB)
  • Procedure: surgical resection of the cancerous lesion
  • Indications:
  • Metastatic disease (stage IVB) or recurrent disease
  • Procedure
  • Primary chemotherapy (combination of two platinum-based agents + bevacizumab)
  • Patients with severe symptoms from advanced disease → palliative radiation
Legend

* Risk features are based on histology and have been shown to have an impact on prognosis. They are taken into account when choosing the appropriate therapy. They include:

References:[3][14][22][23][24][25][26][27]

Complications

References:[28][29]

We list the most important complications. The selection is not exhaustive.

Prognosis

  • Patients without lymph node involvement (N0) have a very good prognosis
  • Onset of disease at a young age is associated with a poorer prognosis
  • Death most often occurs secondary to bilateral ureteral obstruction (subsequent uremia).

References:[3]

Prevention

Primary prevention

Preventing primary infection with HPV with HPV immunization preferably before first sexual intercourse.

  • Indications
    • Previous guidelines
    • Current guidelines: [30][31]
      • Administration of 2 doses of nine-valent HPV vaccine to all individuals between 11–12 years of age
        • The 2nd dose should be administered 6–12 months after the 1st dose.
        • Immunization can be started as early as 9 years of age.
      • 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) [32]
  • FDA-approved vaccines
    • Bivalent vaccine (Cervarix®): protection against high-risk HPV types 16 and 18
    • Tetravalent vaccine (Gardasil®): protection against high-risk HPV types 16 and 18, as well as against low-risk types 6 and 11 (most common cause of genital warts)
    • Nine-valent vaccine (Gardasil®9): protection against high-risk HPV types 16, 18, 31, 33, 45, 52, and 58, as well as against low-risk types 6 and 11
  • Barrier protection (condoms) during sexual intercourse

Secondary prevention

Every woman aged 21–65 should undergo screening for cervical cancer.

The ACOG currently recommends the following screening for women with previously normal exams:

  • < 21 years: no screening required
  • 21–29 years: Pap smear every 3 years
  • 30–65 years: Pap smear every 3 years OR co-testing (Pap smear with HPV test) every 5 years
  • > 65 years: no more testing required if the previous testing was negative
    • Immunocompromised women (e.g., HIV) and women 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

References:[33][34][35]

Special patient groups

Pregnancy

Avoid loop electrosurgical excision in pregnant patients!
References:[36]

References

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