• Clinical science

Cervical cancer (Cervical carcinoma)

Summary

Cervical cancer is the second most common type of cancer in women worldwide. 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
  • Loss of organized epithelial architecture
  • Irregular nuclei and mitotic figures can be found throughout all epithelial layers.
  • Basal membrane is still intact.
  • Koilocytes may be present.
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.

  • Squamous cell carcinoma (∼ 80% of cases)
    • Subtypes include (but are not limited to) large cell keratinizing, large cell nonkeratinizing, small cell, and papillary squamous cell carcinoma.
    • Histology: irregular cell morphology; hyperchromatic cells with nonspherical nuclei, mitotic activity, and prominent nucleoli; loss of basal membrane
  • Adenocarcinoma (∼ 20% of cases; increasing incidence)

References:[20][21]

Complications

References:[22][23]

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

Treatment

Treatment depends on whether disease is invasive or noninvasive.

Noninvasive disease

Cervical intraepithelial neoplasia Management Definitive treatment Follow-up
CIN I
  • Excisional (also provides diagnostic value; e.g., LEEP, laser, and cold-knife conization) or ablative (purely therapeutic) procedures (e.g., cryotherapy or laser ablation)
  • CIN I, II, or III WITH margins:
  • Pap smear after 12 months
  • And/or HPV
    test
  • CIN II or III WITH margins
  • Pap smear after 6 months
  • Repeat endocervical curettage is possible.
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

  • For microinvasive carcinoma
    • Cone biopsy; and follow-up
    • OR hysterectomy
  • For advanced disease: First-line treatment is chemotherapy, radiation therapy, or a combination of both in patients with advanced disease, lymph node metastases, or who are poor surgical candidates.
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
  • Indications:
  • Early-stage cervical cancer (stages IA1 to IB1)
  • Procedure
  • If patient cannot undergo surgery → primary radiation therapy
  • If patient has intermediate-risk features* → adjuvant radiation therapy
  • If patient has high-risk features* → adjuvant chemoradiation

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][24][25][14][26][27][28][29]

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:

  • HPV immunization preferably before first sexual intercourse.
    • Indications
      • Previous guidelines:
        • Women 9–26 years of age and men 9–21 years of age
        • Men who have sex with men: up to 26 years of age
      • Current guidelines: [30][31]
        • 2 doses should be administered 6 months apart to all individuals between the ages of 11 and 12 years
        • Immunization can be started as early as 9 years of age.
        • 3 doses of nine-valent HPV vaccine should be administered for all unvaccinated individuals between the ages of 27 and 45 years.
    • 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)
      • 9-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
  • Sexual abstinence

Secondary prevention

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

  • 21–29 years: Pap smear every 3 years
  • 30–65 years: Pap smear every 3 years OR Pap smear + HPV test every 5 years
  • > 65 years: no testing required if previous testing was negative

References:[32][33][34]

Special patient groups

Pregnancy

Avoid loop electrosurgical excision in pregnant patients!
References:[35]