• Clinical science

Cervical cancer (Cervical carcinoma)

Abstract

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 females aged 9–26 and for males aged 9–21. 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

  • Incidence of gynecological malignancies in the United States
    1. Endometrial
    2. Ovarian
    3. Cervical
  • Mortality rate due to gynecological malignancies in the United States
    1. Ovarian
    2. Cervical
    3. Endometrial
  • Mean age at diagnosis: 48 years
  • Highest incidence and mortality rates in African-American and Hispanic women

References:[1]

Epidemiological data refers to the US, unless otherwise specified.

Etiology

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

References:[2][2][3][4]

Clinical features

Patients with either cervical intraepithelial neoplasia (CIN) or cervical carcinoma are usually asymptomatic in early stages. Symptoms commonly first appear in advanced disease(e.g., at FIGO III).

Always consider cervical cancer as a cause of postcoital bleeding!

References:[2]

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:
    • Scraping of ectocervix
    • Scraping of endocervix
  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

  • Colposcopy
    • If CIN II, III → proceed to treatment
    • If no CIN II, III → depends on age
      • Women > 25: HPV/cytology co-testing at 12 and 24 months
        • If negative → routine screening
        • If positive → colpocopy
        • Alternatively, diagnostic excisional procedure
      • Women 21–24: cytology and colposcopy every 6 months
        • If negative twice → routine screening
        • If HSIL persisting for 1 yearbiopsy or diagnostic excisional procedure
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
  • Colposcopy with endocervical biopsy
  • > 35 years OR abnormal bleeding is present: additional endometrial sampling
  • AGC-endometrial endometrial and endocervical sampling
High-grade squamous intraepithelial lesion

HSIL

  • 21–24 years: colposcopy, then:
    • If CIN II or CIN III absent
      • Colposcopy and cytology every 6 months for 2 years
        • If positive: biopsy
        • If negative twice: routine screening
    • If CIN II or CIN III present: See “Treatment” below.
  • > 24 years: colposcopy or loop electrosurgical excision

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

  • Indications: women > 30 years of age
  • Procedures
  • Prolonged screening interval: screening every 5 years with HPV co-test (Pap smear + HPV test) instead of every 3 years with Pap smear alone

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

Colposcopy

  • Allows for closer visualization of lesions and directed biopsies
  • Cervical leukoplakia: atypical cells that form a white membrane that cannot be scraped off
  • Abnormal staining of the squamocolumnar junction
    • Acetic acid solution: visualization of abnormal areas (abnormal cells appear white)
    • Schiller's solution or Lugol's solution: enables visualization of erosions and dysplasia
  • Abnormal lesions
    • Exophytic tumor growth; bleeding to touch
    • Atypical vessels with corkscrew, hairpin, or comma shape
    • Mosaic or net-like vascular pattern

Conization

Staging

  • Local spread
    • Pelvic examination with speculum; bimanual vaginal and rectovaginal palpation
    • Cervical biopsy obtained by colposcopy, curettage, or conization
    • Cystoscopy, hysteroscopy, or rectoscopy may be used to evaluate areas of possible infiltration by the tumor
  • Imaging studies
    • Imaging might not be useful for assessing local spread. However, if imaging is used, MRI is the best option.
    • Abdominal/pelvic CT prior to radical hysterectomy (stages IA2 to IB1)
    • PET/CT prior to chemoradiation therapy (stages IB2 to IVA)
    • MRI or CT for urinary tract imaging. Intravenous pyelography (IVP) may be used if MRI or CT are not available.

Lymph node metastases have no influence on the FIGO stage. However, they are associated with a poorer prognosis and treatment must be adjusted accordingly!

Tumor markers

Not to be used for screening purposes! Unfortunately, their value in monitoring cervical cancer has not yet been sufficiently studied.

  • SCC in squamous cell carcinoma
  • CEA or CA-125 in adenocarcinoma

References:[2][5][6][7][8][9][10][11][12][13][14][15][16]

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)
    • Subtypes include mucinous, endometrioid, clear cell, and serous adenocarcinoma. The most common is the endocervical mucinous subtype.
    • Histology: atypical columnar epithelium with elongated nuclei

References:[17]

Complications

  • Direct complications of cervical carcinoma
  • Complications of radiation therapy
    • Vaginal stenosis
    • Radiogenic cystitis/proctitis
    • Fistula formation

References:[18][19]

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
  • If 21–24 years of age
  • If > 24 years and preceded by ASC-US, LSIL, or HPV
    • No treatment necessary; only follow-up
    • Pap smear and HPV test at 12 months (or cytology if < 30)
      • If ASC or higher or HPV : colposcopy
      • If negative twice → routine screening
  • If > 24 years and preceded by HSIL
    • Pap smear and HPV test (or cytology if < 30) at 12 and 24 months.
      • If negative: routine screening
      • If HPV or abnormal cytology other than HSIL: colposcopy
  • If > 24 years and HSIL: diagnostic excision procedure
  • 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.

FIGO staging

Anatomic location Recommendations for therapy
Surgery Radiation / Chemotherapy
I IA Identified only by microscopy (and width < 7 mm) IA1 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
IA2

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
IB Clinical lesions confined to cervix or lesions greater than IA IB1

Clinical lesion of < 4 cm in size

IB2

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
II IIA Involvement of the upper two-thirds of the vagina, without parametrial invasion IIA1 Clinically visible lesion ≤ 4 cm
IIA2 Clinically visible lesion > 4 cm
IIB Parametrial invasion but not onto pelvic sidewall
III IIIA Involvement of lower third of vagina
IIIB Invasion of pelvic sidewall or hydronephrosis
IV

IVA

Spread to adjacent organs

IVB

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:[2][20][21][11][22][23][24][25]

Prognosis

  • Patients without lymph node involvement (N0) have a very good prognosis, regardless of their FIGO stage.
  • 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:[2]

Prevention

Primary prevention

Preventing primary infection with HPV:

  • HPV immunization preferably before first sexual intercourse.
    • Indications
      • Women: 9–26 years of age
      • Men: 9–21 years of age
      • Men who have sex with men: up to 26 years of age
    • 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:[26][27][28]

Special patient groups

Pregnancy

  • Cervical cytology should be obtained from women during pregnancy.
  • 1–3% of women suffering from cervical cancer are diagnosed during or shortly after their pregnancy.
  • Management should take the patient's wishes into consideration and depends on the stage of pregnancy and disease.

Avoid loop electrosurgical excision in pregnant patients!
References:[29]