Invasive cervical cancer

Cervical cancer is the third most common cancer of the female genital tract in the US, with a peak incidence in women between 35–44 years of age. Persistent infection with any high-risk HPV genotype is the most common cause of cervical cancer. Consequently, the main risk factors are those that increase the likelihood of contracting HPV infection (e.g., multiple sexual partners) and/or decrease the clearance of ongoing infection (e.g., immunosuppression). Early-stage cervical cancer is typically asymptomatic. Symptoms, such as abnormal vaginal bleeding, dyspareunia, and pelvic pain, usually manifest later in the disease course. Diagnostics for individuals with concerning symptoms include colposcopy with cervical biopsy. Once the diagnosis is confirmed, invasive cervical cancer should be staged (FIGO staging for cervical cancer is preferred) to determine the appropriate treatment and likely prognosis. Surgery (e.g., conization, trachelectomy, hysterectomy) may be appropriate for early-stage disease. Management options for advanced disease include concurrent chemoradiotherapy, systemic chemotherapy, and palliative radiotherapy. Management of pregnant individuals with invasive cervical cancer or precancerous lesions should be individualized. Patients with invasive cervical cancer should be closely followed up for recurrence after management. HPV immunization, counseling on safe sex practices, and screening for cervical cancer are the most effective prevention measures.

Cervical cancer screening and management of precursor lesions are detailed in a separate article.

• 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 ^[4][5][6]

• Infection with high-risk HPV genotypes is the main cause of cervical cancer.
• Nearly all squamous cell carcinoma of the cervix and approximately 90% of adenocarcinoma of the cervix are positive for HPV infection. ^[4][6]
• The major high-risk HPV types are HPV 16 and HPV 18. ^[6]

Risk factors ^[4]

• For contracting 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) ^[7]
  • In-utero exposure to diethylstilbestrol (DES)
  • Low socioeconomic status ^[8]

The most common risk factors for cervical cancer are those that increase the likelihood of HPV infection (e.g., multiple sexual partners) and/or decrease the clearance of ongoing infection (e.g., immunosuppression). ^[4]

Immunocompromised individuals, those who were exposed to DES in-utero, and those with a current or past history of a high-grade precancerous cervical lesion are considered to have a high risk of developing invasive cervical cancer. Screening modalities and intervals in these groups of individuals should account for the increased risk (see “Screening recommendations for individuals at high risk of cervical cancer”). ^[9][10][11]

Cervical cancer is usually asymptomatic in the early stages; symptoms typically develop 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
  • Dyspareunia
  • Pelvic pain
• Late symptoms: hydronephrosis, lymphedema, fistula formation
• Cervical examination: ulceration, induration, or an exophytic tumor (see “Overview of colposcopy findings”)

Always consider cervical cancer as a cause of postcoital bleeding.

Invasive cervical cancer is confirmed on colposcopy with biopsy and histological evaluation. Diagnosis of cervical cancer precursor lesions is detailed in “Cervical cancer screening”.

Colposcopy ^{[12][13] [14][15]}

Indications ^[12][13][14]

• Individuals with symptoms suggestive of cervical cancer
• Abnormal findings on pelvic examination
• Asymptomatic individuals with immediate risk of CIN3 ≥ 4% on cervical cancer screening who do not meet the threshold for or do not wish to undergo expedited treatment
• Certain results on cervical cancer screening (see “Exceptions to the risk-based approach”)

Findings

The cervical transformation zone or squamocolumnar junction is the most common site for squamous cell carcinoma and its precursors and should always be evaluated during colposcopy. Failure to do so may cause cervical cancer or precancerous lesions to be missed. ^[15]

Cervical punch biopsy ^{[11][12][13][14][16]}

• Indications and procedure ^[12][14]
  • Abnormal colposcopy findings: Obtain multiple (2–4) colposcopy-directed biopsies targeting all areas of cervical abnormalities (e.g., acetowhitening, metaplasia) and the squamocolumnar junction. ^[12][16]
  • Normal colposcopy findings in individuals at high risk of CIN3 who do meet the threshold for or do not wish to undergo expedited treatment: Consider random, nontargeted biopsies OR biopsy the squamocolumnar junction.
• Findings: See “Pathology” section. ^[6][17]

Nontargeted (random) biopsies are not recommended in individuals with normal findings on colposcopy who are at low risk for CIN (i.e., HPV negative and cytology less than HSIL). ^[12][14]

Expedited treatment (without a preceding biopsy) is recommended for asymptomatic women at high risk of CIN3 with normal findings on colposcopy. Observation is recommended for women with normal colposcopy findings who are at very low risk of CIN. ^[11][13]

• Invasive cervical carcinoma is characterized by invasion of the tumor beyond the basement membrane of the cervical epithelium.
• HSIL and invasive cervical carcinoma most commonly arise from metaplastic squamous cell epithelium in the cervical transformation zone (see “Microscopic anatomy of the cervix” in “Female reproductive organs” for more information on the histology of the cervix).

Squamous cell carcinoma (∼ 80% of cases) ^[18]

• 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
• Precursor lesion: CIN or SIL ^[19]

Adenocarcinoma (∼ 20% of cases) ^[20]

• Subtypes include mucinous, endometrioid, clear-cell, and serous adenocarcinoma
• The most common is the endocervical mucinous subtype
• Precursor lesion: endocervical adenocarcinoma in situ ^[19]

Clear-cell carcinoma of the cervix (CCC) ^[21]

• Rare form of cervical cancer (∼ 4% of all cervical adenocarcinomas)
• Frequently associated with exposure to diethylstilbestrol (DES).

Atypical columnar epithelium with elongated nuclei

• Small-cell carcinoma: ∼ 2% of cases ^[22][23]
  • Neuroendocrine tumor
  • Infiltration of monotonous round atypical cells, arranged in a nesting pattern
  • Nuclei with salt-and-pepper chromatin

Almost all squamous cell carcinomas and approx. 90% of adenocarcinomas of the cervix are positive for HPV. ^[6]

Cervical carcinoma and HSIL most commonly arise from metaplastic squamous cell epithelium in the cervical transformation zone. ^[6]

• Staging of invasive cervical cancer is based on the extent of the primary tumor and spread; routes of spread include: ^[5]
  • Direct extension into the vagina, uterus, parametrium, pelvic wall, and adjacent organs (e.g., bladder, rectum)
  • Lymphatic spread, first to the regional pelvic lymph nodes, and then to the paraaortic lymph nodes.
  • Hematogenous spread causing distant metastases (e.g., to lungs, liver, bone) occurs late in the course.
• The revised (2018) FIGO staging is preferred to determine the appropriate treatment of cervical cancer and the likely prognosis of the disease. ^[5][17][24]
• FIGO staging aligns closely with the American Joint Committee on Cancer (AJCC) tumor, node, metastasis (TNM) staging. ^[5][25]
• The TNM classification also includes a stage 0 (Tis) for carcinoma in situ (CIN III). ^[25]

Determination of stage ^[5][26][27]

Refer patients with confirmed invasive cervical cancer to a specialist (e.g., gynecologic oncologist, surgical oncologist) for staging. Staging is based on the following parameters. ^[5]

• Clinical examination: comprehensive physical exam, bimanual pelvic examination, colposcopy
• Cervical biopsy and lymph node biopsy findings
• Imaging ^{[5][24][28][29]}
  • Evaluation of primary tumor size and local extent: MRI pelvis without and with IV contrast (preferred)
  • Lymph node involvement: FDG-PET scan
  • Local extent: evaluation for hydronephrosis, cystoscopy, and sigmoidoscopy
  • Distant metastasis: chest imaging, FDG-PET scan

Assessment of the primary tumor and lymph node involvement on imaging and/or intraoperatively is not mandatory for cervical cancer staging. In resource-poor settings, staging can be based on clinical examination and diagnostic histopathology results. ^[26]

Histopathological assessment and imaging are adjuncts to clinical findings in assessing the pretreatment stage of invasive cervical cancer. Histopathological findings take precedence over imaging findings. ^[5][26]

FIGO staging of cervical cancer ^[5][26][27]

If there is any discrepancy in staging, the lower stage should be assigned. ^[26]

Management of invasive cervical cancer in nonpregnant individuals is described here. Management of cervical cancer precursors and management of invasive cervical cancer during pregnancy are detailed separately. ^[5]

Early disease (FIGO stages IA, IB1, IB2 IIA1)

• Surgery is preferred.
  • Conization (with or without pelvic lymphadenectomy) and radical trachelectomy are fertility-sparing options.
  • Hysterectomy (simple hysterectomy, modified radical hysterectomy, and radical hysterectomy) with bilateral pelvic lymphadenectomy is usually recommended for more advanced disease (stage ≥ IA2)
• If surgery is not feasible: Radiotherapy may be considered.

Locally advanced disease (FIGO stages IB3, IIA2, III, IVA)

• Concurrent chemoradiotherapy (CCRT) using platinum-based agents is preferred.
• Pelvic exenteration may be considered in select patients with stage IVA cervical cancer that has not extended to the pelvic side wall.

Distant metastases (FIGO Stage IVB)

• CCRT may be considered depending on the likely prognosis.
• Palliative radiotherapy and/or systemic chemotherapy can be considered for symptom control.

Prior to surgery, patients who opt for fertility-preserving options should be counseled on potential postoperative obstetric complications and be referred to a fertility specialist to discuss future reproductive plans. ^[5][30]

Consider hormone replacement therapy for patients < 50 years of age who have lost ovarian function. ^[5]

Follow-up ^[5]

• General principles
  • A thorough clinical examination and history should be taken at each follow-up visit.
  • Imaging is not routinely indicated.
• After treatment for invasive cervical cancer: Follow-up is recommended at the following intervals.
  • Every 3–4 months for 2–3 years
  • Followed by every 6 months for 3–5 years
  • Then annually for life
• After fertility-sparing surgery for microinvasive cancer: Resume routine age-appropriate screening for cervical cancer if follow-up testing is negative for 5 consecutive years.

Conization (cervical excisional procedure) ^[31]

A fertility-preserving diagnostic and therapeutic procedure in which a cone-shaped portion of the cervix including the ectocervix, endocervix, and cervical transformation zone are excised

• Indications ^[5][11]
  • Treatment of high-grade cervical abnormalities on screening
  • Treatment of early-stage cervical cancer
• Important contraindications include pregnancy and severe cervicitis ^[11]
• Methods
  • Cold-knife conization
    • A scalpel is used to remove a cone-shaped portion of cervical tissue.
    • Typically requires general or regional anesthesia
  • Loop electrosurgical excision procedure (LEEP)
    • A thin electric wire loop is used to remove abnormal cervical tissue.
    • Can be performed under local anesthesia as an office procedure
  • Laser conization
• Common complications: bleeding, infection, obstetric complications (preterm delivery) ^[31]

LEEP is usually the preferred method of conization. ^[11]

Radical trachelectomy ^[30]

A surgical procedure that includes removal of the cervix, upper vagina, and parametrium with or without bilateral pelvic lymphadenectomy; followed by anastomosis of the uterus and vagina. ^[5][30]

• Indication: fertility-sparing procedure for early-stage cervical cancer ^[5][11][30]
• Complications include: ^[30]
  • Anastomosis-related (e.g., dyspareunia, internal cervical stenosis, secondary endometriosis)
  • Obstetric complications: cervical insufficiency, chorioamnionitis, PPROM, preterm delivery

Hysterectomy ^[5]

• Types
  • Simple hysterectomy: removal of the uterus and cervix; vagina and parametrium are preserved
  • Modified radical hysterectomy: en bloc removal of the uterus, cervix, upper ¼ of the vagina, and the parametrium
  • Radical hysterectomy: en bloc removal of uterus, cervix, upper ⅓ to upper ½ of the vagina, the parametrium , and, if needed, resection of involved aspects of the adjacent organs
• Indication (for cervical cancer): early-stage disease
• Approach: laparotomy, laparoscopy, or robotic surgery through a transabdominal or transvaginal approach
• Complications include: bleeding, infections, and injury to surrounding organs (e.g., ureter, bladder, pelvic nerves) ^[32]

Pelvic exenteration (gynecology)^[33]

A radical procedure that involves an en bloc resection of the uterus, ovaries, fallopian tubes, vagina, the lower urinary tract, rectosigmoid, and pelvic lymph nodes. Associated with high morbidity.

• Indication: a potentially curative option for locally advanced cervical cancer
• Complications include: ^[33]
  • Hemorrhage
  • Infection
  • Intestinal obstruction
  • Intestinal and urinary fistulas

Management of invasive cervical cancer during pregnancy ^[5]

• Treatment should be individualized and carried out by a multidisciplinary team (e.g., gynecologic oncologist, maternal-fetal specialist).
• Treatment options are the same as those for nonpregnant individuals (see “Treatment of cervical cancer” for details).
• The timing of treatment depends on the cancer stage, gestational age, and the patient's wish to maintain the current pregnancy.

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 ^[34]
  • 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) ^[35]

Complications of radiation therapy ^[36]

• Vaginal stenosis
• Postirradiation vaginitis (e.g., vaginal dryness, dyspareunia)
• Radiogenic cystitis/proctitis
• Radiation may increase the risk of complications like fistula formation. ^[37]

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 ^[38]
  • 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 ^[7][39][40]
  • HPV immunization (see “ACIP immunization schedule” for details)
  • Use of barrier protection (condoms) during sexual intercourse
• Secondary prevention: adherence to cervical cancer screening recommendations