Approach

Early stage disease is frequently asymptomatic. Pre-invasive lesions are often detected only after a cervical cancer screening. Screening involves one or both of:[80][81][82]

  • Cervical cytology testing (Pap smear or liquid-based cytology) to identify precancerous lesions or cancerous cells on the cervix

  • Human papillomavirus (HPV) testing to identify the presence of high-risk subtypes of HPV.

HPV testing, either alone or in combination with cytology testing, appears to be more sensitive than and superior to cytology alone.[31][83][84] However, HPV testing has a higher false-positive rate and may increase unnecessary referrals and interventions (e.g., colposcopy and biopsy).[83][85]

Reporting of cervical cytology results

Results are commonly reported using the Bethesda system:[86][87]

  • Normal (negative for intra-epithelial lesion or malignancy)

  • Epithelial cell abnormality

    • Squamous cell

      • Atypical squamous cells of undetermined significance (ASC-US)

      • Atypical squamous cells, cannot exclude high-grade squamous intra-epithelial lesion (ASC-H)

      • Low-grade squamous intra-epithelial lesion (LSIL); encompassing HPV infection, mild dysplasia, and cervical intra-epithelial neoplasia (CIN) 1

      • High-grade squamous intra-epithelial lesion (HSIL); encompassing moderate and severe dysplasia, carcinoma in situ, CIN 2, and CIN 3 on biopsy

      • HSIL with features suspicious for invasion (if suspected)

      • Squamous cell carcinoma.

    • Glandular cell

      • Atypical glandular cells (AGC); may be endocervical, endometrial, or glandular cells

      • AGC, favour neoplastic; may be endocervical or glandular cells

      • Endocervical adenocarcinoma in situ (ACIS)

      • Adenocarcinoma.

Atypical cytology results

Epithelial cell abnormalities on cytology testing:[87]

  • Atypical squamous cells of undetermined significance (ASC-US)

  • Atypical squamous cells, cannot exclude high-grade squamous intra-epithelial lesion (ASC-H)

  • Atypical glandular cells (AGC).

ASC-US is by far the most common abnormality, representing two-thirds of abnormal cytology tests. ASC-US should trigger reflexive HPV testing (if not already performed):

  • ASC-US, HPV-positive should be referred for colposcopy

  • ASC-US, HPV-negative followed up in 1 year.

ASC-H should trigger colposcopy and biopsy to confirm invasive disease.

AGC should trigger all of the following:

  • Colposcopy

  • Endocervical curettage

  • Endometrial sampling.

Patients aged 40 years or older with endometrial cells on cytology require endometrial biopsy if AGC persists and the patient is at risk of endometrial cancer. AGC is associated with a high and persistent risk of cervical cancer for up to 15 years, particularly cervical adenocarcinoma.[88]

The following cytology results are suggestive of dysplasia or underlying malignancy, and should be triaged as follows:[89]

  • LSIL: risk of underlying malignancy is low and further evaluation is based on age and HPV status

  • HSIL: risk of invasive cervical cancer is substantial and evaluation with colposcopy or expedited treatment is recommended

  • Squamous cell carcinoma: proceed to biopsy to confirm invasive disease

  • ACIS: proceed to biopsy to confirm non-invasive disease

  • Adenocarcinoma: proceed to biopsy to confirm invasive disease.

Guidelines provide further advice on follow-up strategies for abnormal cervical screening tests, based on age, and current and past cytological abnormalities.[90][91]

Symptomatic presentation

Locally advanced disease may present with symptoms such as abnormal vaginal bleeding, postcoital bleeding, pelvic or back pain, dyspareunia, mucoid or purulent vaginal discharge, menorrhagia, or obstructive uropathy. A cervical mass or cervical bleeding may be revealed on vaginal or speculum examination.

All patients with symptomatic disease require colposcopy and biopsy in the initial work-up. Further tests should be performed to stage the disease and evaluate for complications, if indicated.

Colposcopy and biopsy

Indicated if cervical cancer screening is abnormal, or symptoms suggest more advanced disease. Colposcopy may show abnormal vascularity, white change with acetic acid, or visible exophytic lesions. [ Cochrane Clinical Answers logo ] Biopsy establishes the diagnosis and confirms invasive disease prior to treatment.

Cone biopsy or loop electrosurgical excision are used for lesions that are not clinically visible; punch biopsy may be sufficient for larger, visible lesions.[92]

Staging

Invasive cervical cancer spreads by direct extension into the parametrium, vagina, uterus, and adjacent organs. It also spreads to the regional lymph nodes. Distant metastasis to the lung, liver, and skeleton is a late phenomenon. The International Federation of Gynecology and Obstetrics (FIGO) criteria is used for staging once a diagnosis of invasive cancer has been confirmed on biopsy.[60][93] See Diagnostic Criteria.

FIGO staging allows the option of clinical, radiological, or pathological findings (as available) to assign the stage. Imaging can be used to provide information on tumour size, nodal status, and local/metastatic spread. Modalities include ultrasound (US), computed tomography (CT), magnetic resonance imaging (MRI), or positron emission tomography (PET).

MRI is sensitive in tumours greater than 10 mm.[94] US has good diagnostic accuracy when performed by experienced practitioners.[95] For detection of nodal metastasis greater than 10 mm, PET-CT is more accurate than CT or MRI.[92]

Subsequent testing for prognostic and treatment guidance

Subsequent tests to be performed for prognostic and treatment guidance include full blood count, renal and liver function labs, and chest x-ray (if not done during staging). These tests can screen for anaemia due to bleeding, kidney failure from ureteral obstruction, and liver or lung involvement, respectively.

In patients with frank invasive carcinoma, a chest x-ray and assessment of hydronephrosis (with renal US, CT, or MRI) should be done. Bladder and rectum are evaluated by cystoscopy and sigmoidoscopy only if the patient is clinically symptomatic. Cystoscopy is recommended in cases of a barrel-shaped endocervical growth, or in cases where growth has extended to the anterior vaginal wall. Suspected bladder or rectal involvement should be confirmed by biopsy and histology.[92]

Molecular testing

For patients with recurrent, progressive, or metastatic disease, molecular testing for programmed death-ligand 1 (PD-L1) and human epidermal growth factor receptor 2 (HER2) status is recommended to determine use of targeted therapies.[93] Molecular profiling (e.g., using a US Food and Drug Administration-approved assay or validated test that includes at least HER2, mismatch repair/microsatellite instability [MMR/MSI], tumour mutational burden, and NTRK and RET gene fusions) may also be considered for recurrent or metastatic disease.[93]

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