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Cervical Cancer

By

Pedro T. Ramirez

, MD, The University of Texas MD Anderson Cancer Center;


Gloria Salvo

, MD, MD Anderson Cancer Center

Last full review/revision Sep 2020| Content last modified Sep 2020
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Topic Resources

Cervical cancer is usually a squamous cell carcinoma caused by human papillomavirus infection; less often, it is an adenocarcinoma. Cervical neoplasia is asymptomatic; the first symptom of early cervical cancer is usually irregular, often postcoital vaginal bleeding. Diagnosis is by a cervical Papanicolaou test and biopsy. Staging is clinical, combined with imaging and pathology results when available. Treatment usually involves surgical resection for early-stage disease or radiation therapy plus chemotherapy for locally advanced disease. If the cancer has widely metastasized, chemotherapy is often used alone.

Cervical cancer is the 3rd most common gynecologic cancer and the 8th most common cancer among women in the US. Mean age at diagnosis is 50, but the cancer can occur as early as age 20. The American Cancer Society estimates that in the US, 13,800 new cases of invasive cervical cancer and 4,290 deaths from cervical cancer will occur in 2020.

Cervical cancer results from cervical intraepithelial neoplasia (CIN), which appears to be caused by infection with human papillomavirus (HPV) type 16, 18, 31, 33, 35, or 39.

Risk factors for cervical cancer include

  • Younger age at first intercourse

  • A high lifetime number of sex partners

  • Cigarette smoking

  • Immunodeficiency

Regardless of sexual history, clinicians should assume that women have been exposed to someone with HPV because it is ubiquitous.

Pathology

CIN is graded as

  • 1: Mild cervical dysplasia

  • 2: Moderate dysplasia

  • 3: Severe dysplasia and carcinoma in situ

CIN 3 is unlikely to regress spontaneously; if untreated, it may, over months or years, penetrate the basement membrane, becoming invasive carcinoma.

About 80 to 85% of all cervical cancers are squamous cell carcinoma; most of the rest are adenocarcinomas. Sarcomas and small cell neuroendocrine tumors are rare.

Invasive cervical cancer usually spreads by direct extension into surrounding tissues or via the lymphatics to the pelvic and para-aortic lymph nodes. Hematogenous spread is possible but rare.

If cervical cancer spreads to the pelvic or para-aortic lymph nodes, the prognosis is worse, and the location and size of the radiation therapy field is affected.

Symptoms and Signs

Early cervical cancer can be asymptomatic.

When symptoms occur, they usually include irregular vaginal bleeding, which is most often postcoital but may occur spontaneously between menses. Larger cancers are more likely to bleed spontaneously and may cause a foul-smelling vaginal discharge or pelvic pain. More widespread cancer may cause obstructive uropathy, back pain, and leg swelling due to venous or lymphatic obstruction.

Pelvic examination may detect an exophytic necrotic tumor in the cervix.

Diagnosis

  • Papanicolaou (Pap) test

  • Biopsy

  • Staging

Cervical cancer may be suspected during a routine gynecologic examination. It is considered in women with

  • Visible cervical lesions

  • Abnormal routine Pap test results

  • Abnormal vaginal bleeding

Reporting of cervical cytology results is standardized (see table Bethesda Classification of Cervical Cytology [1]). Further evaluation is indicated if atypical or cancerous cells are found, particularly in women at risk. If cytology does not show any obvious cancer, colposcopy (examination of the vagina and cervix with a magnifying lens) can be used to identify areas that require biopsy. Colposcopy-directed biopsy with endocervical curettage is usually diagnostic. If not, cone biopsy (conization) is required; a cone of tissue is removed using a loop electrical excision procedure (LEEP), laser, or cold knife.

Table
icon

Bethesda Classification of Cervical Cytology*

Category

Specifics

Comments

Specimen type

Conventional (Papanicolaou [Pap]), liquid-based preparation, or another

Type of test is noted.

Adequacy of the specimen

Satisfactory for evaluation

Any quality indicators (eg, presence or absence of endocervical or transformation zone component, partially obscuring blood, inflammation) are described.

Unsatisfactory for evaluation (rejected and not processed)

Reason is specified.

Unsatisfactory for evaluation but processed and evaluated

Reason is specified.

General categorization (optional)

Negative for intraepithelial lesion or cancer

Epithelial cell abnormalities

Other findings

Findings are stated or described under Interpretation, below.

Interpretation of negative (nonmalignant) abnormalities†

Organisms

Possible findings include the following:

  • Trichomonas vaginalis

  • Fungi morphologically consistent with Candida species

  • Shift in vaginal flora suggesting bacterial vaginosis

  • Bacteria morphologically consistent with Actinomyces species

  • Cellular changes consistent with herpes simplex virus

  • Cellular changes consistent with cytomegalovirus

Nonneoplastic findings (reporting is optional)

Possible findings include the following:

  • Nonneoplastic cellular variations (squamous metaplasia, keratotic changes, tubal metaplasia, atrophy, or pregnancy-associated changes)

  • Reactive cellular changes associated with inflammation (lymphocytic cervicitis), radiation, or IUD use

  • Glandular cell status after hysterectomy

Interpretation of epithelial cell abnormalities

Squamous cell

Possible findings include the following:

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

  • Atypical squamous cells for which a high-grade lesion cannot be excluded (ASC-H)

  • Low-grade squamous intraepithelial lesion encompassing HPV‡ infection or mild dysplasia (CIN 1)

  • High-grade squamous intraepithelial lesion encompassing moderate (CIN 2) and severe dysplasia (CIN 3/CIS), noting whether the lesion has features suggesting invasion

  • Squamous cell carcinoma

Glandular cell

Possible findings include the following:

  • Atypical cells: Endocervical, endometrial, or glandular

  • Atypical cells likely to be cancerous: Endocervical or glandular

  • Adenocarcinoma in situ: Endocervical

  • Adenocarcinoma: Endocervical, endometrial, extrauterine, or NOS

Interpretation of other abnormalities

Endometrial cells (in a woman 45)*

Whether sample is negative for squamous intraepithelial lesion is specified.

Other cancers

Type is specified.

* Use of an automated device for scanning should be reported, as should adjunctive tests (eg, HPV) and their results.

† If there is no cellular evidence of neoplasia, clinicians should state negative for intraepithelial lesion or malignancy here or in the general categorization.

‡ Cellular changes of HPV infection—previously called koilocytosis, koilocytotic atypia, and condylomatous atypia—are included in the category of low-grade squamous intraepithelial lesion.

CIN = cervical intraepithelial neoplasia; CIS = carcinoma in situ; HPV = human papillomavirus; IUD = intrauterine device; NOS = not otherwise specified.

Adapted from the Bethesda System 2014, National Institutes of Health.

Staging

Cervical cancer staging was revised in 2018. The previous FIGO 2009 staging system allowed only clinical examination and a few additional tests to assign the stage. The FIGO 2018 staging system allows, when available, cross-sectional imaging (eg, ultrasonography, CT, MRI, positron emission tomography [PET], PET-CT, MRI-PET) and pathology results to supplement clinical findings in all stages. Imaging and pathology results are optional because they may be not available in low- and lower middle-income countries, where cervical cancer is more common (2, 3, 4).

Other changes in the 2018 staging system include

  • Horizontal spread of the tumor is no longer considered part of stage IA1 and IA2.

  • Stage I is subdivided into 3 subgroups according to tumor size (IB1 < 2 cm, IB2 2 to < 4 cm, and IB3 ≥ 4 cm) instead of 2 subgroups (stages IB1 and IB2, which used only 4 cm as a cutoff value).

  • Lymph node status is now part of the staging system. Positive pelvic nodes are now stage IIIC1 and positive paraortic nodes are stage IIIC2. Micrometastases in the lymph nodes are considered positive; however, these isolated tumor cells do not change the stage to III, but they should be recorded. If lymph nodes are classified as positive by imaging studies, an r is added to the stage (eg, IIIC1r, IIIC2r); if they are classified as positive by pathology results, a p is added(IIIC1p, IIIC2p [2, 3, 4]).

If the stage is > IA2, CT or MRI of the abdomen and pelvis is typically done to better determine tumor size, parametrial involvement, vaginal compromise, and nodal metastases. PET with CT (PET/CT) is being used more commonly to check for spread beyond the cervix. If PET/CT, MRI, or CT is not available, cystoscopy, sigmoidoscopy, and IV urography, when clinically indicated, may be used for staging.

Table
icon

FIGO Clinical Staging of Cervical Carcinoma*

Stage

Description

I

Carcinoma confined to the cervix (extension to the uterine corpus should be disregarded)

  • IA

Carcinoma diagnosed only by microscopy, with invasion of stroma ≤ 5 mm in depth*

  • IA1

Measured invasion of stroma < 3 mm in depth

  • IA2

Measured invasion of stroma ≥ 3 mm and < 5 mm in depth

  • IB

Measured invasion of ≥ 5 mm (greater than stage IA) with lesion limited to the cervix.

  • IB1

Lesions < 2 cm in largest dimension

  • IB2

Lesions ≥ 2 and < 4 cm in largest dimension

  • IB3

Lesions ≥ 4 cm in largest dimension

II

Extension beyond the uterus but not to the pelvic wall or to the lower third of the vagina

  • IIA

Limited to the upper 2/3 of the vagina with no obvious parametrial involvement

  • IIA1

Lesion < 4 cm in largest dimension

  • IIA2

Lesion ≥ 4 cm in largest dimension

  • IIB

Parametrial involvement but not up to the pelvic wall

III

Extension to the pelvic wall and/or involves the lower third of the vagina and/or causes hydronephrosis or a nonfunctioning kidney and/or involves pelvic and/or para-aortic lymph nodes

  • IIIA

Extension to lower third of the vagina but not to the pelvic wall

  • IIIB

Extension to the pelvic wall and/or causes hydronephrosis or a nonfunctioning kidney (unless known to be due to another cause)

  • IIIC†

Involves pelvic and/or para-aortic lymph nodes, regardless of tumor size and extent (with r and p notations)†

  • IIIC1

Only metastasis to pelvic lymph nodes

  • IIIC2

Metastasis to para-aortic lymph nodes

IV

Extension beyond the true pelvis or biopsy-proven involvement of the bladder or rectal mucosa

  • IVA

Spread to adjacent pelvic organs

  • IVB

Spread to distant organs

* If the stage is in doubt, the lower stage should be assigned. Imaging and pathology, if available, can be used to supplement clinical findings when determining tumor size and extent in all stages. Depth of invasion should be measured from the base of the epithelium (surface or glandular) from which it originates. Vascular space involvement (venous or lymphatic) should not alter staging. Lateral extension of the lesion is no longer considered.

† The notation r (imaging) and/or p (pathology) should be added to indicate the methods used to assign stage IIIC (eg, stage IIICp). The type of imaging or pathology technique used should always be documented.

Based on FIGO Cancer Report 2018 (Neerja Bhatla N, Aoki D, Sharma DN, Sankaranarayanan, R, et al: Cancer of the cervix uteri. International Journal of Gynecology and Obstetrics 143 (S2):22–36, 2018. https://doi.org/10.1002/ijgo.12611.

When imaging tests suggest that pelvic or para-aortic lymph nodes are grossly enlarged (> 2 cm), surgical exploration, typically with a retroperitoneal approach, may be indicated. Its sole purpose is to remove enlarged lymph nodes so that radiation therapy can be more precisely targeted and more effective.

Diagnosis references

Prognosis

In squamous cell carcinoma, distant metastases usually occur only when the cancer is advanced or recurrent. The 5-year survival rates are as follows:

  • Stage I: 80 to 90%

  • Stage II: 60 to 75%

  • Stage III: 30 to 40%

  • Stage IV: 0 to 15%

Nearly 80% of recurrences manifest within 2 years.

Adverse prognostic factors include

  • Lymph node involvement

  • Large tumor size and volume

  • Deep cervical stromal invasion

  • Parametrial invasion

  • Lymphovascular space invasion (LVSI)

  • Nonsquamous histology

Treatment

  • Surgery or curative radiation therapy if there is no spread to parametria or beyond

  • Radiation therapy and chemotherapy (chemoradiation) if there is spread to parametria or beyond

  • Chemotherapy for metastatic and recurrent cancer

Treatment of cervical cancer may include surgery, radiation therapy, and chemotherapy. If hysterectomy is indicated but patients are not ideal candidates for it, chemoradiation is used and has similar oncologic outcomes.

Stage IA1 (no lymphovascular space invasion)

Treatment involves

  • Conization or simple hysterectomy

Microinvasive cervical cancer, defined as FIGO stage IA1 with no lymphovascular space invasion (LVSI), has a < 1% risk of lymph node metastases and may be managed conservatively with conization using LEEP, laser, or cold knife. Conization is indicated for patients who are interested in preserving fertility (to obtain, if possible, a nonfragmented specimen with a 3-mm margin).

Simple hysterectomy should be done if patients are not interested in preserving fertility or if margins are positive after conization. If margins are positive, sentinel lymph node (SLN) mapping should be considered, and if patients are interested in preserving fertility, repeat conization is an alternative.

Stage IA1 (with lymphovascular space invasion) and stage IA2

For stage IA1 with LVSI or stage IA2, recommended treatments include

  • Modified radical hysterectomy and pelvic lymphadenectomy (with or without SLN mapping)

  • External pelvic radiation therapy with brachytherapy

Stages IB1, IB2, and IIA1

For stages IB1, IB2, and IIA1, the standard recommendation is

  • Open radical hysterectomy with bilateral pelvic lymphadenectomy (with or without SLN mapping)

Radical hysterectomy includes resection of the uterus (including the cervix), parts of the cardinal and uterosacral ligaments, the upper 1 to 2 cm of the vagina, and the pelvic lymph nodes. Results from a phase III prospective randomized trial (1) showed that minimally invasive surgery (MIS) resulted in a lower overall survival rate and a higher recurrence rate than total abdominal radical hysterectomy (TARH). Therefore, open radical hysterectomy is recommended as the appropriate approach (2).

The Querleu & Morrow classification system describes 4 basic types of radical hysterectomy, with a few subtypes that take nerve preservation and paracervical lymphadenectomy into account (3).

When patients are not considered ideal candidates for surgery because of comorbidities, another valid option is external pelvic radiation therapy and brachytherapy with or without concurrent platinum-based chemotherapy.

Another treatment option is radical hysterectomy and bilateral pelvic lymphadenectomy (with or without para-aortic lymphadenectomy), sometimes with adjuvant radiation therapy (see table Sedlis Criteria for External Pelvic Radiation After Radical Hysterectomy).

If extracervical spread is noted during radical hysterectomy, the procedure should be aborted, and postoperative radiation therapy with concurrent chemotherapy is recommended to prevent local recurrence.

Stages IB3, IIA2, IIB, III, and IVA

The standard therapy is

  • External pelvic radiation therapy with brachytherapy and concurrent platinum-based chemotherapy

Surgical staging may be considered to determine whether para-aortic lymph nodes are involved and thus whether extended-field radiation therapy is indicated, particularly in patients with positive pelvic lymph nodes identified during pretreatment imaging. A laparoscopic retroperitoneal approach is recommended.

When cancer is limited to the cervix and/or pelvic lymph nodes, the standard recommendation is

  • External beam radiation therapy, followed by brachytherapy (local radioactive implants, usually using cesium) to the cervix

Radiation therapy may cause acute complications (eg, radiation proctitis and cystitis) and, occasionally, late complications (eg, vaginal stenosis, intestinal obstruction, rectovaginal and vesicovaginal fistula formation).

Chemotherapy (cisplatin or carboplatin) is usually given with radiation therapy, often to sensitize the tumor to radiation.

Although stage IVA cancers are usually treated with radiation therapy initially, pelvic exenteration (excision of all pelvic organs) may be considered. If after radiation therapy, cancer remains but is confined to the central pelvis, exenteration is indicated and cures up to 40% of patients. The procedure may include continent or incontinent urostomy, low anterior rectal anastomosis without colostomy or with an end-descending colostomy, omental carpet to close the pelvic floor (J-flap), and vaginal reconstruction with gracilis or rectus abdominis myocutaneous flaps.

Stage IVB and recurrent cancer

Chemotherapy is the primary treatment. Response rates are about 48%.

Adding bevacizumab to combination chemotherapy (cisplatin plus paclitaxel or topotecan plus paclitaxel) resulted in an improvement of 3.7 months in median overall survival in patients with recurrent, persistent, or metastatic cervical cancer (4).

Metastases outside the radiation field appear to respond better to chemotherapy than does previously irradiated cancer or metastases in the pelvis.

Clinicians should consider testing for mismatch repair (MMR) and microsatellite instability (MSI), PD-L1 (programmed cell death-ligand 1) expression, and/or NTRK gene fusion if patients have recurrent, progressive, or metastatic cervical cancer. Results can help predict responses to immunotherapies such as PD-L1 inhibitors.

Sentinel lymph node mapping for cervical cancer

Sentinel lymph node (SLN) mapping is an alternative to full pelvic lymphadenectomy for patients with early-stage (IA1 with lymphovascular space invasion, IB1, IB2, or IIA1) cervical cancer (5) because only 15 to 20% of these patients have positive nodes. SLN mapping therefore decreases the number of full pelvic lymphadenectomies, which can have adverse effects (eg, lymphedema, nerve damage).

For SLN mapping, blue dye, technetium-99 (99Tc), or indocyanine green (ICG) is directly injected into the cervix, usually at 3 and 9 o’clock. During surgery, SLNs are identified by direct visualization of blue dye, by a camera to detect the fluorescence of ICG, or by a gamma probe to detect 99Tc. SLNs are commonly located medial to the external iliac vessels, ventral to the hypogastric vessels, or in the superior part of the obturator space.

Ultrastaging of all SLNs is done to detect micrometastasis and isolated tumor cells (low-volume disease). Any grossly suspicious node must be removed regardless of mapping. If there is no mapping on a hemipelvis, a side-specific lymphadenectomy is done. In the 2018 FIGO staging system, only macrometastases and micrometastases are considered when classifying cases as IIIC; isolated tumor cells do not change the stage, they are considered pN0.

Detection rates for sentinel node lymph mapping are best for tumors < 2 cm.

Radical trachelectomy

In some patients who have early-stage cervical cancer (IA1 with LVSI, IA2, IB1, some cases of IB2) and who wish to preserve fertility, a radical trachelectomy may be done. An abdominal, vaginal, laparoscopic, or robotic-assisted approach can be used. In this procedure, the cervix, parametria immediately adjacent to the cervix, upper 2 cm of the vagina, and pelvic lymph nodes are removed. The remaining uterus is reattached to the upper vagina, preserving the potential for fertility. Ideal candidates for this procedure are patients with the following:

  • Histologic subtypes such as squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma

  • Stage IA1/grade 2 or 3 with lymphovascular space invasion

  • Stage IA2

  • Stage IB1

Invasion of the upper cervix and lower uterine segment should be excluded by MRI before surgery. Rates of recurrence and death are similar to those after radical hysterectomy. If patients who have this procedure plan to have children, delivery must be cesarean. After a radical trachelectomy, fertility rates range from 50 to 70%, and the recurrence rate is about 5 to 10%.

Criteria for radiation therapy after radical hysterectomy

Criteria used to determine whether pelvic radiation with concurrent chemotherapy should be done after radical hysterectomy include the following (see table Sedlis Criteria for External Pelvic Radiation After Radical Hysterectomy):

  • Presence of lymphovascular space invasion

  • Depth of invasion

  • Tumor size

Table
icon

Sedlis Criteria for External Pelvic Radiation After Radical Hysterectomy*

Lymphovascular Space Invasion

Stromal Invasion

Tumor Size (cm)†

+

Deep third

Any

+

Middle third

≥ 2

+

Superficial third

≥ 5

Middle or deep third

≥ 4

* Criteria apply to node-negative, margin-negative, parametria-negative cases.

† Size is determined by clinical palpation.

Based on Sedlis A, Bundy BN, Rotman MZ, et al: A randomized trial of pelvic radiation therapy versus no further therapy in selected patients with stage IB carcinoma of the cervix after radical hysterectomy and pelvic lymphadenectomy: A gynecologic oncology group study. Gynecol Oncol 73, 177–183, 1999.

Treatment references

Prevention

Screening tests

Two types of screening tests for cervical abnormalities are used:

  • Pap test

  • HPV test

In 2020, the American Cancer Society (ACS) issued new guidelines for cervical cancer screening as follows (1):

  • Screening should begin at age 25, rather than age 21.

  • If primary human papillomavirus (HPV) testing (HPV testing approved by the Food and Drug Administration [FDA] for screening) is available, it should be started at age 25 years, rather than 30 years, and done every 5 years; cytology (eg, Pap tests) is not needed.

  • If primary HPV testing is not available, a Pap test should be done every 3 years or cotesting with Pap and HPV tests should be done every 5 years.

  • Pap tests and cotesting should be phased out when primary HPV testing becomes available.

  • For women over age 65, guidance remains the same: Testing is stopped if test results have been normal in the preceding 10 years; testing should be continued if test results have not been normal for 10 years.

If women have had a hysterectomy for a disorder other than cancer and have not had abnormal Pap test results, screening is not indicated. (See also Cervical Cancer Screening Guidelines, which does not yet reflect the 2020 update of ACS guidelines.)

HPV testing is the preferred method of follow-up evaluation for all women with ASCUS (atypical squamous cells of undetermined significance), an inconclusive finding detected by Pap tests. If HPV testing shows that the woman does not have HPV, screening should continue at the routinely scheduled intervals. If HPV is present, colposcopy should be done.

HPV vaccine

Preventive HPV vaccines include

  • A bivalent vaccine that protects against subtypes 16 and 18 (which cause most cervical cancers)

  • A quadrivalent vaccine that protects against subtypes 16 and 18 plus 6 and 11

  • A 9-valent vaccine that protects against the same subtypes as the quadrivalent plus subtypes 31, 33, 45, 52, and 58 (which cause about 15% of cervical cancers)

Subtypes 6 and 11 cause > 90% of visible genital warts.

The vaccines aim to prevent cervical cancer but do not treat it.

For patients who are age 15 to 26 or who are immunocompromised, three doses are given over 6 months (at 0, 1 to 2, and 6 months). For patients < 15 years, two doses are given 6 to 12 months apart.

The HPV vaccine is recommended for boys and girls, ideally before they become sexually active. The standard recommendation is to vaccinate boys and girls beginning at age 11 to 12 years, but vaccination can begin at age 9.

Prevention reference

  • 1. Fontham ETH, Wolf AMD, Church TR, et al: Cervical cancer screening for individuals at average risk: 2020 guideline update from the American Cancer Society, CA Cancer J Clin 2020. doi: 10.3322/caac.21628. Online ahead of print.

Key Points

  • Consider cervical cancer if women have abnormal Pap test results, visible cervical lesions, or abnormal, particularly postcoital vaginal bleeding.

  • Do a biopsy to confirm the diagnosis.

  • Stage cervical cancer clinically, using biopsy, pelvic examination, and available imaging, including chest x-ray, and if the stage is > IB1, use PET/CT, MRI, or CT to identify metastases.

  • Treatment is surgical resection for early-stage cancer, radiation therapy plus chemotherapy for locally advanced cancer, and chemotherapy for metastatic and recurrent cancer.

  • Screen all women by doing Pap and HPV tests at regular intervals.

  • Recommend HPV vaccination for girls and boys.

More Information

The following is an English-language resource that may be useful. Please note that THE MANUAL is not responsible for the content of this resource.

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