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Cervical Cancer

by Pedro T. Ramirez, MD, David M. Gershenson, MD

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 screening cervical Papanicolaou test and biopsy. Staging is clinical. 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 about 50, but the cancer can occur as early as age 20. It caused an estimated 12,300 new cases and 4000 deaths in 2013.

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

  • Intercourse with men whose previous partners had cervical cancer

Other factors such as cigarette smoking and immunodeficiency also appear to contribute.

Pathology

CIN is graded as 1 (mild cervical dysplasia), 2 (moderate dysplasia), or 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.

Symptoms and Signs

CIN is usually asymptomatic. Early cervical cancer can be asymptomatic. The first symptom is usually 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

  • Clinical staging, usually by biopsy, pelvic examination, and chest x-ray

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

  • Visible cervical lesions

  • Abnormal routine Pap test results

  • Abnormal vaginal bleeding

CIN is usually evident on Pap tests, but about 50% of patients with cervical cancer have not had a Pap test for 10 yr. Patients at highest risk are the least likely to obtain regular preventive health care and to be tested regularly.

Reporting of cervical cytology results is standardized ( Bethesda Classification of Cervical Cytology*). 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.

Bethesda Classification of Cervical Cytology*

Category

Specifics

Comment

Specimen type

Conventional or thin-layer (liquid-based) Papanicolaou (Pap) test or another test

Type of test is noted.

Adequacy of the specimen

Satisfactory for evaluation

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

Evaluated but unsatisfactory

Reason is specified.

Rejected for evaluation

Reason is specified.

General categorization (optional)

Negative for intraepithelial lesion or cancer

Epithelial cell abnormalities

Other abnormalities

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 sp

  • Predominance of coccobacilli consistent with shift in vaginal flora suggesting bacterial vaginosis

  • Bacteria morphologically consistent with Actinomyces sp

  • Cellular changes associated with herpes simplex virus

Other (reporting is optional)

Possible findings include the following:

  • Reactive cellular changes associated with inflammation, radiation, or IUD use

  • Presence of glandular cells after hysterectomy

  • Atrophy

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); whether the lesion has features suggesting invasion noted

  • 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 > 40)

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 other tests (eg, HPV) and their results.

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 2001, National Institutes of Health.

Staging

Cancers are clinically staged based on biopsy, physical examination, and chest x-ray results ( Clinical Staging of Cervical Carcinoma). If the stage is > IB1, CT or MRI of the abdomen and pelvis is typically done to identify metastases, although results are not used for staging. 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.

Clinical Staging of Cervical Carcinoma

Stage

Description

I

Carcinoma confined to the uterus (including to the corpus)

IA

Carcinoma diagnosed only by microscopy, with invasion of stroma ≤ 5 mm in depth and largest extension ≤ 7 mm in width) *

IA1

Measured invasion of stroma 3 mm in depth and 7 mm in width

IA2

Measured invasion of stroma > 3 mm and 5 mm in depth and 7 mm in width

IB

Clinically visible lesions confined to the cervix or microscopic lesions larger than those in stage IA2

IB1

Clinically visible lesions 4 cm

IB2

Clinically visible lesions > 4 cm

II

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

IIA

No obvious parametrial involvement

IIA1

Clinically visible lesion ≤ 4.0 cm in greatest dimension

IIA2

Clinically visible lesion > 4.0 cm in greatest dimension

IIB

Parametrial involvement

III

Extension to the pelvic wall and/or involves the lower third of the vagina and/or causes hydronephrosis or a nonfunctioning kidney

IIIA

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

IIIB

Extension to the pelvic wall, hydronephrosis, or a nonfunctioning kidney

IV

Extension beyond the true pelvis or clinical involvement of the bladder or rectal mucosa (bullous edema does not signify stage IV)

IVA

Invades mucosa of bladder or rectum and/or extends beyond true pelvis

IVB

Spread to distant organs (including peritoneal spread)

*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.

Based on staging established by the International Federation of Gynecology and Obstetrics (FIGO) and American Joint Committee on Cancer (AJCC), AJCC Cancer Staging Manual, ed. 7. New York, Springer, 2010.

The purpose of this staging system is to establish a large database for study; thus, the system uses worldwide uniform diagnostic criteria. The system excludes results of tests that are less likely to be available worldwide (eg, MRI) because most cases of cervical cancer occur in developing countries. Because such tests are not used, findings such as parametrial invasion and lymph node metastases are often missed, and thus understaging is possible.

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


Prognosis

In squamous cell carcinoma, distant metastases usually occur only when the cancer is advanced or recurrent. The 5-yr 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 yr. Adverse prognostic factors include lymph node involvement, large tumor size and volume, deep cervical stromal invasion, parametrial invasion, vascular space invasion, and nonsquamous histology.

Treatment

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

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

  • Chemotherapy for metastatic and recurrent cancer

Treatment may include surgery, radiation therapy, and chemotherapy. If hysterectomy is indicated but patients cannot tolerate it, radiation therapy plus chemotherapy is used.

CIN and squamous cell carcinoma stage IA1

Cone biopsy with LEEP, laser, or cold knife is usually sufficient treatment. Hysterectomy is done for stage IA1 cancer if there are adverse prognostic factors (nonsquamous histology or lymphatic or vascular invasion). Radical hysterectomy is recommended by some experts, particularly if the lymphatic or vascular space is invaded; it includes bilateral pelvic lymphadenectomy and removal of all adjacent ligaments (eg, cardinal, uterosacral) and parametria and the upper 2 cm of the vagina. Hysterectomy can also be done if women no longer desire fertility. If there are no adverse prognostic factors, simple (extrafascial) hysterectomy is usually sufficient because risk of recurrence and lymph node metastasis is < 1%. Pelvic lymph node dissection is not indicated.


Stages IA2 to IIA

Treatment options include a radical hysterectomy and pelvic lymphadenectomy alone (stages IA2 to IB1) or a radical hysterectomy and pelvic lymphadenectomy with possible combined chemotherapy and pelvic radiation (stages IB2 to IIA). Chemotherapy is usually given concurrently with radiation therapy. With either treatment, the 5-yr cure rate in stage IB or IIA is 85 to 90%. Surgery provides additional staging data and preserves the ovaries. If extracervical spread is noted during surgery, postoperative radiation therapy may prevent local recurrence.

In some patients who have early-stage cervical cancer and who wish to preserve fertility, a radical trachelectomy may be done. An abdominal or a 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 carcinoma, adenocarcinoma, or adenosquamous carcinoma

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

  • Stage IA2

  • Stage IB1 with lesions < 2 cm in size

Invasion of the upper cervix and lower uterine segment should be excluded by MRI. 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. Fertility rates after a radical trachelectomy range from 50 to 70%.


Stages IIB to IVA

Radiation therapy plus chemotherapy (eg, cisplatin) is more suitable as primary therapy. Surgical staging should be considered to determine whether para-aortic lymph nodes are involved and thus whether extended-field radiation therapy is indicated; a retroperitoneal approach is used. Staging may be done via laparoscopy. External beam radiation therapy shrinks the central tumor and treats regional lymph nodes. This therapy is followed by brachytherapy (local radioactive implants, usually using cesium) to the cervix, which destroys the central tumor. 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 is usually given with radiation therapy, often to sensitize the tumor to radiation. Treatment is often ineffective for bulky and advanced-stage tumors.

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 a continent urostomy, low anterior rectal anastomosis without 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, but only 15 to 25% of patients respond to it and only briefly. Cisplatin is the most active drug and the current standard, but adding topotecan appears to improve overall response and survival. Paclitaxel plus carboplatin is also used to treat recurrent or metastatic nonsquamous cancer. Metastases outside the radiation field appear to respond better to chemotherapy than does previously irradiated cancer or metastases in the pelvis.


Prevention

Pap tests

Routine cervical Pap tests are recommended every 2 yr for women aged 21 to 30. The Pap test and HPV test should be done simultaneously beginning at age 30. If results of both are negative, the screening interval should be extended to every 3 to 5 yr. Testing continues until age 65. 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 .)

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 vaccines (see Human Papillomavirus Vaccine) that target HPV subtypes 16, 18, and sometimes 6 and 11 are available. These subtypes are the ones most commonly associated with cervical intraepithelial lesions, genital warts, and cervical cancer. The vaccines aim to prevent cervical cancer but do not treat it. Three doses are given over 6 mo. The 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 9.


Key Points

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

  • Do a Pap test and, if indicated, a biopsy to confirm the diagnosis.

  • Stage cervical cancer clinically, using biopsy, pelvic examination, and 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 (usually stages IA to 1B1), radiation therapy plus chemotherapy for locally advanced cancer (usually stages 1B2 to IVA), and chemotherapy for metastatic cancer.

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

  • Recommend HPV vaccination for girls and boys beginning at age 9.

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Drugs Mentioned In This Article

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  • PLATINOL
  • No US brand name
  • TAXOL
  • HYCAMTIN

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