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Cervical Cancer

By Pedro T. Ramirez, MD, Professor, Department of Gynecologic Oncology and Reproductive Medicine, David M. Gershenson Distinguished Professor in Ovarian Cancer Research, and Director of Minimally Invasive Surgical Research and Education, The University of Texas MD Anderson Cancer Center ; David M. Gershenson, MD, Professor and Chairman, Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center ; Gloria Salvo, MD, Rotating Research Resident, Department of Gynecologic Oncology and Reproductive Medicine, MD Anderson Cancer Center

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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. 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. In the US, it caused an estimated 12,990 new cases and 4,120 deaths in 2016.

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

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

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.

Bethesda Classification of Cervical Cytology*

Category

Specifics

Comment

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 sp

  • Shift in vaginal flora suggesting bacterial vaginosis

  • Bacteria morphologically consistent with Actinomyces sp

  • 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.

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

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

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 cancers are clinically staged based on biopsy, physical examination, and chest x-ray results (see Table: FIGO Clinical Staging of Cervical Carcinoma). In the International Federation of Gynecology and Obstetrics (FIGO) staging system, stage does not include information about lymph node status. Although not included as staging, lymph node status is required for treatment planning and affects decisions about the size and location of the radiation therapy field.

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.

FIGO Clinical Staging of Cervical Carcinoma

Stage

Description

I

Carcinoma confined to the cervix

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 in largest dimension

IB2

Clinically visible lesions > 4 cm in largest dimension

II

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

IIA

Involvement of up to the upper 2/3 of the vagina; no obvious parametrial involvement

IIA1

Clinically visible lesion ≤ 4.0 cm in largest dimension

IIA2

Clinically visible lesion > 4.0 cm in largest 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 and/or causes 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.

Diagnosis reference

  • 1. Nayar R, Wilbur DC: The Pap test and Bethesda 2014. Cancer Cytopathology, 123: 271–281, 2015.

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

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

Cervical intraepithelial neoplasia (CIN) and squamous cell carcinoma stage IA1

Treatment involves

  • Conization or simple hysterectomy

Microinvasive cervical cancer, defined as FIGO stage IA1 with no lymphovascular invasion, 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. Simple hysterectomy should be done if patients are not interested in preserving fertility or if margins are positive after conization.

In cases of stage IA1 with lymphovascular invasion, conization (with negative margins) and laparoscopic pelvic sentinel lymph node (SLN) mapping plus lymphadenectomy (lymph node dissection) is a reasonable strategy.

Stages IA2 to IIA

For stage IA2 or IB1 cervical cancer, the standard recommendation is

  • 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. Radical hysterectomy can be done via laparotomy or minimally invasive surgery. Bilateral salpingo-oophorectomy is usually done concurrently.

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 (1).

For stage IB2 to IIA cervical cancer, the most common approach is

  • Combined chemotherapy and pelvic radiation

Another treatment option is radical hysterectomy and bilateral pelvic lymphadenectomy, sometimes with radiation therapy (see Table: Sedlis Criteria for External Pelvic Radiation After Radical Hysterectomy*).

With either treatment, the 5-yr cure rate in stage IB or IIA is 85 to 90%. With surgery, ovarian function can be preserved. Because ovarian metastases are less common in patients with squamous cell carcinoma (0.8%) than in those with adenocarcinoma (5%), the ovaries are typically preserved in patients with squamous cell carcinoma and more commonly removed in those with adenocarcinoma.

If extracervical spread is noted during surgery, radical hysterectomy is not done, and postoperative radiation therapy is recommended to 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, 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 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 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%.

Stages IIB to IVA

For stages IIB to IVA cervical cancer, the standard therapy is

  • Radiation therapy plus chemotherapy (eg, cisplatin)

Surgical staging should 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 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, but only 15 to 25% of patients respond to it.

In a recent study, adding bevacizumab to combination chemotherapy (cisplatin plus paclitaxel or topotecan plus paclitaxel) resulted in an improvement of 3.7 mo in median overall survival in patients with recurrent, persistent, or metastatic cervical cancer (2).

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

Sentinel lymph node mapping for cervical cancer

Sentinel lymph node (SLN) mapping is being evaluated as a potential tool to identify patients who do not need complete pelvic lymphadenectomy and to therefore decrease the number of these procedures, which can have adverse effects (eg, lymphedema, nerve damage).

For SLN mapping, blue dye or technetium-99 (99Tc) is directly injected into the cervix, usually at 3 and 9 o’clock. A dye called indocyanine green (ICG) can be used when open or minimally invasive surgery is done. 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. Any suspicious node must be removed regardless of mapping. If there is no mapping on a hemipelvis, a side-specific lymphadenectomy is done.

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

Criteria for radiation therapy after radical hysterectomy

Criteria used to determine whether pelvic radiation 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

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

  • 1. Querleu D, Morrow CP: Classification of radical hysterectomy. Lancet Oncol 9 (3):297–303, 2008. doi: 10.1016/S1470-2045(08)70074-3.

  • 2. Tewari KS, Sill MW, Long HJ III: Improved survival with bevacizumab in advanced cervical cancer. N Engl J Med 370 (8):734-743, 2014. doi: 10.1056/NEJMoa1309748.

Prevention

Pap tests

Routine screening cervical Pap tests are recommended as follows:

  • From age 21 to 30: Usually every 3 yr for the Pap test (HPV testing is not generally recommended)

  • Age 30 to 65: Every 3 yr if only a Pap test is done or every 5 yr if a Pap test and an HPV test are done (more frequently in women at high risk of cervical cancer)

  • After age 65: No more testing if test results have been normal in the preceding 10 yr

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 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 ≥ 15 yr, three doses are given over 6 mo (at 0, 1 to 2, and 6 mo). For patients < 15 yr, two doses are given 6 to 12 mo apart. 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 11 to 12 yr, but vaccination can begin 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 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 IB1), radiation therapy plus chemotherapy for locally advanced cancer (usually stages IB2 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.

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