Obstetrics and Gynecology

Cervical cancer in pregnancy

Cervical Cancer in Pregnancy

1. What every clinician should know

Clinical features and incidence

Cervical cancer is the second most common malignancy in women worldwide. As cervical cancer frequently occurs in young women, it is not surprising that the disease is one of the most common cancers diagnosed during pregnancy.

It is now recognized that human papillomavirus (HPV) is a prerequisite for the development of cervical cancer. As HPV is extremely common in young women, preinvasive cytologic abnormalities are frequently diagnosed in pregnant women. The majority of these changes represent low-grade abnormalities that often are transient and resolve without intervention. A smaller subset of women have high-grade abnormalities that carry a significant risk for persistence and ultimately progression to invasive cervical cancer.

Pathophysiology

HPV infects the basal keratinocytes of the cervix and can lead to a series of progressive precancerous changes known as cervical intraepithelial neoplasia (CIN). While HPV is extremely common, particularly among young sexually active women, the development of cervical cancer is rare. The long preinvasive phase from HPV infection to the development of cervical cancer allows for the detection and eradication of preinvasive changes.

2. Diagnosis and differential diagnosis

What is the first step in screening for cervical cancer in pregnancy?

Papanicoalou (Pap) testing can be safely performed during pregnancy and it is recommended that all pregnant women undergo cytologic screening with the Pap test at their initial prenatal visit (unless a recent Pap smear has been performed prior to pregnancy). As in non-pregnant women, cervical sampling can be performed safely with sampling of the ectocervix as well as endocervical sampling with a cytobrush or comparable device.

What features of the presentation will guide me toward possible causes and next treatment steps?

The normal pregnant cervix is typically characterized by ectropion which may be accompanied by inflammation and may be mistaken as an abnormality. Women with a normal Papanicoalou test do not require further evaluation during pregnancy. Abnormal pap results require further assessment.

How are abnormal pap smear results interpreted and managed?

Atypical squamous cells of undetermined significance (ASC-US) is an abnormality that is frequently seen in young women. While the lesion is poorly reproducible, the overall risk of cancer is low (between approximately 0.1-0.2%). Pregnant women over the age of 20 years may either elect to undergo colposcopy or may safely defer colposcopy until 6 weeks or more postpartum.

Low-grade squamous intraepithelial lesions (LSIL) are also common in reproductive age women. CIN 2 or greater will be detected in approximately 12-16% of women with LSIL. For pregnant women over the age of 20 colposcopy is preferred for evaluation although it is acceptable to defer colposcopy until 6 weeks or more postpartum. Pregnant women 20 years of age or younger do not require evaluation and should undergo cytologic follow-up in 1 year.

Women with high-grade squamous intraepithelial lesions (HSIL) on cytology have a high prevalence of underlying CIN 2 or greater. Pregnant women with HSIL should undergo colposcopy with directed biopsy of any lesions suspicious for CIN 2 or 3, or cancer. Women with HSIL should not undergo ECC or an excisional procedure as part of their evaluation.

Although atypical glandular cells (AGC) is a relatively uncommon cytologic diagnosis, these women are at substantial risk for underlying high-grade abnormalities. Studies have suggested that 9-38% of women have high-grade cervical intraepithelial neoplasia or adenocarcinoma in situ and a further 3-17% of women have invasive cancer. Pregnant women with AGC should undergo colposcopy with biopsy of any suspicious lesions.

What initial studies should you perform to help make the diagnosis?

Like non-pregnant women, pregnant women with cytologic abnormalities are typically evaluated with colposcopy. During the procedure acetic acid is applied to the cervix and the cervix and vagina are visualized under low power magnification. An adequate colposcopy should allow visualization of the entire transformation zone. While the ectropion that accompanies pregnancies facilitates visualization of the transformation zone, it may be mistaken for a cervical abnormality. A number of studies have suggested that colposcopy during pregnancy is safe and not associated with adverse fetal outcomes.

When do you need more aggressive tests?

Although cervical biopsy is safe during pregnancy, the procedure may be associated with more bleeding than typically is seen in non-pregnant women. Many experts recommend performing biopsy only in women with a lesion that is suspicious for high-grade cervical intraepithelial neoplasia. In contrast to cervical biopsy, endocervical curettage (ECC) is not recommended during pregnancy. While data are lacking that ECC is associated with adverse outcomes, the theoretical concern that the procedure could lead to pregnancy-related complications precludes routine performance of ECC.

Cervical excisional procedures, including cold knife conization, large loop excision of the transformation zone (LLETZ), and loop electrosurgical excision procedure (LEEP) are usually only performed during pregnancy to rule out a microinvasive cancer

How are the colposcopy results interpreted?

The understanding of cervical intraepithelial neoplasia (CIN) is rapidly involving. Management of young women with CIN must carefully balance the risks of progression to cancer against the adverse effects of treatment with conization. For management cervical intraepithelial neoplasia is classified as either CIN 1, CIN 2 or CIN 3.

CIN 1 is a heterogenous diagnosis that includes women who may progress to higher grade CIN as well as women with non-oncogenic HPV. The diagnosis of CIN 1 is poorly reproducible. Pregnant women with CIN 1 do not require any further evaluation.

Cervical intraepithelial neoplasia 2 and 3 (CIN 2 and CIN 3) represent moderate to severe cervical intraepithelial neoplasia. The distinction between CIN 2 and 3 is poorly reproducible and as such, these lesions are classified similarly. The underlying risk of progression to invasive cancer is substantial. Pregnant women with a diagnosis of CIN 2 or CIN 3 may either be followed during pregnancy with repeat colposcopy or defer repeat colposcopy until at least 6 weeks postpartum.

For those women who undergo repeat colposcopy during pregnancy the procedure should not be performed more frequently than every 12 weeks. Repeat biopsy is unnecessary unless the appearance of the lesion worsens. An excisional procedure should not be performed unless invasive cancer is suspected.

What signs and symptoms should make you concerned for invasive disease?

Women with microscopic tumors are usually asymptomatic. Among women with clinically visible lesions vaginal bleeding is the most common symptom. Classically, vaginal bleeding is postcoital. Abdominopelvic pain and vaginal discharge may also occur. Women with advanced-stage tumors may have back pain, hydronephrosis or sciatica.

3. Management

If a diagnosis of cervical cancer is made, how is a pregnant patient treated?

The management of cervical cancer during pregnancy depends primarily on the stage of the cancer and the gestational age of the mother at the time of diagnosis. Cervical cancer is staged using the 2009 International Federation of Gynecology and Obstetrics staging system. The staging of women with cervical cancer relies on clinical examination.

What imaging studies (if any) will be helpful?

Both CT and MRI are anatomic imaging modalities that have been used to evaluate tumor size, parametrial spread and nodal dissemination. A prospective study by the Gynecologic Oncology Group suggested that both tests were only moderately accurate in disease assessment. Computed tomography of the pelvis results in fetal radiation exposure and should be used with caution. In contrast, MRI does not expose the fetus to ionizing radiation and may be safely used during pregnancy. More recently, PET imaging has been widely utilized in women with newly diagnosed cervical cancer. However, as the effects of the radioisotope on the fetus are unknown, PET is contraindicated during pregnancy.

How is treatment of cervical cancer made specific to pregnant women?

Treatment planning for women with invasive cervical cancer must take into account both maternal and fetal considerations. Treatment is predominately guided by the stage of disease and the gestational age of the fetus. As randomized trials are lacking, most recommendations for the treatment of cervical cancer during pregnancy are based on observational studies and expert opinion. In general, women diagnosed prior to 20-24 weeks of gestation are encouraged to receive immediate therapy, while those women diagnosed after 20-24 weeks may delay treatment until delivery which is typically planned at 32-34 weeks depending on the clinical scenario.

What are the various treatments available based on stage?

For Stage IA1 cervical cancer, women who have tumors with a depth of invasion of less than 3 mm and less than 7 mm of lateral spread have an excellent prognosis. Given the increased blood flow to the gravid uterus, cervical excisional procedures such as conization performed during pregnancy can result in substantial blood loss.

Conization is typically reserved for women at less than 20-24 weeks of gestation to confirm the diagnosis of a microinvasive cervical cancer and exclude a more extensive tumor or when invasion is suspected on a cervical biopsy but the results are inconclusive. In general, patients with stage IA1 cervical cancer can defer treatment until delivery.

Treatment of pregnant women with stage IA2, IB1, and small IB2 and IIA cervical cancer at less than 20-24 weeks of gestation may elect to undergo immediate radical hysterectomy, which can be performed either after elective termination or with the fetus in situ. Patients diagnosed after 20-24 weeks of gestation generally defer treatment until the time of delivery. For these patients the timing of delivery should be coordinated with a multidisciplinary team including maternal-fetal medicine experts.

For pregnant women with stage IIB-IVA cervical cancer as well as those women with larger stage IB2-IIA lesions, many experts recommend initiation of treatment immediately in women at less than 20-24 weeks of gestation and delay of therapy until after delivery in women at later gestational ages. While chemoradiation is now the standard of care for non-pregnant patients with advanced-stage cervical cancer, data specifically evaluating combination therapy during pregnancy are largely lacking.

Are alternative treatments available?

Neoadjuvant chemotherapy is a potential therapeutic consideration for patients with cervical cancer who wish to delay treatment. Neoadjuvant treatment has been shown to decrease the size of local tumors and facilitate surgical management. Unfortunately, large studies to describe the effects of chemotherapy in pregnancy are lacking. Some reports have suggested that women treated with chemotherapy are at increased risk for preterm delivery and adverse neonatal outcomes. Treatment early in gestation, particularly with 5-fluorouracil and cyclophosphamide, has been associated with fetal anomalies.

What novel therapeutics are emerging?

Over the course of the last decade there has been an increasing interest in more conservative surgical procedures for cervical cancer. A number of case reports of radical trachelectomy for pregnant women with localized cervical cancer have now been reported. While the application of radical trachelectomy to pregnancy is evolving, in non-pregnant women the procedure is usually reserved for women with tumors less than 2 cm in greatest diameter. In addition to the abdominal approach, radical vaginal trachelectomy has also been performed during pregnancy.

What mode of delivery is recommended for pregnant patients with cervical cancer?

Cesarean delivery is recommended for most women with bulky cervical tumors to decrease the risk of bleeding at the time of delivery. Other reports have suggested that vaginal delivery is safe, particularly for women with microinvasive or small tumors in which the risk of bleeding is less. A potential concern for women who deliver vaginally is local recurrence.

How do you counsel the patient and family on prognosis of cervical cancer in pregnancy?

While it is difficult to directly compare the outcome of pregnant and non-pregnant women with cervical cancer, it appears that pregnancy does not worsen outcomes. Stage appears to be the most important prognostic factor. The effect of delaying treatment on outcome has long been debated. However, in at least one small series of patients with predominantly early-stage disease, treatment delay had no apparent adverse effect on survival.

4. What’s the evidence?

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Wright, TC, Massad, LS, Dunton, CJ, Spitzer, M, Wilkinson, EJ. "2006 consensus guidelines for the management of women with abnormal cervical cancer screening tests". Am J Obstet Gynecol. vol. 197. 2007. pp. 346-55.

Arbyn, M, Kyrgiou, M, Simoens, C. "Perinatal mortality and other severe adverse pregnancy outcomes associated with treatment of cervical intraepithelial neoplasia: meta-analysis". BMJ. vol. 337. 2008. pp. a1284.

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Colombo, N, Peiretti, M. "Critical review of neoadjuvant chemotherapy followed by surgery for locally advanced cervical cancer". Int J Gynecol Cancer. vol. 20. 2010. pp. S47-8.

Tewari, K, Cappuccini, F, Gambino, A, Kohler, MF, Pecorelli, S. "Neoadjuvant chemotherapy in the treatment of locally advanced cervical carcinoma in pregnancy: a report of two cases and review of issues specific to the management of cervical carcinoma in pregnancy including planned delay of therapy". Cancer. vol. 82. 1998. pp. 1529-34.

Cliby, WA, Dodson, MK, Podratz, KC. "Cervical cancer complicated by pregnancy: episiotomy site recurrences following vaginal delivery". Obstet Gynecol. vol. 84. 1994. pp. 179-82.

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