Evaluation and diagnosis

As part of the initial visit, every newly pregnant woman should undergo a thorough history, a complete review of systems, comprehensive physical examination, including a breast examination and a Papanicolaou test, if indicated per the American Society for Colposcopy and Cervical Pathology guidelines, which may help detect the presence of an occult cancer. When a suspicion of malignancy arises, clinicians may be hesitant to order testing because of concern for harm to the fetus. Because delays in diagnosis can affect prognosis and limit options for therapy, concerning and/or persistent symptoms or examination findings should be promptly investigated. Although blood work may be part of the evaluation, tumor markers, particularly for ovarian tumors, should be interpreted with caution because elevations may be expected in pregnancy. Furthermore, tissue biopsies and fine-needle aspirations can be accomplished with minimal to no risk on the developing pregnancy.

Often evaluation of malignancy or assessment for metastatic disease will require imaging. When diagnostic imaging is required in pregnancy, preferable modalities are ultrasound and magnetic resonance imaging, which are associated with minimal to no increased risk. This is in comparison with imaging such as computed tomography scans or plain radiograph films, which use ionizing radiation, a known teratogen. Although this exposure has been associated with adverse outcomes such as miscarriage, malformation, mental retardation, or carcinogenesis, the effect on the developing pregnancy is dependent on the dose of radiation, anatomic location of interest, and gestational age.

Based on current data, most imaging studies with ionizing radiation exposure have a fetal dose less than 5 rads and are not typically associated with adverse outcome, especially once organogenesis is completed. Exposure of radiation doses greater than 10-20 rads has been associated with malformations and decreased intelligence quotient levels. Patients should be aware of an increased incidence of childhood malignancy, particularly leukemia, with in utero radiation exposure as low as 1 rad from 2-3 per 1000 to 3-4 per 1000 pregnancies. Therefore, when there are no alternatives and the use of these tests warrant the use of these tests, efforts to decrease fetal dose, such as the shielding of the maternal pelvis, should be undertaken. Table 1 provides an overview of the most commonly utilized tests and associated radiation dose.

Cancers in pregnancy

Although malignancy during pregnancy can arise from any site, the most common diagnoses are breast cancer, cervical cancer, lymphoma, ovarian cancer, and melanoma. Because the obstetrician-gynecologist is often on the front line in making the diagnosis, awareness of symptoms and findings of malignancy as well as management of the initial work-up is required. In the following text, we have described the evaluation for breast cancer and the most common gynecological malignancies and cervical and ovarian cancer. A more comprehensive list is provided in Table 2 .

Cancers in pregnancy

Although malignancy during pregnancy can arise from any site, the most common diagnoses are breast cancer, cervical cancer, lymphoma, ovarian cancer, and melanoma. Because the obstetrician-gynecologist is often on the front line in making the diagnosis, awareness of symptoms and findings of malignancy as well as management of the initial work-up is required. In the following text, we have described the evaluation for breast cancer and the most common gynecological malignancies and cervical and ovarian cancer. A more comprehensive list is provided in Table 2 .

Breast cancer

Similarly to nonpregnant women, breast cancer often presents as a palpable mass, skin changes, or bloody nipple discharge; however, symptoms and examination may be confounded by physiological changes associated with pregnancy. Because delay in diagnosis may result in poorer prognosis, when clinically suspicious/persistent mass or symptoms are present, further investigation is warranted. This evaluation may include an ultrasound, mammogram, and/or a core needle biopsy, all of which can be safely utilized in pregnancy.

Treatment depends on the extent of the disease and the gestational age. In the first trimester, options include termination of pregnancy or surgery followed by adjuvant chemotherapy in the second trimester. This latter option is also recommended when diagnosis is made in the second to early third trimester. When diagnosis is made in the late third trimester, consideration of aforementioned treatment or delay into the postpartum period can be selected. Of note, radiation and/or hormonal therapy are deferred to the postpartum period. Coordination of care with surgical and medical oncology, the maternal-fetal medicine specialist, and the obstetrician-gynecologist will help determine management options at all steps.

Cervical dysplasia and cancer

Cervical cytological abnormalities are found in up to 5% of all pregnancies. Low-grade lesions often regress or remain unchanged throughout pregnancy. Women who are found to have atypical cells of undetermined significance or low-grade lesions on cytology can be offered repeat evaluation after pregnancy or, if older than age 30 years, may undergo human papillomavirus (HPV) testing. If HPV testing is performed and is positive for high-risk types, colposcopy should be performed. High-grade lesions should be evaluated with colposcopy and biopsies only because endocervical curettage is contraindicated. Colposcopy should be performed every trimester with additional biopsies if progression to malignancy is suspected. Although these lesions rarely progress, postpartum follow-up is mandatory because approximately 50% of high-grade lesions will persist.

Diagnosis of invasive cervical cancer ranges between 1-10 per 10,000 pregnancies and almost three-fourths of cases are diagnosed in the early stages. If microinvasive or invasive disease is suspected, management with conization or trachelectomy may be indicated, and referral to a gynecological oncologist is recommended. When a diagnosis of invasive cancer is confirmed, management recommendations are dependent on the stage of disease. Delay of treatment until fetal maturity may be appropriate when evaluation confirms early-stage disease with negative lymph node status (which can be assessed with lymphadenectomy). In locally advanced disease, the primary option for management is chemoradiation with termination of pregnancy; however, options such as neoadjuvant chemotherapy in pregnancy have been used and are continuing to be studied.

Ovarian tumors and cancer

With the use of routine ultrasound imaging in pregnancy, finding adnexal masses is not uncommon, with an estimated 1 in 600 to 1500 pregnancies requiring surgery. Fortunately, although most are benign, distinguishing those that may be malignant, which comprises 1-3% of adnexal masses, is often challenging. Because spontaneous resolution occurs in approximately 70% of adnexal masses, serial ultrasounds can determine whether further intervention is needed for masses that persist. In addition to acute symptoms such as pain, hemorrhagic rupture, or torsion, masses that are large in size (greater than 8 cm), complex in nature, those that persist after 16 weeks of gestation, or are associated with the presence of extraovarian disease may also warrant surgical intervention.

The use of tumor markers associated with common ovarian malignancies, which may indicate surgical intervention, may be affected by pregnancy. The markers whose reliability may be altered in pregnancy include human chorionic gonadotropin, alpha-fetoprotein, and CA-125 values, whereas the markers that are not affected include carcionembryonic antigen, CA 19-9, and lactate dehydrogenase levels. More recently the biomarker human epididymis protein 4 (HE4), which has been shown to be useful in the detection and management of ovarian cancer, was found to have lower values in pregnant women compared with their premenopausal counterparts. Further studies on the impact of pregnancy on HE4 and other biomarkers for ovarian tumors, including OVA1, are warranted.

In pregnancy, the most common ovarian malignancies are diagnosed in early stages and are comprised of germ cell, sex cord-stromal, borderline tumors, and less commonly, invasive epithelial ovarian cancer. When surgery is performed, either laparoscopy or laparotomy, care to avoid rupture is imperative and surgical staging (with preservation of the contralateral ovary and uterus) is advised when possible. The use of standard chemotherapy, namely platinum and taxanes, may be utilized with minimal fetal consequences in the second and third trimester and treatment should be individualized.

Treatment

After diagnosis of malignancy has been established, a review of outcomes and expectations with the patient and her family along with coordination of care with oncologists should occur as soon as possible. The necessary treatment must balance oncological outcomes with the effect on the pregnancy, and decisions regarding the management of pregnancy include termination, iatrogenic prematurity, or intentional delay in treatment of the maternal malignancy. When making this decision, one must account for the wishes of the patient/family, stage of cancer diagnosis, gestational age, and effects of the specific therapeutic option because any of these may have an impact on the management. An overview of the most commonly utilized therapeutic options is provided below.

Surgery

The role of surgery may be either diagnostic or therapeutic in the management of malignancy during pregnancy. The primary adverse effect of surgery is prematurity secondary to preterm labor and may be attributed to either the surgical procedure or the exposure to anesthesia. In the first trimester, administration of anesthesia has not been associated with an increased risk of congenital malformation; however, because of several reports of increased rates of miscarriage in the first trimester, surgery is often deferred to the second trimester when possible. Regardless of the type of surgery, fetal well-being should be monitored with Doppler or ultrasound preceding and following general anesthesia during the first trimester. Surgery that is performed after 24 weeks of gestation should include continuous fetal monitoring along with consultation of an obstetrician. Patients should be aware of the need for emergent delivery secondary to nonreassuring fetal well-being on monitoring, and consented for cesarean section prior to surgery.

When abdominal surgery is required, the laparoscopic approach is the preferred approach when feasible during pregnancy, and the surgeon may have to adjust techniques to accommodate physiological changes of pregnancy. Consideration for the safest technique for entry is dependent on the size of the gravid uterus.

Chemotherapy

The impact of chemotherapy exposure during pregnancy is based on both gestational age and the specific agent being administered. For the former, chemotherapy given from conception to approximately 10 days represents the all-or-nothing period. From this period to 8 weeks (organogenesis), chemotherapy is associated with teratogenesis and major congenital malformations. After this period, the effects of chemotherapy are inversely related to gestational age, with rates of congenital malformations 16%, 8%, and 6% in the first, second, and third trimester, respectively. Additionally, combination therapy was associated with only a slight increase in adverse outcomes (25%) when compared with single-agent therapy (17%). Therefore, introduction of chemotherapy should be delayed to later gestational period if possible. It is important to recognize that adverse outcomes occurring in the second and third trimesters include minor anomalies, fetal hematological suppression, growth restriction, prematurity, and rarely fetal/neonatal death.

Although a full review is beyond the scope of this paper, the impact of chemotherapy exposure is also dependent on the agent given. In brief, alkylating agents (eg, cyclophosphamide) and antimetabolites (eg, methotrexate) were found to have the greatest risk for adverse pregnancy outcomes, particularly first-trimester malformations. Platinum adducts (carboplatin), taxanes (paclitaxel), and antibiotic agents (doxorubicin) have the lowest associated risks. All patients who require chemotherapy during pregnancy should undergo thorough counseling with the treating oncologist, neonatologist, and obstetrician.