Cancer in pregnancy

The incidence of cancer in pregnancy is increasing. The most frequent malignancies include breast and cervical cancers. Diagnosis may be complicated by late presentation. Imaging during pregnancy should consider risks to the fetus. Diagnostic work‐up, including tumor markers, can be influenced by the physiology of pregnancy. Treatment of cancer can often be safely administered with good maternal and fetal outcomes. Chemotherapy, radiotherapy, and surgery must be adapted to the pregnancy state. Counselling and emotional support are an essential part of management.


| INTRODUCTION
Cancer in pregnancy, although uncommon, has been increasing in recent years as demonstrated by various epidemiological studies.
The Danish registry showed a rise in the proportion of cancer associated with pregnancy from 5.4% (n=572) to 8.3% (n=1052) over a 30-year period-the most common cancers being melanoma, cervical, and breast cancer. 1 The increased incidence could not be explained by advanced maternal age alone. An Australian study on pregnancyassociated cancer reported 1798 cancers over a 14-year period, 499 during pregnancy and 1299 in the postpartum period, giving a crude incidence of 137.3 per 100 000 pregnancies. 2 There was a statistically significant increase in pregnancy-associated malignancy during this period and the number of mothers aged over 35 years increased from 13.2% to 23.6%. However, age explained only a 14% increase in incidence. The postpartum period (up to 12 months after delivery) was included, bearing in mind a delay in diagnosis during pregnancy or considering it part of the cancer-in-pregnancy continuum.
In a recent Italian population-based linkage study, breast cancer was the most common cancer (32%, n=479) and the risk of developing a pregnancy-related cancer increased significantly with age, from 60 per 100 000 for women younger than 30 years to 265 per 100 000 for women older than 40 years. 3 Melanoma, breast, and thyroid cancers were more common in the Australian population than those reported from other registries, and cervical and ovarian cancer incidence was lower. 2 In an international cohort of 1170 woman diagnosed with cancer during pregnancy, the most common invasive cancers in pregnancy were breast cancer (39%, n=462), followed by cervical (13%, n=147), lymphoma (10%, n=113), ovarian (7%, n=88), and leukemia (6%, n=68). 4 A population-based study from Sweden found that the most common cancer during pregnancy was melanoma (25%, n=232), followed by breast (15%, n=139), cervical (15%, n=139), and ovarian cancer (6%, n=54). 5 The change in treatment and outcome of cancer in pregnancy was reflected in the international cohort study. 3 For every five years of the study (1996-2016), treatment increased by 10% (95% CI 5-15) and use of chemotherapy increased by 31% (95% CI 20-43). Live birth rates increased and preterm births decreased. Maternal survival was similar to nonpregnant women treated for cancer and encouraging fetal, neonatal, and early childhood outcomes were observed in this study. As such, oncologic treatment is possible during pregnancy, often without significantly endangering maternal or fetal safety.

| DIAGNOSIS
Diagnosis of cancer is vital for successful treatment regardless of pregnancy status. Diagnosis of cancer in pregnancy is, unfortunately, often delayed; this is in part because many symptoms of malignancy are similar to the symptoms of pregnancy, including nausea/vomiting, breast changes, abdominal pain, anemia, and fatigue. Breast changes and the pregnant uterus may make physical examination difficult. In addition, the clinician may be more hesitant to assign the appropriate tests because of concerns that laboratory results may be inaccurate or that radiologic testing is harmful. Owing to its rarity, cancer might not be considered in the differential diagnosis. This delay in diagnosis can lead to late presentation, complex treatment, and poor prognosis. 6

| Laboratory testing
Tumor markers should be used with caution owing to pregnancy-

| Imaging
Imaging in pregnancy to diagnose and stage cancer may create conflict between maternal benefit and fetal risk. Therefore, the following issues need to be taken into account when choosing the appropriate imaging technique: 1. Safety of the fetus.

Risk of metastasis.
3. Viability of the fetus.
Radiation exposure above 100 mGy is associated with fetal malformation and childhood cancer. 10 If X-rays are needed, proper abdominal shielding should be provided. Mammogram images are increasingly difficult to interpret owing to physiological hypervascularity and density of the breast tissue. 11 Computed tomography (CT scan) is best avoided during pregnancy because of the unacceptable cumulative radiation and contrast doses. 12 Positron-emission tomography (PET) imaging in pregnancy is debatable owing to the risk to the fetus of radiation exposure. 13 Ultrasound as a tool for diagnosis and staging is used worldwide.
It is noninvasive and helps to perform guided biopsies of the breast and lymph nodes.
Magnetic resonance imaging (MRI) is safe in all trimesters of pregnancy. It is the imaging technique of choice for diagnosis and staging. 14 Histopathology of tissues provides definitive diagnosis of tumor type and grading. The pathologist should always be informed of the patient's pregnancy status to avoid incorrect diagnosis resulting from pregnancy-associated tissue changes. 15 Aside from the changes to the uterine corpus and ovaries, pregnancy has various effects on benign conditions that may mimic malignancy.

| Cervical cancer
Cervical cancers are best diagnosed by cytology in early pregnancy, but may also present with abnormal bleeding, vaginal discharge, and abdominopelvic pain. 16 Cervical cancers in pregnancy generally present as Stage I disease at diagnosis. Pregnant women are three times more likely to have Stage I disease than nonpregnant women with cervical cancer. 17 Management of preinvasive disease (CIN 1 to CIN 3) can be deferred until 6-8 weeks after delivery. However, it is recommended that a colposcopy is performed in each trimester to assess lesion size and disease progress. Colposcopy can be challenging during pregnancy owing to increased vascularity and an increase in genital edema. 18 Immediate definitive treatment, regardless of gestational age, is generally appropriate for invasive cancer in the following settings 19 : 1. Documented lymph node metastases.
2. Progression of disease during the pregnancy.

Patient choice to terminate the pregnancy.
Stage IA1 disease can be managed by conization and is best done between 12 and 20 weeks of pregnancy. 19 The term "coin biopsy" is sometimes used in pregnancy to highlight that the incision should not be deep enough to cause damage to the fetal membranes. This is best performed in theatre with adequate anesthesia. Prophylactic cerclage may be an option both for prevention of premature labor and management of operative bleeding.
In stages IA2-IB1 (less than 2 cm) disease, conization or simple trachelectomy can be performed because parametrial extension is seen in less than 1% of women. Simple trachelectomy is a less complicated procedure and is defined as excision of the cervix 1 cm above the tumor border. 20 However, it is necessary to assess lymph node status by laparoscopic pelvic lymphadenectomy before conservative surgery. In the event of node-positive disease, the woman should be told that immediate treatment is recommended. Laparoscopic lymphadenectomy is best performed before 20 weeks of pregnancy. 17,19 The second international consensus guidelines recommend this treatment in pregnancies of less than 22-25 weeks. 19 Abdominal and vaginal radical trachelectomy have also been performed during pregnancy, with variable pregnancy outcomes. Abdominal radical trachelectomy is technically more challenging and is associated with significant blood loss and prolonged surgery (3.5-7.5 hours, median 5.3 hours). 21 Obstetric outcome is poor and, therefore, radical trachelectomy is not recommended during pregnancy. 19 Stage IB1 tumors larger than 2 cm may be treated with neoadjuvant chemotherapy (NACT) with or without pelvic lymphadenectomy. Chemotherapy is relatively safe in the second trimester although there is a higher risk of preterm labor, premature rupture of membranes, and fetal growth restriction. NACT stabilizes the tumor until fetal maturity is achieved so that cesarean delivery and radical hysterectomy can be performed. In women with advanced pregnancy (greater than 22-25 weeks), pelvic lymphadenectomy is not possible and those with Stage IA1 to Stage IB1 disease can postpone definitive treatment until fetal maturity is achieved without compromising survival. NACT can also be given for locally advanced cancers and in advanced pregnancy to preserve pregnancy until optimal fetal survival Where pregnancy preservation is not desired or in advanced cases, pregnancy termination and treatment as in nonpregnant women is advocated. In early gestation (less than 12 weeks), spontaneous abortion occurs after pelvic radiation. In second trimester cases, hysterotomy followed by definitive chemoradiation is preferred because obstetric complications are fewer.

| Breast cancer
Breast cancer, although uncommon, is the most prevalent malignancy encountered in pregnancy and the postpartum period. The difficulty and delay in diagnosis may be attributed to pregnancyrelated changes in the breast and diagnostic challenges that allow these cancers to go undetected until the first postpartum year.
Breast cancers in pregnancy are usually larger in size, node positive, Stage II or III, high-grade invasive ductal cancer, and usually ER/PR/HER2/neu-negative. 23,24 Prognosis is related to tumor characteristics and delay in starting treatment and not to pregnancy alone.
When breast cancer is suspected in pregnancy, delay in diagnosis should be avoided. Mammography and ultrasound are the best imaging modalities; mammography has a sensitivity of more than 80% despite pregnancy-associated breast changes. 25 Ultrasound can be used to assess the extent of the disease in breast and lymph nodes and for guiding biopsies. 26 Core needle biopsy is the preferred modality.
Experience with MRI in pregnancy is limited and gadolinium-enhanced contrast is contraindicated in the first trimester because it crosses the placenta. A recent study of breast MRI showed 98% sensitivity in diagnosis of pregnancy-associated breast cancer and changed treatment modality in 28% of women. 27 Comprehensive staging studies are needed because breast cancer in pregnancy may present in advanced stage. Chest X-ray with abdominal shielding to evaluate the lungs and ultrasound for liver involvement are safe in pregnancy. Bone scans can be performed postpartum, but if a woman is symptomatic, noncontrast skeletal MRI is safe. 25 Treatment is as for nonpregnant women with the goal of achieving local control and preventing distant metastases. Modified radical mastectomy with axillary staging is the treatment of choice in the first trimester. Adjuvant chemotherapy can be started in the second trimester and radiation therapy given postpartum. 28,29 Breast conserving surgery can be done safely in the second and third trimesters. Experience in using sentinel lymph node biopsy (SLNB) in pregnancy is limited.
Blue dye is contraindicated but technetium-99m has been used safely.
Adjuvant chemotherapy with anthracycline-based regimes, such as various combinations of cyclophosphamide, doxorubicin, and fluorouracil, can be started in the second and third trimester. There are insufficient data to recommend taxanes, but paclitaxel can be used after the first trimester if indicated by disease status. Trastuzumab is contraindicated and oligohydramnios/anhydramnios have been reported.
Endocrine treatments including tamoxifen, aromatase inhibitors, and LHRH analogues are contraindicated in pregnancy due to the high risk of birth defects. If a woman becomes pregnant while on tamoxifen, pregnancy termination should be advised. 28,29

| Ovarian cancer
Adnexal masses are not uncommon in pregnancy and occur in roughly 1 in 600 to 1 in 1500 pregnancies. The majority of these are benign and only 1%-3% may be malignant. The most commonly encountered ovarian malignancy is germ cell, followed by sex cord stromal tumors, borderline tumors, and lastly invasive epithelial cancers. 30 The most common symptom is abdominal or pelvic pain and one-third of ovarian cancers are diagnosed incidentally. The majority of tumors present as Stage I, with a mean age of 25.8 years and 31.6 years in germ cell tumors and invasive epithelial cancers, and mean size of 18 and 12 cm, respectively. 31,32 Transvaginal and abdominal ultrasound have high sensitivity and specificity in the diagnosis of ovarian masses. However, MRI has the best diagnostic accuracy in the diagnosis of ovarian malignancy in pregnancy. 33  Bevacizumab is not recommended during pregnancy. Vaginal delivery is ideal in early-stage ovarian cancer treated surgically. In germ cell tumors, a BEP regime is considered too toxic because fetal growth restriction and neonatal complications are high. Weekly paclitaxel and cisplatin is recommended as per ESMO guidelines. 29 Advanced cancers (Stage III and IV) detected in the first trimester and early second trimester will need complete debulking surgery and adjuvant chemotherapy. In the late second and third trimesters, NACT is given until fetal maturity is reached. Cesarean delivery followed by complete cytoreductive surgery is feasible. Although pregnancy outcomes are good, prematurity, fetal loss due to surgical complications, and fetal growth restriction do occur. Oncological outcomes are the same as in nonpregnant women. 34

| Radiotherapy
Radiotherapy in a pregnant patient should be planned carefully.
The radiation oncologist and the physicist must minimize direct and indirect sources of radiation to the fetus. The fetal dose should not exceed 50-100 mGy. 35 The risks at various times of fetal development are summarized in Table 1.
Scatter and leakage radiation are a concern even with proper shielding, although adequate shielding can minimize risks. Shielding

| Chemotherapy
After the first trimester, most chemotherapeutic agents can be used with relative safety. Transplacental transport of chemotherapeutic agents differs widely, with some agents such as paclitaxel crossing the placenta at a low rate, anthracyclines crossing the placenta at an intermediate rate, and carboplatin at a high rate. 8,9 Despite this, carboplatin administered after 12-14 weeks of pregnancy seems to do little harm to the developing fetus. 37 Trastuzumab is generally contraindicated in pregnancy because of HER2 receptors on the kidneys of the fetus, resulting in oligo-or anhydramnios and fetal lung hypoplasia. The antifolates, such as methotrexate, are also contraindicated.
The risk of congenital malformation is linked directly to gestational age and before 12 weeks there is a risk for abnormalities of the eyes, ears, and blood systems; the risk decreases significantly after complete organogenesis.
Chemotherapy may cause a significant reduction in maternal blood production, leading to low platelet counts and risk of overwhelming infection. When chemotherapy is used, timing of delivery should be planned carefully. Elective delivery should not be planned within three weeks after chemotherapy. For this reason, chemotherapy should not be administered after 37 weeks of pregnancy owing to risk of spontaneous onset of labor.
Long-term follow-up of children born to mothers who received chemotherapy during pregnancy does not indicate an increased risk of congenital abnormalities or mental delay. The number of children with long-term follow-up is still small and the data should be interpreted with caution. Potential risks include concern for cardiac function in children exposed to anthracyclines during the fetal period.
Anthracyclines are commonly used for breast cancer treatment and have a direct effect on cardiac function. In a follow-up study of 17 children, no changes in electrocardiogram or echocardiography could be found after the use of anthracyclines.

| Surgery
Cancer surgery in pregnancy may be indicated for diagnosis, treatment, and staging. Surgery is urgent but not an emergency and may be delayed until fetal maturity is established without compromising total care. As a principle, surgical procedures are best undertaken in the second trimester to prevent spontaneous abortion. 38,39 Surgery in the second trimester is technically less complicated compared with in the third trimester owing to the size of the uterus. When surgery is performed after 28 weeks, tocolytics should be administered to prevent premature labor and corticosteroids to enhance lung maturity. Handling of the uterus should be kept to a minimum.
Unilateral or bilateral oophorectomy can be carried out safely after the first trimester. Whenever possible, regional anesthesia is preferred over general anesthesia owing to the potential risk of aspiration. 40 A lateral tilt during surgery may help to prevent aortocaval compression. 41 The patient should be consented for emergency cesarean delivery in the third trimester if fetal compromise is encountered.
Therapeutic surgery can be performed in any trimester.

| PLACENTAL AND FETAL TUMOR INVOLVEMENT
Metastatic disease to the placenta and the fetus is rare. The most likely tumors to metastasize to the placenta include melanomas and hematological malignancies. In all cases where malignant spread is T A B L E 1 Risks to the fetus of radiotherapy during pregnancy. a