14.18 Malignant disease in pregnancy 2696

14.18 Malignant disease in pregnancy 2696

ESSENTIALS Cancer in pregnancy is rare, affecting less than 1 in 1000 live births. It may be specific to pregnancy (gestational trophoblastic disease) or incidental to it, the less infrequent conditions being melanoma, lymphoma, breast and cervical malignancy. Malignant disease particular to pregnancy Gestational trophoblastic disease—​a group of conditions that arise in the fetal chorion during various types of pregnancy: histologically they are categorized as (1) partial or complete hydatidiform mole, (2) gestational choriocarcinoma, or (3) placental site trophoblastic tumour. The most common of these conditions is molar pregnancy, when villi are present in association with malignant trophoblast in gestational choriocarcinoma. Any woman of reproductive age who has an undiagnosed tu- mour or unexplained bleeding from any organ other than the uterus should have a human chorionic gonadotrophin estimation to ex- clude highly treatable gestational trophoblastic disease. General aspects of management during pregnancy Consideration must be given both to the mother who is affected and the unborn fetus, with the balance of care favouring the mother’s well-​being. Anaesthesia and extra-​abdominal surgery—​ rarely carries risks in the second trimester. Ionizing radiation—​exposure during the first trimester increases the risk of fetal abnormalities and childhood cancers. Chemotherapy—​administration during the first trimester increases risk of miscarriage and congenital abnormalities, but administration after organogenesis may be appropriate. Introduction Cancer is rare during pregnancy, occurring in only about 1 per 1000 live births. Most malignancies affecting this age group have been seen during pregnancy. Tumours of the uterine cervix, ovary, breast, or thyroid can metastasize to the placenta, but not to the fetus. Gestational trophoblastic disease arises from fetal chorion and is a malignant transformation of the placenta. Melanoma and haematological tumours, which also can invade the placenta, may cross into the fetal circulation. Pregnancy may cause enlargement of a pituitary tumour and a previously silent tumour may present with symptoms in pregnancy. Rare cases of colonic and neurological can- cers developing in pregnancy have been reported. Concurrence of pregnancy and cancer raises complex therapeutic and ethical dilemmas because the most appropriate and timely treat- ment for the mother may not be in the best interests of the fetus. Anaesthesia and extra-​abdominal surgery during pregnancy rarely carry any risks to the fetus, and intra-​abdominal surgery may be safely carried out in the second trimester. However, fetal cells divide and differentiate rapidly during the first trimester, hence radiation and chemotherapy carry well-​recognized risks to the fetus, including the risk of miscarriage, congenital abnormalities, or preterm birth. As a result, physicians may be reluctant to treat the mother aggres- sively at the time of initial diagnosis, preferring to defer treatment for several weeks or months until the fetal lungs have matured, a delay which may substantially reduce the mother’s chance of sur- viving the disease. It is impossible to establish a threshold dose of ionizing radiation below which such treatment is safe for the fetus, inasmuch as exposure during the first trimester to a dose as low as 10 cGy appears to increase the risk of fetal abnormalities and exposure to 3–​5 cGy increases the risk of childhood cancers. The risk is negligible if exposure to the fetus is less than 1 cGy. The dose of radiation, the gestational age of the fetus, and the practicability of shielding the fetus from radiation must be balanced against potential benefits to the mother. Chemotherapy administered to the mother during the first tri- mester carries well-​recognized risks that include miscarriage or congenital abnormalities. Drugs that preferentially interfere with rapidly growing tissues (e.g. methotrexate), can harm the fetus. Use of antagonists of folate, purine, or pyrimidine synthesis during organogenesis result in congenital malformations in up to 25% of fetuses, although this figure is much lower if the mother only re- ceives therapy with a single agent. Treatment after the first trimester, when structural development is largely complete, is reasonably safe in many diseases and more appropriate than postponement of treatment. Chemotherapy after the first trimester has been asso- ciated with slight increases in the incidence of preterm birth and fetal growth restriction and, when administered shortly before de- livery, with transient neonatal myelosuppression. Nevertheless, the 14.18 Malignant disease in pregnancy Robin A.F. Crawford

14.18  Malignant disease in pregnancy 2697 long-​term outcomes of the children of women who received chemo- therapy during the second or third trimester are generally good. In practical terms, acute leukaemia is virtually the only condition requiring immediate chemotherapy in a pregnant woman. When faced with cancer in the first trimester, the available information should be explained to the woman and her partner, who should give informed, unhurried consent before treatment starts. In most situ- ations a consensus decision to proceed with chemotherapy can be reached between the woman, her partner, and the responsible phys- ician, but the ethical issues are very complex, and decisions must be made on an individual basis. Increasing success with the treatment of childhood cancers means that more women are entering the reproductive age group having survived cancer treatment. An increased incidence of spontaneous miscarriage, low birth weight babies, and neonatal deaths has been described in women with Wilms’ tumour who had received at least 20 Gy abdominal radiation. Survivors of Hodgkin’s disease treated with both radiation and chemotherapy (but not either alone) also appear to be at increased risk of spontaneous miscarriage. However, based on series of several thousand children there appears to be no overall increased risk of either congenital malformations or child- hood cancers in the offspring of cancer survivors. Malignant diseases specific to pregnancy Gestational trophoblastic disease Gestational trophoblastic disease is a group of diseases that arise in the fetal chorion during various types of pregnancy. Histologically they are categorized as one of two types of hydatidiform mole (par- tial or complete), gestational choriocarcinoma, or placental site trophoblastic tumour (Table 14.18.1). Gestational trophoblastic disease is notable for several reasons. First, the tumours are genetically different from the host, having antigens derived from the male partner. Secondly, apart from pla- cental site tumour, they secrete human chorionic gonadotrophin (hCG) in amounts proportional to the viable tumour volume, al- lowing hCG to be used as an ideal tumour marker. Thirdly, even metastatic disease can be cured with chemotherapy, the use of methotrexate in the early 1950s having shown reproducible results. Complete and partial hydatidiform moles present as abnormal pregnancies ending in first or second trimester miscarriages. Gestational choriocarcinoma is a highly malignant tumour derived from syncytial and cytotrophoblastic cells. When villi are present in association with malignant trophoblasts, it is classified as a molar pregnancy. If there is diagnostic doubt about the possibility of com- bined molar pregnancy with a viable fetus, then ultrasound scan- ning should be repeated before intervention. If a twin pregnancy is associated with a partial mole, it should be allowed to proceed; if a twin pregnancy is associated with a complete mole, it may proceed after appropriate counselling. These pregnancies are associated with a reduced live birth rate of 25% and are at risk of pre-​eclampsia and haemorrhage. The subsequent need for chemotherapy in these rare cases is about 20% and is the same whether the pregnancy is termin- ated spontaneously or therapeutically, or allowed to proceed to term. Gestational trophoblastic disease arises in various types of preg- nancy, most of which are clinically recognized as abnormal. The in- cidence is 1.54 per 1000 live births. The most common are molar pregnancies, but gestational trophoblastic disease can also arise fol- lowing miscarriages, ectopic pregnancies, or even normal full-​term pregnancies. Clinical surveillance of patients who have had a molar pregnancy is the only practical method of detecting and preventing gestational trophoblastic disease. In the United Kingdom all patients with a histological diagnosis of a molar pregnancy are registered and followed up at one of three screening centres (Charing Cross Hospital in London, Sheffield, and Dundee). Only 7.5% of women with hydatidiform mole require chemotherapy, and more than half of the patients who require chemotherapy for gestational tropho- blastic disease have a preceding molar pregnancy. Patients who develop gestational trophoblastic disease after a miscarriage or full-​term pregnancy are more difficult to detect. They present with symptoms attributable to metastases, the sites of initial metastasis being (in order of frequency) lung, vagina, brain, liver, gastrointestinal tract, and kidney. The interval between preg- nancy and the development of metastatic gestational trophoblastic disease may be years. Because these tumours are rare, many clin- icians are unfamiliar with them and do not consider gestational trophoblastic disease as part of any differential diagnosis. Any woman of reproductive age who has an undiagnosed tumour or un- explained bleeding from any organ other than the uterus should have an hCG estimation to exclude highly treatable gestational trophoblastic disease. Patients with gestational trophoblastic disease are classified as having a low or high risk depending on a scoring system devised at Charing Cross Hospital and now modified by the World Health Organization. The score relies on factors such as age, the antecedent pregnancy, the interval between presentation and the previous preg- nancy, the hCG level, the blood group, the size of the largest tumour, site, and number of metastases, and whether the patient had previ- ously received chemotherapy. In the United Kingdom the low-​risk group will be offered methotrexate with folinic acid rescue. The high-​risk group and those low-​risk patients who have resistant or persistent disease will be offered combination chemotherapy. The initial diagnosis may be made by surgical excision or biopsy of a sus- picious lesion, but surgery otherwise has little role, excepting rarely to remove a cerebral metastasis to prevent a cerebral bleed. The overall survival for patients with gestational trophoblastic disease is now about 94%. Women should be advised not to con- ceive for six months after a negative hCG reading. The risk of further molar pregnancy is low (1 in 74). Table 14.18.1  Types of hydatidiform mole Type of hydatidiform mole Genetic basis Clinical presentation Partial mole Triploid with paternal, maternal, and fetal elements Usually diagnosed on products of conception pathologically Complete mole Diploid (parental origin) with no fetal elements Commonly diagnosed on ultrasound

Section 14  Medical disorders in pregnancy 2698 Malignant diseases not specific to pregnancy The cancers observed in pregnancy are similar to those seen in the non​pregnant woman (Table 14.18.2). Fewer cancers are diagnosed during pregnancy than might other- wise be expected, most markedly so in breast, cervix, and ovary. Melanoma Melanoma in pregnancy is unusual in that it can metastasize to the placenta and to the fetus. As this is a rare phenomenon, therapeutic abortion is not indicated, but careful examination and follow-​up of the baby is warranted. Current evidence suggests that the clinical outcome for pregnant patients is similar to that of those who are not pregnant. Early detection and biopsy are performed as usual, and the surgical management is the same. Since most recurrences of melanoma occur in the first three years following initial diagnosis, it may be appropriate to delay further pregnancies until this time period has elapsed. Gynaecological cancers Cancer of the cervix The incidence of cervical cancer during pregnancy may be falling in those countries that have introduced effective cervical screening programmes. Pregnant women with cervical cancer generally pre- sent with early stage disease, their prognosis being similar to that of patients who are not pregnant. The presenting symptom is usually vaginal bleeding, hence it is important to check the cervix with a visual examination when pregnant women present with irregular vaginal bleeding. There is a tendency to assume that vaginal bleeding in early pregnancy is re- lated to miscarriage, organize an ultrasound scan to check for fetal viability, and forget vaginal examination. In the case of an obvious cancer, a wedge biopsy under general anaesthetic is appropriate for diagnosis and staging. If there is any doubt, colposcopy can be used to assess the cervix. There is an increased risk of bleeding when taking a biopsy from the pregnant cervix, but there is no increased rate of fetal loss. Patients with cervical intraepithelial neoplasia can be managed expectantly until after delivery. There is no contraindication to a vaginal delivery for women with cervical intraepithelial neoplasia; indeed, there are several series which suggest that vaginal delivery is associated with a higher rate of regression of severe dysplasia than is usually seen. Standard practice would be to review with colposcopy at about three months after delivery. Management of women with microinvasion of the cervix is usually via cone biopsy under a gen- eral anaesthetic, allowing the pregnancy to continue. When cervical cancer is diagnosed in early pregnancy, treatment options include immediate radical hysterectomy or delaying treat- ment until the fetus is viable, followed by classical caesarean section (scar in the upper segment of the uterus) and radical hysterectomy. This is appropriate for stage 1B cases, where the tumour is confined to the cervix and is less than 4 cm in diameter. In one series there was no difference in survival between the two modes of treatment. Typically, women diagnosed in the first trimester will be offered im- mediate surgery. Women diagnosed after 24–​28 weeks’ gestation are usually managed expectantly until after 32 weeks’ gestation and then delivered by caesarean radical hysterectomy. Steroids are usually given to accelerate fetal lung maturity. The outlook may be worse for patients who deliver vaginally across a cervical cancer, but this has not been substantiated. Cancer of the ovary The incidence of adnexal masses occurring in pregnant women has been reported as being as rare as 1 in 2500 to as frequent as 1 in 81 live births. With the use of routine early ultrasound, the true inci- dence of adnexal masses is closer to the latter figure. Most of these (>95%) are benign. Complications of a benign adnexal mass include pain due to torsion, rupture, or haemorrhage; obstruction of the pelvic outlet; and infection. Most cysts are managed conservatively, avoiding surgery, but when necessary surgery to remove cysts is usually performed in the second trimester. The advantage of waiting until the second trimester is that most cysts resolve spontaneously and that the rate of fetal loss is reduced. The rationale for removing a persistent adnexal mass is to exclude malignancy, but ovarian cancer in pregnancy is rare because the Table 14.18.2  Incidence of cancer during pregnancy Type of cancer Number of cases during pregnancy of women aged 15–​44 years
in Sweden, 1963–​2007 Incidence rate of pregnancy-​associated cancer in
New South Wales (Australia), 1994–​2008 Total number Rate per 100 000 live births Rate per 100 000 maternities Melanoma 232 5.1 15.1 Breast 139 3.0   7.3 Cervix 139 3.0   1.8 Ovary 54 1.2   1.5 Colon 44 1.0   0.8 Endocrine glands 43 0.9   3.2 (combined endocrine and thyroid) Nervous system 42 0.9   0.9 Thyroid 37 0.8   –​ Hodgkin disease 35 0.8   4.0 (lymphohaematopoietic) Leukaemia 20 0.4   –​ From Andersson TM, et al. Cancer 2015; 121: 2072–​7. From Lee YY, et al. BJOG, 2012; 119: 1572–​82.

14.18  Malignant disease in pregnancy 2699 usual age of childbirth is greater than the peak incidence of germ cell tumours and substantially less than the usual age of those with epithelial cancer. In addition, pregnancy protects against ovarian cancer. Two-​thirds of the cancers detected are epithelial and the remaining are germ cell (usually dysgerminoma) and stromal cell types. Cysts that are simple on ultrasound scan and less than 5 cm in diameter have almost no malignant potential: larger cysts with nodules, septa, or rapid growth are more likely to be malignant. Tumour markers are not helpful in pregnancy: CA-​125 can be raised by pregnancy, as can α-​fetoprotein and hCG. The management of the ovarian cancer is similar to that in the non​pregnant woman. Appropriate surgical staging is required, the author’s preference being removal of the cyst, taking of peritoneal washings for cytology, biopsy of the contralateral ovary, and biop- sies of any abnormal areas are sufficient at the primary operation. It is also preferable to wait 48 h for a definitive diagnosis from paraffin sections, rather than expect the pathologist to give an immediate result from frozen section. This delay also allows the woman and her partner to consider the implications of the diagnosis. Most of the women seen with a malignant diagnosis in pregnancy will have early stage epithelial cancer: FIGO stage 1A or B, meaning a well or moderately differentiated tumour confined to one or both ovaries, or will have borderline histology. No further therapy would then be necessary. Therapeutic termination is not required and preg- nancy per se does not worsen outcome. Fuller staging may be con- sidered 6–​12 weeks after delivery. The decision to use chemotherapy postoperatively depends on the stage and differentiation of the tu- mour, the gestational age of the fetus, and the wishes of the mother. The treatment of malignant germ cell tumours can be carried out without affecting the pregnancy in the second two trimesters, espe- cially if alkylating agents are avoided. Other gynaecological cancers Other gynaecological cancers are rarely seen. Cancer of the endo- metrium is associated with infertility in the reproductive age group and cancer of the vulva is predominantly a disease of older women. Cancer of the breast Gestational breast cancer is defined as a breast cancer presenting ei- ther during pregnancy or up to one year postpartum. It was originally thought that pregnancy-​related cancer carried a worse prognosis, but this has not been substantiated. Although breast cancer is re- garded as a hormone-​dependent tumour, termination of pregnancy and oophorectomy do not provide a better outcome for the woman. Women becoming pregnant after treatment for breast cancer have a similar or better survival when controlled for age and stage. Breast cancer is often diagnosed at a late stage as breast lumps may be difficult to detect against a background of pregnancy-​related hypertrophy. Consequently, investigation of masses is often de- layed. Mammography is not harmful to the fetus with appropriate shielding. When a breast mass is found, the most important step is to make a histological diagnosis. If the diagnosis of breast cancer is made, treatment is the same as for the non​pregnant woman. Chemotherapy in the first trimester is associated with risks for the developing fetus but may be given after the first trimester and evi- dence supports treating with chemotherapy and continuing the pregnancy until term as the best option for the baby. Suppression of lactation as a therapeutic manoeuvre is not neces- sary, with two exceptions. Firstly, if breast surgery is required during the puerperium, suppression of lactation can decrease the size and vascularity of the breast and allow a safer surgical procedure. Secondly, suppression of lactation is recommended in women re- ceiving chemotherapy as some of the drugs can reach the breast milk and cause neonatal neutropenia. Cancer of the colon The reported incidence of colorectal cancer in pregnancy may now be an underestimate as a reflection of the trend for women to delay pregnancy until later in life. By contrast, with increased awareness of inherited genetic traits and the availability of genetic testing, more and more patients at risk (e.g. those with familial adenoma- tous polyposis and hereditary non​polyposis coli) are undergoing screening, which may reduce the numbers of pregnant women diag- nosed with colon cancer. Colorectal cancer in pregnancy is particularly common in the rectal region, below the peritoneal reflection. The importance of this is that 88% of tumours are within reach of the flexible sigmoido- scope, allowing detection with a minimum of inconvenience to the patient and no risk to the fetus. Presenting symptoms are similar to those in non​pregnant women. However, the combination of altered bowel habit, abdom- inal pain/​swelling, and anaemia is common in pregnancy, such that these symptoms are frequently ascribed to the pregnancy itself. Assessment of the pregnant patient with colorectal cancer is similar to that of the non​pregnant patient. Radiological imaging is avoided in the first trimester. Carcinoembryonic antigen is not affected sig- nificantly by pregnancy and so can be used as a marker. Patients younger than 40 years generally have a poorer prognosis because of delayed diagnosis and advanced stage at presentation. Pregnant women are no different in this respect. The overall fetal prognosis is relatively favourable as the diagnosis is usually made close to term and the fetus can be delivered coincident with the sur- gery for the colon cancer. Thyroid and other endocrine cancers It is not uncommon to find thyroid nodules that require further in- vestigation during pregnancy. Most cancers are well differentiated, with a very good prognosis. When a diagnosis is made, treatment proceeds as normal, with the exception that radio-​iodine is contra- indicated. Cancers discovered early in the pregnancy can be treated surgically in the second trimester. Tumours discovered in later preg- nancy can be investigated and treated after delivery. Thyroxine is given to reduce the level of thyroid-​stimulating hormone. There is no evidence to suggest that pregnancy alters the outcome for thy- roid cancer. Thyroid cancer is not an indication for termination of pregnancy. Phaeochromocytoma is rare in pregnancy but has been described. It is difficult to diagnose because elevation of blood pressure is al- most invariably attributed to pregnancy-​induced hypertension, which is very much more common. Lymphoma Hodgkin’s disease is a disease of young adults (mean age 32 years), hence it is not surprising that there are more cases diagnosed in

Section 14  Medical disorders in pregnancy 2700 pregnancy than there are of non-​Hodgkin’s lymphoma (mean age of diagnosis 42 years). Although it was historically believed to be exacerbated by preg- nancy, there does not seem to be any influence of pregnancy on the outcome for Hodgkin’s disease. If treatment is required, most patients can be managed without compromise to mother or fetus. Patients presenting with localized Hodgkin’s disease relatively late in pregnancy may be observed with limited staging and not treated until after delivery. By contrast, in non-​Hodgkin’s lymphoma, pa- tients with Burkitt’s lymphoma in pregnancy appear to have a highly aggressive disease involving the breast or ovary. A recent study of 39 cases (31 Hodgkin, 8 non-​Hodgkin) reported overall survival 82% and progression free survival 75% at five years. Leukaemia Leukaemia in pregnancy is rare. This may be because most cases of acute lymphoblastic leukaemia occur before reproductive age and most cases of acute myeloid leukaemia occur afterwards. Chronic lymphocytic leukaemia is a disease of older people, hence chronic myeloid leukaemia constitutes 90% of the cases of chronic leu- kaemia seen in pregnancy. Since the introduction of intensive chemotherapy, the survival of pregnant women with leukaemia is similar to that of non-​ pregnant women. It does not appear that intrauterine exposure to antileukaemic chemotherapy produces detrimental late effects on the resulting children. Women treated with non​alkylating agents have no apparent decrease in fertility, although this is reduced by one-​third when alkylating agents are used. FURTHER READING Amant F, et al. (2012). Breast cancer in pregnancy. Lancet, 379, 570–​9. Barnea ER, Jauniaux E, Schwartz PE (eds) (2001). Cancer and preg- nancy. Springer, London. Charing Cross Hospital Trophoblast Disease Service. Hydatidiform Mole and Choriocarcinoma UK Information and Support Service. http://​www.hmole-​chorio.org.uk Morice P, et al. (2012). Gynaecological cancers in pregnancy. Lancet, 379, 558–​69. Ngan S, Seckl MJ (2007). Gestational trophoblastic neoplasia manage- ment: an update. Curr Opin Oncol, 19, 486–​91. Royal College of Obstetricians and Gynaecologists (RCOG) (2011). Pregnancy and Breast Cancer (Green-​top Guideline No. 12). https://​www.rcog.org.uk/​globalassets/​documents/​guidelines/ ​gtg_​12.pdf Wright TC Jr, et al. (2007). 2006 consensus guidelines for the manage- ment of women with cervical intraepithelial neoplasia or adenocar- cinoma in situ. Am J Obstet Gynecol, 197, 340–​5.