Australian and New Zealand Journal of Obstetrics and Gynaecology 2003; 43: 414– 420
Review Article
Blackwell Publishing Ltd.
Gynaecological malignancies in pregnancy
Gynaecological malignancies in pregnancy: A review Martin K. OEHLER, Gerard V. WAIN and Alison BRAND Department of Gynaecological Oncology, Westmead Hospital, University of Sydney, Westmead, New South Wales, Australia
Abstract Gynaecological malignancies frequently occur in women of reproductive age and are estimated to complicate approximately one in 1000 pregnancies. The incidence of gynaecological malignancies during pregnancy is expected to rise as more women delay childbearing into their later reproductive years, and maternal age is the most powerful predictor of cancer risk. Pregnancy-associated malignancies present significant challenges as a result of the conflict between optimal maternal therapy and fetal well-being. The lack of prospective randomised treatment studies has prevented the development of clinical guidelines for most of the issues complicating the management. In the present review, recent diagnostic and treatment strategies for cervical, ovarian, vulvar and endometrial carcinomas during pregnancy are presented. Key words: cancer, cervical cancer, endometrial cancer, ovarian cancer, pregnancy, review, vulvar cancer.
Introduction Gynaecological cancers are among the most common malignancies.1 They frequently occur in reproductive age women and it is estimated that gynaecolgical malignancies complicate approximately one in 1000 pregnancies.2 This number is expected to rise as more women delay childbearing into their later reproductive years and maternal age is known to be the most powerful predictor of cancer risk.3 The most common gynaecological malignancies associated with pregnancy are cervical and ovarian cancer. Reported incidences vary considerably as population series or geographical studies are rare and most data are from single hospital institutions (Table 1).3–8 Incidences of other gynaecological malignancies such as endometrial cancer or vulvar cancer during pregnancy are very low and only small series or single cases have been reported. Pregnancy-associated malignancies present significant challenges as a result of the conflict between optimal maternal therapy and fetal well-being. In addition, cancer diagnosis may be delayed because of difficulties in distinguishing symptomatology from physiologic changes in pregnancy and the difficulty in applying the standard diagnostic work-up in a pregnant woman. Finally, the lack of prospective randomised treatment studies and therefore objective data has prevented the development of clinical guidelines for most of the issues complicating the treatment of pregnancy associated cancer.
Cervical cancer Carcinoma of the cervix is one of the most common malignancies diagnosed in pregnancy. The incidence of 414
invasive cervical cancer is approximately one in 4500–9000 pregnancies, while cervical intra-epithelial neoplasia (CIN) is estimated to occur in 1% of the pregnant population.4–6,9 Pregnancy-associated invasive cervical cancer is usually diagnosed at an early stage (approximately 70% stage Ia, Ib and IIa). It is, also, three times more likely to be stage I disease when compared with a cervical malignancy diagnosed in a non-pregnant women. 10 This might be explained by routine examinations during antenatal care but also by the younger age of pregnant women in comparison to the average cervical cancer patient. Pregnant women with early cervical cancer are usually asymptomatic and diagnosed by abnormal cytology. The antenatal care visit offers a good opportunity to carry out routine cervical cytology. Cervical cancer should therefore be a malignancy for which screening is a standard component of antenatal care. A pregnant woman with a low grade abnormality in her cervical cytology should have the Pap smear repeated after 12 months. However, in some pregnant women with increased anxiety about both her fetus and the pregnancy, a colposcopy can be appropriate in order to alleviate unjustified anxiety. In the case of a high grade abnormality during pregnancy an early colposcopy is mandatory. It is usually feasible to visualise the complete transformation zone as a result of the eversion of the squamocolumnar junction associated with
Correspondence: Dr Martin K. Oehler, Department of Gynaecological Oncology, Westmead Hospital, University of Sydney, Westmead, New South Wales 2145, Australia. Email:
[email protected] Received 6 August 2003; accepted 8 September 2003.
Gynaecological malignancies in pregnancy
Table 1 Incidences of cervical and ovarian cancer in pregnancy Malignancy Cervical cancer Ovarian cancer
Incidence 1:4500 –9000 1:12 500 –25 000
the pregnant state. Nevertheless, increased vascularity and decidual changes of the cervix can make the interpretation of colposcopic findings difficult and a high degree of expertise is warranted. Experienced colposcopists will usually not carry out a biopsy when invasive cancer has been excluded. The likelihood of a high grade lesion progressing to invasive disease during pregnancy is extremely low, whereas treatment of a high grade lesion in pregnancy is associated with an increased risk of complications and persistence of disease. Nevertheless, a repeat colposcopy should be carried out between 24 and 28 weeks’ gestation to exclude progression of disease. Furthermore, because of a high persistance rate for high grade lesions after pregnancy adequate post-partum follow-up and treatment are warranted.11,12 If there is suspicion of invasive cancer a colposcopically directed punch biopsy should be taken. These biopsies are rarely associated with severe haemorrhage, infection or preterm labour.13 Endocervical curettings, however, are contraindicated in pregnancy. An occult endocervical malignancy might therefore create an extremely difficult diagnostic challenge. In this case, sampling of the endocervix with the cervical brush might be an alternative with an acceptable morbidity rate.14 A suspected microinvasive lesion on colposcopy or biopsy may be an indication for a cold knife conisation during pregnancy. This procedure carries a risk of significant morbidity for both the mother and fetus with excessive bleeding, usually more common in the third trimester, and a postconisation abortion/miscarriage, highest in the first trimester.13 As the size of the conisation affects the outcome of the procedure and deep cones are rarely required because of the eversion of the squamocolumnar junction, shallower biopsies like socalled ‘coin’ or ‘wedge’ biopsies usually provide an adequate specimen.15,16 Once diagnosed, invasive cervical cancer is clinically staged according to the International Federation of Gynaecology and Obstetrics (FIGO) classification as this provides information affecting the treatment to be chosen and the prognosis of the patient. Pregnancy and the tissue changes around the cervix, sometimes make clinical assessment difficult. Although FIGO staging is derived from physical examination, an additional chest X-ray and computed tomography scan of the abdomen and pelvis are usually recommended in the non-pregnant state to exclude distant metastasis and pelvic lymph node involvement. As those modalities involve ionising radiation which may have deleterious effects on the embryo/fetus alternative procedures are recommended in pregnancy. Magnetic resonance imaging (MRI) of the abdomen-pelvis and the chest will most often be the procedure of choice because this does not involve
radiation. However, if an MRI is not available, a two-view chest X-ray with proper shielding is also appropriate for examining the lungs of a pregnant patient.17 Management of invasive cervical cancer in pregnancy is dependent on: (i) gestational age at diagnosis; (ii) stage of disease; (iii) the mother’s beliefs regarding pregnancy termination and (iv) future childbearing desires. A microinvasive cervical cancer (Ia1) without lymphovascular invasion is sufficiently treated by excision with negative margins. In this case the pregnancy can be safely continued and a vaginal delivery carried out. A repeat colposcopic examination should be performed post-partum. Choice of treatment of more advanced (non-microinvasive) cervical cancer does not differ in pregnant compared to nonpregnant women. It depends on the depth of invasion and local extent of the tumour: when the tumour is limited to the cervix or extends only to the upper two-thirds of the vagina (Ia2-IIa), radical hysterectomy and radiation-chemotherapy are both treatments of choice, yielding similar outcomes. However, most pregnant patients eligible for radical surgery might benefit from surgery rather than radiation, given the advantage of ovarian preservation and the avoidance of radiation-induced vaginal fibrosis. In higher stages combined radiation-chemotherapy is the treatment of choice. As those treatment options are incompatible with continuation of pregnancy the timing of therapy, to attain fetal maturity without compromising maternal prognosis, is a critical issue. Although it is difficult to apply strict rules, it is usual to proceed with the definitive therapy if the patient is at less than 20 weeks’ gestation, and to sacrifice the fetus in doing so.18 Radical hysterectomy or radiation therapy are commonly performed with the fetus in situ. Radiotherapy in the first trimester usually induces a spontaneous abortion after a mean dose of 34 –40 Gy.19 If the decision is made to proceed with treatment after 20 weeks’ gestation, evacuation of the uterus before surgery or radiation is recommended, especially to avoid protracted miscarriage under radiation.20 Neither radical hysterectomy nor radiation treatment has been reported as having a higher complication rate in pregnant women compared with nonpregnant controls.21,22 Several cases of women with advanced local disease who opposed a termination and were therefore treated with neoadjuvant platinum-chemotherapy in an attempt to prevent disease progression while gaining time for the fetus to mature have been reported.23,24 As a result of the small number of cases and the short follow-up period, the information on the outcome of the mother is limited and this approach still has to be considered experimental. However, no adverse effects on a fetus or child by the neoadjuvant chemotherapy have been reported.23,24 After 20 weeks’ gestation delay of treatment to allow the patient to go to term is an option which has to be assessed critically. Most case series (approximately 20 published works) reporting on patients with early stage (IA or IB) disease who had treatment delay after 20 weeks’ gestation did not observe an adverse maternal outcome.18 However,
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Ovarian cancer is the second most frequent gynaecological cancer complicating pregnancy. Although the overall incidence of ovarian cancer is very low (one in 12 500–25 000 pregnancies), the routine use of ultrasound in pregnancy has led to more frequent findings of adnexal masses, making diagnosis and management increasingly challenging. The estimated incidence of ovarian tumours is approximately one in 1000 pregnancies. Of those tumours approximately 3–6% are malignant.8 The histological properties of ovarian tumours discovered during pregnancy are shown in Table 2.8,29–31 A significant number of pregnant women are asymptomatic and are found to have an adnexal mass on physical examination, during ultrasound or at the time of Caesarean section. Ovarian masses, however, may also cause various complications such as ovarian torsion, haemorrhage and rupture of cysts, sometimes requiring emergency laparotomy.
Adnexal masses during pregnancy are treated according to the patient’s symptoms, and the degree of suspicion regarding malignancy derived from the tumour’s characteristics, including imaging and the gestational age. Simple, unilateral masses less than 5 cm in diameter detected in the first trimester are functional in most cases and represent follicular or corpus luteum cysts. More than 90% of these functional cysts involute and are undetectable by the 14th week of gestation.32 However, if adnexal tumours are greater than 5 cm in diameter, persist into the second trimester, are found in both adnexa and/or have ultrasonographic features including solid components, papillary projections, septations or multicystic appearance, further investigation is warranted. Magnetic resonance imaging, as an imaging modality without ionising radiation exposure, may provide additional information on a pelvic mass detected during ultrasound. Small studies suggested that MRI aids in the differential diagnosis of ovarian masses thus permitting expectant management in a subset of women.33 Most of the common tumour markers for ovarian neoplasms, such as CA125, α-fetoprotein, human chorion gonadotropin, lactate dehydrogenase and inhibin are elevated and fluctuate with gestational age. They are therefore of limited value during pregnancy. CA125 concentrations, for example, peak in the first trimester, return to normal levels in the second trimester and usually rise again after delivery.34 One exception, however, is the carcinoembryonic antigen; it is known to stay in normal range during pregnancy and might therefore be useful for monitoring if produced by the ovarian tumour.35,36 If surgical intervention is indicated and none of the above mentioned complications warrant emergency surgery, laparotomy is commonly delayed until 16–18 weeks’ gestation. At this time hormonal dependence of the pregnancy from the corpus luteum and the risk of spontaneous abortion is minimised.37 Surgical exploration using a midline incision is recommended to limit uterine manipulation and to enable adequate staging and debulking. Depending upon the appearance of the adnexal mass either a simple cystectomy or oophorectomy is carried out after peritoneal washings have been collected. A frozen section diagnosis must be made to guide further decisions. Consistent with the young age of these patients, germ cell tumours and epithelial borderline malignancies are common ovarian malignancies in pregnancy (Table 3).15,38,39 In the germ cell category, dysgerminomas are most frequently encountered in pregnancy. For most patients with
Table 2 Histology of ovarian tumours in pregnancy
Table 3 Histology of ovarian malignancies in pregnancy
other groups have reported on a negative impact on maternal prognosis if treatment was delayed.25 Therefore, at present insufficient data are available to make a definitive statement regarding the safety of a delay of cervical cancer treatment in pregnancy. Nevertheless, delaying the treatment of cervical cancer diagnosed in the third trimester is widely accepted, as the capabilities of modern neonatal intensive care have led to an improved fetal salvage rate, particularly after 28 weeks, which enables an earlier delivery once fetal lung maturation is completed. The mode of delivery should be selected carefully for a woman with cervical cancer. The main concerns are possible haemorrhage, infection, dissemination of tumour cells and episiotomy site recurrence.26 As there are no prospective randomised studies addressing the benefit of vaginal versus Caesarian delivery, all information comes from retrospective case–control studies. However, vaginal delivery has been reported to be a significant adverse prognostic factor for recurrent disease and poor survival and therefore Caesarean section might be the safest mode of delivery.27 In operable disease a classical Caesarean section followed by a radical hysterectomy in the same setting should be performed. Pregnancy has not been shown to adversely affect the outcome of women with cervical cancer. The prognosis of pregnant women with this disease is similar to that of nonpregnant patients.28
Ovarian cancer
Ovarian tumour
Frequency (%)
Dermoid Cystadenoma Functional cyst Other Malignancy
23– 47 16 –37 7–22 12–16 3– 6
416
Ovarian malignancy Germ cell Borderline Epithelial invasive Sex-cord stromal Other
Frequency (%) 6– 40 21–35 28–30 9–16 3–5
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ovarian germ cell tumours, unilateral salpingo-oophorectomy with preservation of the contralateral ovary and the uterus followed by surgical staging is adequate. It is therefore possible to continue the pregnancy. Staging should include omental and peritoneal biopsies and pelvic and paraaortic lymph node sampling. Routine biopsy of the contralateral ovary is only warranted if the ovary appears to be affected by tumour. Similar to germ cell tumours, early stage low malignant potential epithelial and sex cord-stromal tumours can be managed by unilateral adnexectomy and staging and the pregnancy continued. Invasive epithelial ovarian cancers associated with pregnancy are staged in the same manner as in non-pregnant patients. The extent of surgical debulking, however, needs to be adjusted according to the patient’s wishes, the stage of disease, and the fetal age and viability. Removal of the gravid uterus, however, is rarely indicated.37 Cumulative published works suggests that laparoscopic surgery for benign adnexal masses is reasonably safe in pregnancy and has similar maternal and fetal outcomes as laparotomy.40,41 Possible risks of laparoscopy in pregnancy, however, include injury to the pregnant uterus, decreased uterine blood flow secondary to increase in intra-abdominal pressure and the carbon dioxide absorption by the fetus. Potential drawbacks are also technical difficulties of laparoscopic surgery as a result of the enlarged pregnant uterus.42 Advantages of laparoscopic surgery are its diagnostic value, the usually reduced need for intraoperative uterine manipulation and, when performed by experienced surgeons, the decreased duration of surgery and exposure to general anaesthesia.43 The main obstacle for laparoscopic surgery is the preoperative difficulty of distinguishing accurately between benign and malignant lesions. Opening of malignant cysts has been shown to be a significant adverse prognostic factor and should be avoided whenever possible.44 Apart from well known complications of laparoscopy in ovarian cancer like port site metastases, it is impossible to perform adequate staging because of limited exposure and the inability to palpate unvisualised areas.45 A meticulous preoperative evaluation of ovarian cysts is therefore recommended. Several diagnostic models, although limited in their specificity, have been published46 and only strictly non-suspicious adnexal masses must be operated by laparoscopy during pregnancy. With the exception of the low-risk grade I–II stage IA or IB malignancies, most germ cell tumours and invasive epithelial carcinomas require adjuvant chemotherapy. Given the poor prognosis of ovarian malignancies treatment cannot be delayed in affected patients. The decision to start cytotoxic therapy in a pregnant patient remains a dilemma. The main concern is the effect of the drugs on the developing fetus and the long-term sequelae in offspring born after exposure in uterus. The effect of pregnancy on the pharmacology of the chemotherapeutic drugs is also an important issue. Almost all cytotoxic agents when given in pregnancy are known to be associated with increased rates of malformations, fetal loss and intrauterine growth retardation. Fetal
toxicity is dependent on the time and length of exposure, with the most severe effects noted during organogenesis in the first trimester. The estimated risk of congenital malformations with single agent chemotherapy during the first trimester is over 10% and increases when combinations of cytotoxic agents are used.47 After the first trimester, when organogenesis is completed with the exception of the brain and the gonads, the risk of fetal abnormalities is low, and intrauterine growth retardation and preterm birth are the principal effects.48,49 The long-term risks to the offspring after chemotherapy exposure in pregnancy are less well defined as research addressing this issue is sparse and mainly consists of small series and case reports with limited follow-up. Potential longterm effects include compromised physical and neurologic development, transplacental carcinogenesis with increased risk for a malignancy in childhood or later life and mutagenesis of germ-line tissue with teratogenicity and increased risk for malignancies in subsequent generations. No association, however, has been demonstrated for any chemotherapeutic agent yet.50 While the standard adjuvant treatment for germ cell tumours consists of bleomycin, etoposide, and cisplatin, the standard regimen for invasive epithelial cancer is the combination carboplatin-paclitaxel. Various small series and case reports of platinum-based regimens without paclitaxel during pregnancy have been published. Treatment after the first trimester seems to be safe, at least regarding the short-term sequelae, as it was not observed to be associated with an increased risk of malformations and preterm delivery.49,51 Nevertheless, the data on paclitaxel during pregnancy are still extremely sparse. The only reported case of cisplatinpaclitaxel therapy of ovarian cancer during pregnancy, however, was characterised by an uneventful pregnancy and resulted in an healthy child with normal follow-up.52 Thus, as data are still limited and publication bias cannot be excluded, the risks and benefits of administering chemotherapeutic agents in ovarian cancer and other malignancies during pregnancy must be carefully balanced on a case by case basis. Treatment has to be individualised. Choice of regimens should be guided by current knowledge of the most effective and least teratogenic drugs for the maternal situation. Finally, the timing of chemotherapy and delivery is an important issue. The mother should not give birth within 2 weeks of the last treatment as myelosuppression with pancytopenia is expected to be maximal at this time. It is also known that the placenta helps to eliminate drugs in a fetus while a newborn may not be able to metabolise the agents leading to harmful toxicity.53 Furthermore, delivery shortly after chemotherapy exposes health care personnel to contaminated blood and amniotic fluid.36
Vulvar cancer Vulvar cancer accounts for approximately 4% of all gynaecological malignancies and is mainly a disease of women
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beyond the menopause. Approximately 15% of all vulvar cancers, however, occur in patients younger than 40 years.15 Furthermore, there has been a significant increase in the incidence of human papilloma virus-associated vulvar intraepithelial neoplasia (VIN) and VIN-associated squamous cell carcinoma of the vulva in younger women over the last few years.54,55 The rising incidence of vulvar neoplasms in young women and the already mentioned increasing age of women having children demands growing awareness of vulvar symptoms in pregnancy. The long-term risk of invasive cancer in women who have previously been treated for VIN3 is approximately 4%.56 Nevertheless, pregnancy-associated vulvar carcinoma is rare and only approximately 30 cases have been reported.57,58 Many of these were characterised by a considerable diagnostic delay and illustrate the importance of careful vulvar examination and biopsy of all suspicious lesions during pregnancy. Vulvar cancer during pregnancy is treated in the same manner as in the non-pregnant patient. Local excision or vulvectomy with or without inguinal lymph node dissection, as indicated by the size and location of the lesion, is performed until 36 weeks’ gestation. Marked increase in genital vascularity in the third trimester is believed to be associated with higher surgical morbidity and delay of treatment into the post-partum period has therefore been suggested for women diagnosed after 36 weeks.59 With regard to the route of delivery for patients with vulvar cancer treated in pregnancy, there is no contraindication to vaginal delivery provided the vulvar wounds are well healed. In some cases, however, Caesarean section may be preferred by both the patient and the obstetrician because of introital stenosis and scarring. Whether a patient with untreated vulvar cancer should deliver vaginally or by Caesarean section is a decision which is heavily influenced by the size of the vulvar lesion. Nevertheless, there is no data indicating that the mode of delivery has an impact on the course of the disease. When a vulvar malignancy is treated adequately, pregnancy does not appear to significantly alter the course of the disease. Survival of patients for every stage is similar to that of non-pregnant patients.15
effects on the endometrium and is therefore believed to inhibit the development of endometrial malignancy in the pregnant state. In most reported cases the diagnosis of endometrial carcinoma was made after curettage for abortion or postpartum for abnormal bleeding.61 Therefore, unlike cervical cancer, there is rarely a conflict between optimal maternal treatment and fetal well-being. Consequently, pregnancyassociated endometrial carcinoma may be treated by standard surgery consisting of a total hysterectomy with bilateral salpingo-oophorectomy and pelvic lymph node dissection. Adjuvant radiotherapy is added in locally advanced disease to decrease the risk of recurrence. It is unknown whether pregnancy influences the prognosis of an endometrial adenocarcinoma. However, the majority of the reported pregnancy-associated endometrial cancers have been focal, well differentiated and minimally invasive.61 These malignancies have an excellent prognosis with a 5year survival of over 96%1 which is reflected by the favourable outcome of the reported cases.61
Conclusion Although prospective randomised data are lacking, diagnosis and management of gynaecological malignancies in pregnancy can be guided by case reports and retrospective cohort studies when tailored to each individual patient. Decision-making requires a multidisciplinary approach involving gynaecological oncologists, obstetricians, maternal-fetal specialists, and neonatalogists. Further research is needed to acquire more information on the long-term impact of treatment modalities like chemotherapy on the offspring.
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