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Current management of gestational trophoblastic disease
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Current management of gestational trophoblastic disease
Gestational trophoblastic neoplasia (GTN). It is likely that Obstetrics and Gynaecology trainees will see a handful of cases throughout their career, and it is important to manage and counsel these women and their partners accurately and compassionately at such a difficult time.
Incidence (Table 1)
Victoria L Parker
Demographics The risk of GTD is around 20 times higher in teenagers aged <15 years and over 200 times greater in women aged >50 years compared to those aged between 20 and 35 years. The most common underlying theory is that the probability of fertilising an abnormal oocyte is much higher at the extremes of reproductive age. A study by Savage et al., compared the rates of molar pregnancy and chemotherapy requirement to National (Department of Health) age-related pregnancy statistics. Amongst women diagnosed with partial and complete molar pregnancies, the highest risk occurred in women 50 years, with the risk of a complete hydatidiform mole as high as 1 in 8 patients. A peak in incidence at the opposite end of the reproductive spectrum (women aged 13 years) was seen for complete, but not partial moles. The risk of complete hydatidiform mole was seen to decline gradually until the age of 36 years, after which the incidence gradually increased. The risk of a partial molar pregnancy gradually increased with age. Chemotherapeutic requirement increased in women with a partial hydatidiform mole until age 30e34 years, before declining thereafter. In complete hydatidiform moles the chemotherapeutic requirement increased steadily with age, peaking at 50 years. Interestingly, there was not a corresponding peak in chemotherapy treatment amongst teenagers. There is insufficient evidence to imply a relationship between gravidity, parity and the risk of GTD, often due to the presence of confounding risk factors (e.g.: maternal age) within the analyses. There is conflicting data regarding the role of female infertility and menstrual disorders upon the risk of GTD; some studies have reported higher rates, while others have not found an association. One group observed significantly higher rates of GTD amongst women who had undergone assisted reproductive techniques, specifically intrauterine insemination using donor semen. The role of smoking upon the risk of GTD is controversial, with some studies showing longer durations of smoking to be associated with an increased incidence of trophoblastic disease. Despite this, several subsequent papers have failed to identify a correlation. Ethnicity has an important role in the incidence of GTD, yet the exact underlying mechanism remains unknown. Black women are w50% less likely to develop GTD, whilst the highest rates occur in patients originating from Asia, especially the Philippines and Japan. The blood group of the patient and her partner is an interesting risk factor, as this was previously deemed one of the most important variables and historically included in prognostic scoring systems for GTN throughout the world. The highest risk for GTN development involved women of blood group B or AB with an incompatible partner blood group, i.e.: O or A. It is this patient and partner incompatibility that seems to be the main causative factor, yet in 2000 the International Society for the Study of Trophoblastic Disease
John A Tidy
Abstract Gestational trophoblastic disease incorporates a spectrum of disorders ranging from benign to malignant subtypes. At one end of the condition, hCG level monitoring is all that is required, whereas other patients require combination chemotherapy regimens and surgery to cure the disease. The diagnosis can have profound effects on both the patient and her family and it is essential this is recognised and managed appropriately. Although rare, clinicians in non-specialist units are expected to inform patients of their diagnosis and explain the management steps prior to being referred to a specialised Trophoblastic centre and unfortunately, patients may be given inaccurate or incomplete information and use the Internet as their primary source of information. This article intends to explain the diagnosis itself (incidence, genetics, subtypes), clinical presentation and management, whilst answering some of the most commonly encountered questions asked by affected patients.
Keywords gestational trophoblastic disease; management; molar pregnancy
Introduction Gestational trophoblastic disease (GTD) has historically been described as ‘God’s first cancer and man’s first cure’. GTD is a rare but serious condition, affecting women of childbearing age with an incidence of 1:714 live births. The diagnosis encompasses a heterogeneous group of placental trophoblastic diseases; subdivided into benign (partial (PHM) and complete hydatidiform moles (CHM)) and neoplastic subtypes classified as Gestational Trophoblastic Neoplasia (GTN), which include invasive mole, choriocarcinoma, placental site- (PSTT) and epithelioid trophoblastic tumours (ETT). There are only three specialist referral centres for GTD in the United Kingdom, namely Ninewells Hospital in Dundee, Weston Park Hospital in Sheffield and Charing Cross Hospital in London. Only two of these centres; (Weston Park and Charing Cross Hospital) have established units for the screening, monitoring and treatment of patients with
Victoria L Parker MB BChir MA (Cantab) Academic Unit of Reproductive and Developmental Medicine, Department of Oncology and Metabolism, The University of Sheffield, UK. Conflicts of interest: none declared. John A Tidy BSc MD FRCOG Department of Gynaecological Oncology, Sheffield Teaching Hospitals NHS Foundation Trust, Royal Hallamshire Hospital, Sheffield; Sheffield Centre for Trophoblastic Disease, Weston Park Hospital, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK. Conflicts of interest: none declared.
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Incidence of GTD and GTN according to histological subtype
Partial Complete Invasive mole hydatidiform hydatidiform (GTN) mole (GTD) mole (GTD) Incidence 1 in 695 pregnancies
1 in 945 pregnancies
Choriocarcinoma (GTN)
15e20% following Europe & USA: 0.02e0.05/1000 pregnancies. CHM, 0.5e1.7% SE Asia: 0.4e2/1000 pregnancies. following PHM. 2e3% following complete hydatiform mole, <0.5% after partial hydatiform mole
PSTT (GTN)
ETT (GTN)
1 per 100,000 pregnancies Accounts for 1e2% of GTN
Accounts for < 1% of GTN. w90 cases published in the literature.
Table 1
(ISSTD) removed this risk factor from the prognostic scoring system due to a lack of definitive evidence regarding it’s influence on outcome.
partial moles, complete molar pregnancies have marked cytological atypia, which may be difficult to distinguish from choriocarcinoma in some cases. Histologically, invasive moles are similar to complete hydatidiform moles and choriocarcinoma, with hyperplastic cytotrophoblast, syncytial components and marked cellular atypia. However, unlike choriocarcinoma, invasive moles have chorionic villi, which in comparison to their benign complete mole counterparts are less swollen, more irregular and atypical in appearance. In choriocarcinoma, there are trimorphic sheets containing all three types of malignant trophoblastic cells, with evidence of focal pleomorphism, central necrosis and lymphovascular space invasion. The tumour lacks intrinsic stroma or vasculature, but comprises marked cytological atypia, with numerous mitotic figures. Using immunohistochemistry complete and partial hydatidiform moles can be distinguished, as complete moles lack the maternally derived p57 gene due to paternal imprinting of this gene expression. Partial moles have p57 nuclear staining in both the villous stromal cells and cytotrophoblast. Choriocarcinomas have a distinctive immunohistochemical profile, displaying a high Ki-67 labelling index, often exceeding 90%.
Histology and immunohistochemistry GTD is characterised by abnormal trophoblastic proliferation, leading to an excess of highly vascular placental tissue. This is evident at the time of surgical evacuation, whereby copious amounts of tissue is removed, often associated with higher than average blood loss; potentially reaching several litres. Macroscopically, the hyperplastic trophoblast forms hydropic, transparent grape-like clusters, which characteristically invade into the myometrium in malignant subtypes forming bulky haemorrhagic masses with varying degrees of necrosis (Figures 1 and 2). Uterine perforation and invasion into surrounding structures (bladder and rectum) may occur in invasive moles, choriocarcinoma, PSTT or ETT subtypes. In partial hydatidiform moles, an intact fetus, gestation sac, fetal parts or fetal erythrocytes may be identifiable, yet the fetus typically demises by eight to nine weeks gestation. This is due to the abnormal placental component, which causes growth restriction and non-viability of the associated fetus. As would be expected from a spectrum of diseases ranging from benign to malignant subtypes, there is a corresponding continuum of syncytio-, cytotrophoblastic and cytological atypia; ranging from mild in partial hydatidiform moles to moderate to marked in complete and invasive moles, choriocarcinoma. Histologically, partial hydatidiform moles are characterized by mild trophoblast proliferation (less compared to complete hydatidiform moles) in focal or circumferential areas. The villi are dentate and angulated, compared to complete moles, which have oval shaped, asymmetrical villi. There are occasional and more localised cistern formation and scallops as opposed to the widespread change seen in complete moles. Vasculature and enucleated red blood cells may be present and there is mild cytological atypia. In a complete mole there is marked, grossly abnormal trophoblastic proliferation, occupying a circumferential pattern that surrounds budding, hydropic villi, collapsed stromal blood vessels and stromal karyorrhectic fragments. The stroma is highly cellular and myxoid with evidence of apoptosis. Intervillous trophoblastic bridging is often present; yet different to partial hydatidiform moles, vasculature and nucleated red cells are absent. Unlike
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Genetics Partial and complete hydatidiform moles both arise at the point of fertilisation, yet these two subtypes are genetically distinct. Partial moles generally compose a triploid conceptus containing 69 chromosomes, and most commonly arise when an ovum is fertilized by two spermatozoa, otherwise known as a dispermic or diandric, monogynic partial hydatidiform mole (Figure 3). An alternative cause involves a disruption in gametogenesis during meiotic division to create a diploid spermatozoa or oocyte, whilst one in ten partial molar pregnancies result from a tetraploid conceptus or mosaic events. Complete hydatidiform moles are diploid and androgenetic in origin; containing no fetal tissue due to an absence of maternal genetic material. Most (90%) have a 46XX karyotype; with 75% resulting from the fertilization of an empty ovum with a single sperm, which then duplicates its genetic material (monospermic complete hydatidiform mole). The genetic material within this ovum may have been lost either before or after fertilisation (Figure 4a). Approximately 25% of complete moles arise from the fertilization of an empty ovum by two sperms
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Presentation Most patients present to Early Pregnancy Assessment Units in the first trimester with vaginal bleeding; occurring in up to 97% of patients diagnosed with a complete hydatidiform mole. This may range from light spotting to relatively heavy or persistent bleeding with clots, and occurs due to the disruption of maternal vessels by molar chorionic villi, which separates them from the decidua and leaves the endometrial cavity distended with blood. Vaginal bleeding may be associated with cramping, lower abdominal pain. The presence of maternal genetic material and tissue within partial hydatidiform moles means that they may present later than complete moles, in the late first or early second trimester. Due to the advent of early pregnancy ultrasonography and earlier diagnosis, patients now rarely present with symptoms suggestive of anaemia, hyperemesis, pre-eclampsia or hyperthyroidism, all of which result from extremely high levels of circulating hCG. Previously, over 50% patients were anaemic at presentation and approximately 25% of complete hydatidiform mole patients were pre-eclamptic at diagnosis (symptoms of hypertension, oedema and proteinurea). Fortunately eclamptic seizures have always been a rare occurrence in women diagnosed with GTD. Other now uncommon presentations include pelvic mass, representing excessive uterine enlargement compared to the gestational age or the presence of palpable theca lutein ovarian cysts; both of which arise due to hyper-stimulation of the uterus or ovaries secondary to high circulating hCG levels. Very rarely (<1e2%) patients develop haemoptysis, reflecting the presence of pulmonary metastases or the embolisation of molar tissue following uterine evacuation, which can also produce significant respiratory compromise (hypoxia, respiratory alkalosis) potentially requiring cardiovascular or respiratory support in an intensive care setting. GTD may additionally present after a non-molar pregnancy (most PSTTs) or after a live birth of a healthy infant (1:50,000 live births). Understandably, these cases are more indolent and often lead to delayed diagnosis, more advanced disease spread and worsened prognosis. Excessive blood loss at delivery and persistent post-partum bleeding may indicate GTD, although these are easily attributed to other obstetric causes such as prolonged second stage, assisted delivery or retained placental tissue
Figure 1 Complete hydatidiform mole with grape-like clusters.
Figure 2 Invasive mole e molar villi penetrating the uterine wall.
(dispermic complete hydatidiform mole), while very rarely, complete moles occur due the fertilization of an anucleate ovum by a diploid sperm, which has unsuccessfully undergone meiotic division (Figure 4b). Dispermic hydatidiform moles may have a karyotype of 46XY but 46YY is never seen, as an X chromosome is required for viability, with 46YY proving rapidly lethal to the ovum.
Genetic basis of a dispermic, partial hydatidiform mole
23X or 23Y 23X 23X 23X or 23Y
23X
23X
69XXY
Dispermic PHM
Figure 3
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Genetic basis of a monospermic complete hydatidiform mole
23X
23X
23X
Loss of maternal chromosomes
23X
23X
Duplication of paternal chromosomes
46XX
23X Monospermic CHM 23X
23X
23X
23X
23X
(a)
Genetic basis of a dispermic complete hydatidiform mole
23X
23X
23X or 23Y
23X
23Y
46XY 23X Diploidisation Dispermic CHM
23X 23X or 23Y
23X
23X
23X
23Y
23Y
(b) Figure 4
in the case of post-partum bleeding. For all cases of persistent post-partum bleeding (which again may range from light to heavy), it is vital that hCG levels are measured, a transvaginal ultrasound performed and surgical evacuation of products sent for histological examination. A potential diagnosis of choriocarcinoma should always be kept in mind.
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Diagnosis The rise of ultrasonography in early pregnancy through the establishment of specialist Early Pregnancy Assessment Units in almost all Gynaecology centres have resulted in much earlier GTD diagnoses. Ultrasound diagnoses of delayed miscarriage or anembryonic pregnancy are most commonly associated with
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the cervix, as this does not increase chemotherapy requirement or promote increasing uterine size. Planned surgical evacuation must be expedited in the case of significant haemorrhage. In some partial hydatidiform moles, the size of fetal parts may preclude suction evacuation, hence medical evacuation is required, yet this is less likely to lead to complete uterine evacuation compared to a surgical approach. Medical evacuation using prostaglandin derived agents and oxytocin should be avoided in particular for complete molar pregnancies, due to observational data suggesting an increased risk of developing GTN and needing further treatment. By stimulating uterine contractions, prostaglandin agents may promote the embolisation and widespread dissemination of trophoblastic tissue throughout the venous system. However, in cases of excessive blood loss, it may be necessary to use oxytocin. Very rarely, primary hysterectomy is required in the case of excessive and unresponsive vaginal bleeding, yet in young women who wish to preserve their fertility; this is only indicated as a life-saving measure. Most cases of heavy vaginal bleeding can be managed using intravenous Tranexamic acid, replacement of blood products and in the case of a known arteriovenous malformation (more common in trophoblastic disease) using interventional radiology to embolise the feeding vessels. Women who are Rhesus-D negative should receive anti-D prophylaxis following evacuation of the molar pregnancy. In fact, the anti-D antigen is absent in complete hydatidiform moles due to the poor vascularisation of the chorionic villi, yet the delay to obtain a histological diagnosis necessitates the routine administration of prophylactic anti-D immunoglobulin in the required time frame to all cases of suspected GTD. Products of conception for all non-viable pregnancies must undergo histological examination, regardless of ultrasound findings or the mode of evacuation, but particularly cases in which GTD is suspected. This confirms the diagnosis of GTD and excludes overt malignancy (GTN). If products of conception are not sent for histological review, patients should undertake a urinary pregnancy test three weeks after the evacuation as a delayed diagnosis in such patients leads to significantly increased morbidity, including a higher risk of further surgery (hysterectomy) and combination chemotherapy due to more advanced disease at presentation. This should be negative and is a cost effective way of excluding persistent trophoblastic disease. Products of conception are not required for routine histological examination following termination of pregnancy, providing that fetal parts have been identified on ultrasound, given that the rate of developing GTN is estimated at 1:20,000 cases. If lesions suspicious of vaginal metastases are visualised at the time of uterine evacuation, these should simply be noted and never biopsied. Biopsy can lead to torrential bleeding that is extremely difficult to control. All patients with a histologically confirmed molar pregnancy should be promptly registered at their nearest specialist Trophoblastic Centre, designed to monitor hCG levels, provide advice on the duration of surveillance and further pregnancies, identify the development of persistent trophoblastic disease and coordinate the management of these patients accordingly. The Centres involve a multi-disciplinary, expert team of Clinical Nurse Specialists, Medical Oncologists, Radiologists, Pathologists, Gynaecological Oncologists and counsellors to support
histologically confirmed complete hydatidiform moles. Previously, most molar pregnancies were diagnosed on ultrasound at 16 weeks, whereas nowadays suspicions are raised as early as 6e8 weeks gestation. However, this must be balanced against the fact that earlier ultrasounds are less accurate at diagnosing GTD, with rates of 35e40% before 14 weeks compared to 60% after 16 weeks. Furthermore, approximately 50% of histologically confirmed cases of GTD have no diagnostic features on ultrasound, particularly in the case of partial hydatidiform moles. Under- or over-diagnosis is certainly problematic. Patients may undergo surgical evacuations unnecessarily for non-molar pregnancies, or alternatively if not diagnosed on ultrasound imaging, patients with GTD may receive suboptimal conservative or medical management whereby products of conception are not sent for histological review. These patients may then present between one and three weeks later with persistent or increasing vaginal bleeding and pain, before a transvaginal ultrasound reveals persistent trophoblast tissue, suspicious of GTD. Partial hydatidiform moles are specifically associated with two ultrasonic features, namely focal cystic areas within the placental tissue, and a ratio of >1.5 when comparing the transverse to antero-posterior diameter of the gestation sac. These features, combined with a growth restricted, hydropic fetus with congenital anomalies is highly suggestive of a partial molar pregnancy. hCG levels may be normal or only mildly elevated when compared to complete hydatidiform moles which display disproportionately elevated hCG levels compared to the gestational age (>100 103). Invasive moles and choriocarcinoma are equally characterised by persistently elevated hCG levels (>10 103), whereas in PSTT and ETT hCG levels usually display mild to moderate elevation (<3 103). Complete moles have a characteristic heterogeneous mass forming a ‘snowstorm’ or vesicular pattern on ultrasound, which fills the uterine cavity owing to placental proliferation. The fetus is absent and bilateral thecal luteal cysts may be present. Invasive moles, choriocarcinoma, ETT or PSTT subtypes may be seen to invade into or even through the uterine myometrium and serosa, encroaching on neighbouring structures such as bladder or bowel. Patients that have a viable pregnancy but a suspicion of coexisting molar changes on ultrasound imaging should not be advised to have a termination of pregnancy, as the outcome will become clear over time. Partial hydatidiform moles have a higher risk of trisomy and fetal demise, hence expectant management with serial ultrasound scans at intervals of ten to fourteen days is most appropriate. A twin pregnancy involving a viable fetus and a molar pregnancy is more common with complete than partial hydatidiform moles, yet is associated with higher obstetric risks for the viable fetus, including an increased risk of pre-eclampsia and stillbirth. A recent series suggests a live birth rate of 40e57%. Women should be informed that continuing with the pregnancy is not associated with higher rates of malignant conversion (GTN) or chemotherapeutic requirement. Initial management Women with suspected GTD should undergo surgical evacuation of the uterus using suction curettage where possible, conducted by a senior Gynaecologist due to the anticipated higher blood loss and complication rate. A single 400 mg dose of Misoprostol per vagina can be used one hour prior to the procedure to ripen
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patients and their families. Obstetrics and Gynaecology trainees or Consultants can refer patients using an online portal or a paper based form (located on the website of each Trophoblastic Centre). Histological samples are also sent to the centres for central review by a specialist Pathologist to confirm the diagnosis. This is particularly important considering that half of all partial hydatidiform moles are incorrectly diagnosed by nonspecialist centres; instead being mistaken for trisomy or other chromosomal abnormalities.
Patients diagnosed with PTD are requested to attend the nearest Trophoblast Centre for clinical review and staging investigations to determine their ongoing management. This includes a full history and clinical examination, bloods (FBC, group and save, U&E, LFT, hCG level and hormonal profile including oestradiol, LH, FSH, TSH, free T3, T4) and imaging (transvaginal ultrasound scan, chest X-ray). If metastatic lesions are noted on the chest X-ray, patients should undergo a CT abdomen pelvis and MRI brain to exclude additional metastatic sites, which would significantly alter management. Patients are subsequently managed using a prognostic scoring system developed by FIGO and the WHO, designed to predict resistance to first line chemotherapy (Table 4). The system incorporates eight clinical risk factors and divides patients into low- and high-risk groups. Low-risk patients have a WHO score 6 and are given single agent chemotherapy (intramuscular Methotrexate on days 1, 3, 5 and 7 alternating with Folinic acid 24 hours after each Methotrexate injection on days 2, 4, 6, 8) with a seven day rest period between each treatment cycle. Alternatively, patients with highrisk disease (score 7) receive combination chemotherapy (intravenous EMA-CO: EMA on days 1e2: Actinomycin, Etoposide, Methotrexate alternating with CO: Cyclophosphamide and Vincristine on day 8) given weekly without a break. Established central nervous system disease can be managed with specialised regimens of intrathecal methotrexate or stereotactic radiotherapy. Fortunately, the cure rate for GTN is excellent due to it’s highly chemosensitive nature; 100% amongst low-risk patients and 95% for high-risk patients. Treatment cycles are continued until the hCG levels normalise, followed by consolidation chemotherapy for a further six weeks. Shortening the consolidation phase is associated with significantly higher relapse rates. Notably, due to the differing histological and clinical behaviour of PSTT and ETT subtypes, these tumour types cannot be scored according to the FIGO/WHO classification system. Typically, they are less chemosensitive and require primary surgical
Medical consultation Following a suspected diagnosis of molar pregnancy on radiological and biochemical investigations, women should be counselled by a suitably qualified member of the medical team to discuss the diagnosis and management approach. The condition should be promptly managed and women should receive a lucid explanation of the next steps in their care and follow up including permission to register the woman with the relevant trophoblastic centre (Table 2). Persistent trophoblastic disease Persistent trophoblastic disease (PTD) is defined as a molar pregnancy that is unlikely to resolve without further treatment, and can follow any type of antecedent pregnancy and histological subtype. Overall in the U.K approximately 8% of all patients require treatment with chemotherapy or additional surgery, which is typically evident by a rising or plateauing hCG level (Table 3). The U.K adopts a conservative treatment approach; aiming to minimise patient exposure to toxic chemotherapy regimens, whereas worldwide, treatment levels are much higher, reaching 30% in Latin America. Complete hydatidiform moles more commonly display malignant conversion (15%) than partial moles (0.5e1%) and patients should be counselled accordingly. Conversion to an overt choriocarcinoma is less common, occurring in <0.5% of partial hydatidiform moles and 2e3% of complete moles.
Summary of topics that should be discussed prior to referral to the Trophoblastic Centre
C C C
C C C C
C C C C C C
Suspected diagnosis and genetics of GTD (use diagrams). Diagnostic results; ultrasound appearances and hCG level. Explore patient symptoms; pain, bleeding, nausea, vomiting, neurological symptoms, oedema, headache, abdominal pain (symptoms suggestive of pre-eclampsia), weight loss, sweating, palpitations, diarrhoea (symptoms indicative of hyperthyroidism). Initial management e surgical evacuation recommended. Referral to a specialist Trophoblastic Centre for ongoing monitoring Monitoring process; blood tests and urine samples that can be done locally and posted to the Trophoblastic Centre. Difference between GTD and malignant conversion into GTN. Give approximate rates of requiring further treatment (additional surgery/ chemotherapy). Overall cure rate if additional treatment is required. Risk of GTD in a subsequent pregnancy. Contraception advice and avoidance of pregnancy until advised by Trophoblastic Centre. Explore patient’s ideas, concerns and expectations. Offer support and further face-to-face visits locally or at the Trophoblastic Centre. Provide contact numbers in case of emergency both in and out-of-hours (heavy bleeding, pain).
Table 2
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Indications for commencing chemotherapy in U.K Trophoblastic Centres
C C
C
C C C C
hCG levels 20,000 IU/L after one or two uterine evacuations e risk of uterine perforation. Static or rising hCG after one or two uterine evacuations. Static levels are defined as four or more equivalent values of hCG over at least 3 weeks (days 1, 7, 14, 21). Rising hCG is defined as two consecutive rises in hCG of 10% over at least 2 weeks (days 1, 7 and 14). Persistent elevation of hCG levels six months following uterine evacuation e Review patient at Trophoblastic Centre. If hCG levels are falling, can monitor for up to 1 year. Histological diagnosis of choriocarcinoma, Placental Site Trophoblastic Tumour (PSTT) or Epithelioid Trophoblastic Tumour (ETT) Heavy vaginal bleeding, evidence of gastrointestinal or intraperitoneal haemorrhage in the presence of raised hCG levels. Metastases in the liver, gastrointestinal tract or brain Pulmonary metastases with static or rising hCG levels.
Table 3
management (hysterectomy), followed by adjuvant chemotherapy if required.
40%, particularly in low-risk patients where the hCG level is <5000 IU/L. This evidence originates from the multicentre, phase II GOG 242 trial, which examined sixty-four women with low-risk, non metastatic GTN. Surgical success was independent of hCG burden, tumour size and depth of invasion, however only patients with a FIGO/WHO score 4 were cured by a second evacuation, suggesting chemotherapy is required in the low-risk patient subgroup who score 5e6. Ideally, regional centres should always consult the Trophoblastic Centres before performing a second evacuation, yet this may not be possible in the case of heavy vaginal bleeding.
Second uterine evacuation Second uterine evacuations for persistent trophoblastic disease detected on ultrasound imaging are indicated in some circumstances, and can reduce the requirement for chemotherapy by
The Combined FIGO/WHO prognostic classification system (2000)
Primary chemotherapy resistance Overall, approximately 25e35% of patients are resistant to first line chemotherapy, yet this rises to 75e85% amongst low-risk women who score 5 or 6. This may have detrimental psychological consequences for the patient and their family, as more potent single or combination agent chemotherapy is subsequently required, with an increased side effect profile. Interestingly, the time to achieve remission does not appear to be affected by this switch. In the Sheffield Trophoblastic centre, low-risk patients with primary chemotherapy resistance and hCG levels <300 IU/L are switched to intravenous Dactinomycin repeated every two weeks, whereas patients with levels 300 IU/ L receive intravenous Carboplatin every three weeks. At the Trophoblastic Centre in London, patients with first-line chemotherapy resistance and levels >1000 IU/L are commenced on combination chemotherapy (high-risk EMA/CO). High-risk patients who display primary resistance to combination chemotherapy are given different combination regimens (EP/EMA [etoposide and cisplatin alternating with Dactinomycin, etoposide and methotrexate] or TP/TE [paclitaxel and cisplatin alternating with paclitaxel and etoposide). Salvage hysterectomy may additionally be required.
FIGO anatomical stage Stage I II
III IV
Disease confined to the uterus GTN extends outside of the uterus but is limited to the genital structures (adnexae, vagina, broad ligament) GTN extends to the lungs, with or without known genital tract involvement All other metastatic sites
Modified WHO prognostic classification system, as adapted by FIGO Score
0
Age (years) Antecedent pregnancy Interval months from index pregnancy Pre-treatment hCG (IU/L) Largest tumour size including uterus (cm) Site of metastases
<40 40 e Mole Abortion Term <4 4e6 7e12
e e >12
<103 103e104 104e105 <3 3e4 5
>105 e
Number of metastases Previous failed chemotherapy
1
Lung Spleen, kidney e 1e4 e e
2
4
Gastrointestinal Liver, brain 5e8 >8 Single drug 2 drugs
Side effect profile Most young women are understandably very anxious about commencing chemotherapy, and the immediate questions commonly encountered include the effect on hair loss and future fertility. Low-risk chemotherapy regimens (methotrexate and dactinomycin) are generally well tolerated and are not associated with hair loss. Instead, emesis, stomatitis, mouth sores,
Score <6 ¼ Low-risk, Score 7 ¼ High-risk.
Table 4
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weeks later. By discontinuing monitoring after two normal urine samples, there is a 1:300 risk of missing GTN. Following any further pregnancy, irrespective of the outcome (miscarriage, live birth, ectopic), women should contact the Trophoblastic centre who will arrange for a urinary hCG sample to be checked six to eight weeks following the end of the pregnancy to exclude disease recurrence. Trophoblastic disease can recur after any pregnancy, and some subtypes in particular can recur even when separated by a normal, healthy pregnancy.
diarrhoea and abdominal pain are most commonly experienced. Carboplatin may cause nausea, vomiting and myelosuppression, whilst etoposide within the high-risk combination chemotherapy is predominantly associated with hair loss and higher rates of bone marrow toxicity. Combination chemotherapy with EMA/ CO significantly increases the risk of secondary leukaemia in a dose dependent manner and brings forward the age of menopause by three years. Aside from this, patients can be reassured that low- or high-risk chemotherapy regimens do not otherwise affect fertility. Evidence suggests that there is no increased risk of congenital abnormalities, miscarriage, ectopic pregnancy or stillbirth in future pregnancies compared to the general population. Patients are advised not to conceive for a year following the completion of chemotherapy, due to the risk of fetal teratogenicity secondary to the chemotherapeutic agents. Furthermore, recurrence risk is also highest during this period.
Concluding remarks Trophoblastic disease is a rare but extremely important condition that most clinicians will encounter during their training. Women who are affected by the disease are extremely anxious and upset, not only having to face losing their baby and having an unsuccessful pregnancy, but being diagnosed with a condition that the majority will not have heard of. The mention of chemotherapy should the condition fail to clear spontaneously, can induce additional concern. It is therefore essential that clinicians who initially encounter these patients in non-specialised centres are well informed and deal with patient’s concerns and questions in a sensitive and considerate manner. A
Contraception Contraceptive guidance following a molar pregnancy has now changed. The combined oral contraceptive pill can be used following uterine evacuation, whilst awaiting histological review, even if the hCG levels remains elevated. Progesterones are not considered to increase the risk of GTN and are safe to use. Intrauterine contraceptive coils should not be inserted at the time of uterine evacuation or indeed until hCG levels have returned to normal due to the risk of uterine perforation.
FURTHER READING Berkowitz RS, Goldstein DP. Current management of gestational trophoblastic diseases. Gynecol Oncol 2009; 112: 654e62. Hancock BW, Seckl MJ, Berkowitz RS. Gestational trophoblastic disease. Chapman & Hall Medical, 2015. http://isstd.org/gtd-book/ front-page/. Osborne RJ, Filiaci VL, Shink JC, et al. Second curettage for low-risk nonmetastatic gestational trophoblastic neoplasia. Obstet Gynecol 2016; 128: 535e42. RCOG. Green top guideline number 38, The management of gestational trophoblastic disease. 2010, https://www.rcog.org.uk/ globalassets/documents/guidelines/gtg_38.pdf. Savage PM, Sita-Lumsden A, Dickson S, et al. The relationship of maternal age to molar pregnancy incidence, risks for chemotherapy and subsequent pregnancy outcome. J Obstet Gynaecol 2013; 33: 406e11. Savage P, Williams J, Wong SL, et al. The demographics of molar pregnancies in England and Wales from 2000e2009. J Reprod Med 2010; 55: 341e5. Seckl MJ, Sebire NJ, Fisher RA, Golfier F, Massuger L, Sessa C. Gestational trophoblastic disease: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2013; 24(suppl 6). vi:39e50. Tidy J, Winter M, Singh K, Hancock B.W. Gestational trophoblastic neoplasia: a guide to management at Weston Park hospital, Sheffield teaching hospitals foundation trust. http://stdc.group. shef.ac.uk/resources/gtngm2014.pdf2014. WHO. WHO classification of tumours of female reproductive organs (IARC WHO classification of tumours). International Agency for Research on Cancer, 2014.
Recurrence Compared to the general population, women with a history of molar pregnancy have a higher risk of a recurrent mole, yet the absolute risk is low (1:100). However, women with a history of 2 molar pregnancies, have a risk of 1:6 in their third pregnancy. A specialist geneticist within the Trophoblastic Centres should review women with clusters of trophoblastic disease, as a condition called familial recurrent hydatidiform mole is now known to exist. This autosomal recessive condition involves a mutation in two genes, namely NLRP7 and more rarely, KHDC3L. Follow-up Patients diagnosed with a partial or complete hydatidiform mole have their urinary hCG levels monitored on a two weekly basis by the specialist Trophoblastic Centre. If their hCG level returns to normal within 56 days of the end of the molar pregnancy, patients are monitored for six months from the end of the pregnancy. However, if the hCG level does not return to normal within 56 days, the patient continues to be monitored for six months from the date of the first normal result. This monitoring regime carries a 1:2000 risk of missing disease, and during this time, patients should avoid a new pregnancy. These recommendations must be followed for a complete hydatidiform mole, but experience has shown that the follow-up for partial mole can be shortened without exposing the patient to significantly increased risk, due to the lower risk of malignant conversion. Partial moles are now commonly followed up until the urine hCG levels return to normal, followed by a confirmatory level four
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Current management of gestational trophoblastic disease
Gestational trophoblastic neoplasia (GTN). It is likely that Obstetrics and Gynaecology trainees will see a handful of cases throughout their career, and it is important to manage and counsel these women and their partners accurately and compassionately at such a difficult time.
Incidence (Table 1)
Victoria L Parker
Demographics The risk of GTD is around 20 times higher in teenagers aged <15 years and over 200 times greater in women aged >50 years compared to those aged between 20 and 35 years. The most common underlying theory is that the probability of fertilising an abnormal oocyte is much higher at the extremes of reproductive age. A study by Savage et al., compared the rates of molar pregnancy and chemotherapy requirement to National (Department of Health) age-related pregnancy statistics. Amongst women diagnosed with partial and complete molar pregnancies, the highest risk occurred in women 50 years, with the risk of a complete hydatidiform mole as high as 1 in 8 patients. A peak in incidence at the opposite end of the reproductive spectrum (women aged 13 years) was seen for complete, but not partial moles. The risk of complete hydatidiform mole was seen to decline gradually until the age of 36 years, after which the incidence gradually increased. The risk of a partial molar pregnancy gradually increased with age. Chemotherapeutic requirement increased in women with a partial hydatidiform mole until age 30e34 years, before declining thereafter. In complete hydatidiform moles the chemotherapeutic requirement increased steadily with age, peaking at 50 years. Interestingly, there was not a corresponding peak in chemotherapy treatment amongst teenagers. There is insufficient evidence to imply a relationship between gravidity, parity and the risk of GTD, often due to the presence of confounding risk factors (e.g.: maternal age) within the analyses. There is conflicting data regarding the role of female infertility and menstrual disorders upon the risk of GTD; some studies have reported higher rates, while others have not found an association. One group observed significantly higher rates of GTD amongst women who had undergone assisted reproductive techniques, specifically intrauterine insemination using donor semen. The role of smoking upon the risk of GTD is controversial, with some studies showing longer durations of smoking to be associated with an increased incidence of trophoblastic disease. Despite this, several subsequent papers have failed to identify a correlation. Ethnicity has an important role in the incidence of GTD, yet the exact underlying mechanism remains unknown. Black women are w50% less likely to develop GTD, whilst the highest rates occur in patients originating from Asia, especially the Philippines and Japan. The blood group of the patient and her partner is an interesting risk factor, as this was previously deemed one of the most important variables and historically included in prognostic scoring systems for GTN throughout the world. The highest risk for GTN development involved women of blood group B or AB with an incompatible partner blood group, i.e.: O or A. It is this patient and partner incompatibility that seems to be the main causative factor, yet in 2000 the International Society for the Study of Trophoblastic Disease
John A Tidy
Abstract Gestational trophoblastic disease incorporates a spectrum of disorders ranging from benign to malignant subtypes. At one end of the condition, hCG level monitoring is all that is required, whereas other patients require combination chemotherapy regimens and surgery to cure the disease. The diagnosis can have profound effects on both the patient and her family and it is essential this is recognised and managed appropriately. Although rare, clinicians in non-specialist units are expected to inform patients of their diagnosis and explain the management steps prior to being referred to a specialised Trophoblastic centre and unfortunately, patients may be given inaccurate or incomplete information and use the Internet as their primary source of information. This article intends to explain the diagnosis itself (incidence, genetics, subtypes), clinical presentation and management, whilst answering some of the most commonly encountered questions asked by affected patients.
Keywords gestational trophoblastic disease; management; molar pregnancy
Introduction Gestational trophoblastic disease (GTD) has historically been described as ‘God’s first cancer and man’s first cure’. GTD is a rare but serious condition, affecting women of childbearing age with an incidence of 1:714 live births. The diagnosis encompasses a heterogeneous group of placental trophoblastic diseases; subdivided into benign (partial (PHM) and complete hydatidiform moles (CHM)) and neoplastic subtypes classified as Gestational Trophoblastic Neoplasia (GTN), which include invasive mole, choriocarcinoma, placental site- (PSTT) and epithelioid trophoblastic tumours (ETT). There are only three specialist referral centres for GTD in the United Kingdom, namely Ninewells Hospital in Dundee, Weston Park Hospital in Sheffield and Charing Cross Hospital in London. Only two of these centres; (Weston Park and Charing Cross Hospital) have established units for the screening, monitoring and treatment of patients with
Victoria L Parker MB BChir MA (Cantab) Academic Unit of Reproductive and Developmental Medicine, Department of Oncology and Metabolism, The University of Sheffield, UK. Conflicts of interest: none declared. John A Tidy BSc MD FRCOG Department of Gynaecological Oncology, Sheffield Teaching Hospitals NHS Foundation Trust, Royal Hallamshire Hospital, Sheffield; Sheffield Centre for Trophoblastic Disease, Weston Park Hospital, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK. Conflicts of interest: none declared.
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Incidence of GTD and GTN according to histological subtype
Partial Complete Invasive mole hydatidiform hydatidiform (GTN) mole (GTD) mole (GTD) Incidence 1 in 695 pregnancies
1 in 945 pregnancies
Choriocarcinoma (GTN)
15e20% following Europe & USA: 0.02e0.05/1000 pregnancies. CHM, 0.5e1.7% SE Asia: 0.4e2/1000 pregnancies. following PHM. 2e3% following complete hydatiform mole, <0.5% after partial hydatiform mole
PSTT (GTN)
ETT (GTN)
1 per 100,000 pregnancies Accounts for 1e2% of GTN
Accounts for < 1% of GTN. w90 cases published in the literature.
Table 1
(ISSTD) removed this risk factor from the prognostic scoring system due to a lack of definitive evidence regarding it’s influence on outcome.
partial moles, complete molar pregnancies have marked cytological atypia, which may be difficult to distinguish from choriocarcinoma in some cases. Histologically, invasive moles are similar to complete hydatidiform moles and choriocarcinoma, with hyperplastic cytotrophoblast, syncytial components and marked cellular atypia. However, unlike choriocarcinoma, invasive moles have chorionic villi, which in comparison to their benign complete mole counterparts are less swollen, more irregular and atypical in appearance. In choriocarcinoma, there are trimorphic sheets containing all three types of malignant trophoblastic cells, with evidence of focal pleomorphism, central necrosis and lymphovascular space invasion. The tumour lacks intrinsic stroma or vasculature, but comprises marked cytological atypia, with numerous mitotic figures. Using immunohistochemistry complete and partial hydatidiform moles can be distinguished, as complete moles lack the maternally derived p57 gene due to paternal imprinting of this gene expression. Partial moles have p57 nuclear staining in both the villous stromal cells and cytotrophoblast. Choriocarcinomas have a distinctive immunohistochemical profile, displaying a high Ki-67 labelling index, often exceeding 90%.
Histology and immunohistochemistry GTD is characterised by abnormal trophoblastic proliferation, leading to an excess of highly vascular placental tissue. This is evident at the time of surgical evacuation, whereby copious amounts of tissue is removed, often associated with higher than average blood loss; potentially reaching several litres. Macroscopically, the hyperplastic trophoblast forms hydropic, transparent grape-like clusters, which characteristically invade into the myometrium in malignant subtypes forming bulky haemorrhagic masses with varying degrees of necrosis (Figures 1 and 2). Uterine perforation and invasion into surrounding structures (bladder and rectum) may occur in invasive moles, choriocarcinoma, PSTT or ETT subtypes. In partial hydatidiform moles, an intact fetus, gestation sac, fetal parts or fetal erythrocytes may be identifiable, yet the fetus typically demises by eight to nine weeks gestation. This is due to the abnormal placental component, which causes growth restriction and non-viability of the associated fetus. As would be expected from a spectrum of diseases ranging from benign to malignant subtypes, there is a corresponding continuum of syncytio-, cytotrophoblastic and cytological atypia; ranging from mild in partial hydatidiform moles to moderate to marked in complete and invasive moles, choriocarcinoma. Histologically, partial hydatidiform moles are characterized by mild trophoblast proliferation (less compared to complete hydatidiform moles) in focal or circumferential areas. The villi are dentate and angulated, compared to complete moles, which have oval shaped, asymmetrical villi. There are occasional and more localised cistern formation and scallops as opposed to the widespread change seen in complete moles. Vasculature and enucleated red blood cells may be present and there is mild cytological atypia. In a complete mole there is marked, grossly abnormal trophoblastic proliferation, occupying a circumferential pattern that surrounds budding, hydropic villi, collapsed stromal blood vessels and stromal karyorrhectic fragments. The stroma is highly cellular and myxoid with evidence of apoptosis. Intervillous trophoblastic bridging is often present; yet different to partial hydatidiform moles, vasculature and nucleated red cells are absent. Unlike
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Genetics Partial and complete hydatidiform moles both arise at the point of fertilisation, yet these two subtypes are genetically distinct. Partial moles generally compose a triploid conceptus containing 69 chromosomes, and most commonly arise when an ovum is fertilized by two spermatozoa, otherwise known as a dispermic or diandric, monogynic partial hydatidiform mole (Figure 3). An alternative cause involves a disruption in gametogenesis during meiotic division to create a diploid spermatozoa or oocyte, whilst one in ten partial molar pregnancies result from a tetraploid conceptus or mosaic events. Complete hydatidiform moles are diploid and androgenetic in origin; containing no fetal tissue due to an absence of maternal genetic material. Most (90%) have a 46XX karyotype; with 75% resulting from the fertilization of an empty ovum with a single sperm, which then duplicates its genetic material (monospermic complete hydatidiform mole). The genetic material within this ovum may have been lost either before or after fertilisation (Figure 4a). Approximately 25% of complete moles arise from the fertilization of an empty ovum by two sperms
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Presentation Most patients present to Early Pregnancy Assessment Units in the first trimester with vaginal bleeding; occurring in up to 97% of patients diagnosed with a complete hydatidiform mole. This may range from light spotting to relatively heavy or persistent bleeding with clots, and occurs due to the disruption of maternal vessels by molar chorionic villi, which separates them from the decidua and leaves the endometrial cavity distended with blood. Vaginal bleeding may be associated with cramping, lower abdominal pain. The presence of maternal genetic material and tissue within partial hydatidiform moles means that they may present later than complete moles, in the late first or early second trimester. Due to the advent of early pregnancy ultrasonography and earlier diagnosis, patients now rarely present with symptoms suggestive of anaemia, hyperemesis, pre-eclampsia or hyperthyroidism, all of which result from extremely high levels of circulating hCG. Previously, over 50% patients were anaemic at presentation and approximately 25% of complete hydatidiform mole patients were pre-eclamptic at diagnosis (symptoms of hypertension, oedema and proteinurea). Fortunately eclamptic seizures have always been a rare occurrence in women diagnosed with GTD. Other now uncommon presentations include pelvic mass, representing excessive uterine enlargement compared to the gestational age or the presence of palpable theca lutein ovarian cysts; both of which arise due to hyper-stimulation of the uterus or ovaries secondary to high circulating hCG levels. Very rarely (<1e2%) patients develop haemoptysis, reflecting the presence of pulmonary metastases or the embolisation of molar tissue following uterine evacuation, which can also produce significant respiratory compromise (hypoxia, respiratory alkalosis) potentially requiring cardiovascular or respiratory support in an intensive care setting. GTD may additionally present after a non-molar pregnancy (most PSTTs) or after a live birth of a healthy infant (1:50,000 live births). Understandably, these cases are more indolent and often lead to delayed diagnosis, more advanced disease spread and worsened prognosis. Excessive blood loss at delivery and persistent post-partum bleeding may indicate GTD, although these are easily attributed to other obstetric causes such as prolonged second stage, assisted delivery or retained placental tissue
Figure 1 Complete hydatidiform mole with grape-like clusters.
Figure 2 Invasive mole e molar villi penetrating the uterine wall.
(dispermic complete hydatidiform mole), while very rarely, complete moles occur due the fertilization of an anucleate ovum by a diploid sperm, which has unsuccessfully undergone meiotic division (Figure 4b). Dispermic hydatidiform moles may have a karyotype of 46XY but 46YY is never seen, as an X chromosome is required for viability, with 46YY proving rapidly lethal to the ovum.
Genetic basis of a dispermic, partial hydatidiform mole
23X or 23Y 23X 23X 23X or 23Y
23X
23X
69XXY
Dispermic PHM
Figure 3
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Genetic basis of a monospermic complete hydatidiform mole
23X
23X
23X
Loss of maternal chromosomes
23X
23X
Duplication of paternal chromosomes
46XX
23X Monospermic CHM 23X
23X
23X
23X
23X
(a)
Genetic basis of a dispermic complete hydatidiform mole
23X
23X
23X or 23Y
23X
23Y
46XY 23X Diploidisation Dispermic CHM
23X 23X or 23Y
23X
23X
23X
23Y
23Y
(b) Figure 4
in the case of post-partum bleeding. For all cases of persistent post-partum bleeding (which again may range from light to heavy), it is vital that hCG levels are measured, a transvaginal ultrasound performed and surgical evacuation of products sent for histological examination. A potential diagnosis of choriocarcinoma should always be kept in mind.
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Diagnosis The rise of ultrasonography in early pregnancy through the establishment of specialist Early Pregnancy Assessment Units in almost all Gynaecology centres have resulted in much earlier GTD diagnoses. Ultrasound diagnoses of delayed miscarriage or anembryonic pregnancy are most commonly associated with
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the cervix, as this does not increase chemotherapy requirement or promote increasing uterine size. Planned surgical evacuation must be expedited in the case of significant haemorrhage. In some partial hydatidiform moles, the size of fetal parts may preclude suction evacuation, hence medical evacuation is required, yet this is less likely to lead to complete uterine evacuation compared to a surgical approach. Medical evacuation using prostaglandin derived agents and oxytocin should be avoided in particular for complete molar pregnancies, due to observational data suggesting an increased risk of developing GTN and needing further treatment. By stimulating uterine contractions, prostaglandin agents may promote the embolisation and widespread dissemination of trophoblastic tissue throughout the venous system. However, in cases of excessive blood loss, it may be necessary to use oxytocin. Very rarely, primary hysterectomy is required in the case of excessive and unresponsive vaginal bleeding, yet in young women who wish to preserve their fertility; this is only indicated as a life-saving measure. Most cases of heavy vaginal bleeding can be managed using intravenous Tranexamic acid, replacement of blood products and in the case of a known arteriovenous malformation (more common in trophoblastic disease) using interventional radiology to embolise the feeding vessels. Women who are Rhesus-D negative should receive anti-D prophylaxis following evacuation of the molar pregnancy. In fact, the anti-D antigen is absent in complete hydatidiform moles due to the poor vascularisation of the chorionic villi, yet the delay to obtain a histological diagnosis necessitates the routine administration of prophylactic anti-D immunoglobulin in the required time frame to all cases of suspected GTD. Products of conception for all non-viable pregnancies must undergo histological examination, regardless of ultrasound findings or the mode of evacuation, but particularly cases in which GTD is suspected. This confirms the diagnosis of GTD and excludes overt malignancy (GTN). If products of conception are not sent for histological review, patients should undertake a urinary pregnancy test three weeks after the evacuation as a delayed diagnosis in such patients leads to significantly increased morbidity, including a higher risk of further surgery (hysterectomy) and combination chemotherapy due to more advanced disease at presentation. This should be negative and is a cost effective way of excluding persistent trophoblastic disease. Products of conception are not required for routine histological examination following termination of pregnancy, providing that fetal parts have been identified on ultrasound, given that the rate of developing GTN is estimated at 1:20,000 cases. If lesions suspicious of vaginal metastases are visualised at the time of uterine evacuation, these should simply be noted and never biopsied. Biopsy can lead to torrential bleeding that is extremely difficult to control. All patients with a histologically confirmed molar pregnancy should be promptly registered at their nearest specialist Trophoblastic Centre, designed to monitor hCG levels, provide advice on the duration of surveillance and further pregnancies, identify the development of persistent trophoblastic disease and coordinate the management of these patients accordingly. The Centres involve a multi-disciplinary, expert team of Clinical Nurse Specialists, Medical Oncologists, Radiologists, Pathologists, Gynaecological Oncologists and counsellors to support
histologically confirmed complete hydatidiform moles. Previously, most molar pregnancies were diagnosed on ultrasound at 16 weeks, whereas nowadays suspicions are raised as early as 6e8 weeks gestation. However, this must be balanced against the fact that earlier ultrasounds are less accurate at diagnosing GTD, with rates of 35e40% before 14 weeks compared to 60% after 16 weeks. Furthermore, approximately 50% of histologically confirmed cases of GTD have no diagnostic features on ultrasound, particularly in the case of partial hydatidiform moles. Under- or over-diagnosis is certainly problematic. Patients may undergo surgical evacuations unnecessarily for non-molar pregnancies, or alternatively if not diagnosed on ultrasound imaging, patients with GTD may receive suboptimal conservative or medical management whereby products of conception are not sent for histological review. These patients may then present between one and three weeks later with persistent or increasing vaginal bleeding and pain, before a transvaginal ultrasound reveals persistent trophoblast tissue, suspicious of GTD. Partial hydatidiform moles are specifically associated with two ultrasonic features, namely focal cystic areas within the placental tissue, and a ratio of >1.5 when comparing the transverse to antero-posterior diameter of the gestation sac. These features, combined with a growth restricted, hydropic fetus with congenital anomalies is highly suggestive of a partial molar pregnancy. hCG levels may be normal or only mildly elevated when compared to complete hydatidiform moles which display disproportionately elevated hCG levels compared to the gestational age (>100 103). Invasive moles and choriocarcinoma are equally characterised by persistently elevated hCG levels (>10 103), whereas in PSTT and ETT hCG levels usually display mild to moderate elevation (<3 103). Complete moles have a characteristic heterogeneous mass forming a ‘snowstorm’ or vesicular pattern on ultrasound, which fills the uterine cavity owing to placental proliferation. The fetus is absent and bilateral thecal luteal cysts may be present. Invasive moles, choriocarcinoma, ETT or PSTT subtypes may be seen to invade into or even through the uterine myometrium and serosa, encroaching on neighbouring structures such as bladder or bowel. Patients that have a viable pregnancy but a suspicion of coexisting molar changes on ultrasound imaging should not be advised to have a termination of pregnancy, as the outcome will become clear over time. Partial hydatidiform moles have a higher risk of trisomy and fetal demise, hence expectant management with serial ultrasound scans at intervals of ten to fourteen days is most appropriate. A twin pregnancy involving a viable fetus and a molar pregnancy is more common with complete than partial hydatidiform moles, yet is associated with higher obstetric risks for the viable fetus, including an increased risk of pre-eclampsia and stillbirth. A recent series suggests a live birth rate of 40e57%. Women should be informed that continuing with the pregnancy is not associated with higher rates of malignant conversion (GTN) or chemotherapeutic requirement. Initial management Women with suspected GTD should undergo surgical evacuation of the uterus using suction curettage where possible, conducted by a senior Gynaecologist due to the anticipated higher blood loss and complication rate. A single 400 mg dose of Misoprostol per vagina can be used one hour prior to the procedure to ripen
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patients and their families. Obstetrics and Gynaecology trainees or Consultants can refer patients using an online portal or a paper based form (located on the website of each Trophoblastic Centre). Histological samples are also sent to the centres for central review by a specialist Pathologist to confirm the diagnosis. This is particularly important considering that half of all partial hydatidiform moles are incorrectly diagnosed by nonspecialist centres; instead being mistaken for trisomy or other chromosomal abnormalities.
Patients diagnosed with PTD are requested to attend the nearest Trophoblast Centre for clinical review and staging investigations to determine their ongoing management. This includes a full history and clinical examination, bloods (FBC, group and save, U&E, LFT, hCG level and hormonal profile including oestradiol, LH, FSH, TSH, free T3, T4) and imaging (transvaginal ultrasound scan, chest X-ray). If metastatic lesions are noted on the chest X-ray, patients should undergo a CT abdomen pelvis and MRI brain to exclude additional metastatic sites, which would significantly alter management. Patients are subsequently managed using a prognostic scoring system developed by FIGO and the WHO, designed to predict resistance to first line chemotherapy (Table 4). The system incorporates eight clinical risk factors and divides patients into low- and high-risk groups. Low-risk patients have a WHO score 6 and are given single agent chemotherapy (intramuscular Methotrexate on days 1, 3, 5 and 7 alternating with Folinic acid 24 hours after each Methotrexate injection on days 2, 4, 6, 8) with a seven day rest period between each treatment cycle. Alternatively, patients with highrisk disease (score 7) receive combination chemotherapy (intravenous EMA-CO: EMA on days 1e2: Actinomycin, Etoposide, Methotrexate alternating with CO: Cyclophosphamide and Vincristine on day 8) given weekly without a break. Established central nervous system disease can be managed with specialised regimens of intrathecal methotrexate or stereotactic radiotherapy. Fortunately, the cure rate for GTN is excellent due to it’s highly chemosensitive nature; 100% amongst low-risk patients and 95% for high-risk patients. Treatment cycles are continued until the hCG levels normalise, followed by consolidation chemotherapy for a further six weeks. Shortening the consolidation phase is associated with significantly higher relapse rates. Notably, due to the differing histological and clinical behaviour of PSTT and ETT subtypes, these tumour types cannot be scored according to the FIGO/WHO classification system. Typically, they are less chemosensitive and require primary surgical
Medical consultation Following a suspected diagnosis of molar pregnancy on radiological and biochemical investigations, women should be counselled by a suitably qualified member of the medical team to discuss the diagnosis and management approach. The condition should be promptly managed and women should receive a lucid explanation of the next steps in their care and follow up including permission to register the woman with the relevant trophoblastic centre (Table 2). Persistent trophoblastic disease Persistent trophoblastic disease (PTD) is defined as a molar pregnancy that is unlikely to resolve without further treatment, and can follow any type of antecedent pregnancy and histological subtype. Overall in the U.K approximately 8% of all patients require treatment with chemotherapy or additional surgery, which is typically evident by a rising or plateauing hCG level (Table 3). The U.K adopts a conservative treatment approach; aiming to minimise patient exposure to toxic chemotherapy regimens, whereas worldwide, treatment levels are much higher, reaching 30% in Latin America. Complete hydatidiform moles more commonly display malignant conversion (15%) than partial moles (0.5e1%) and patients should be counselled accordingly. Conversion to an overt choriocarcinoma is less common, occurring in <0.5% of partial hydatidiform moles and 2e3% of complete moles.
Summary of topics that should be discussed prior to referral to the Trophoblastic Centre
C C C
C C C C
C C C C C C
Suspected diagnosis and genetics of GTD (use diagrams). Diagnostic results; ultrasound appearances and hCG level. Explore patient symptoms; pain, bleeding, nausea, vomiting, neurological symptoms, oedema, headache, abdominal pain (symptoms suggestive of pre-eclampsia), weight loss, sweating, palpitations, diarrhoea (symptoms indicative of hyperthyroidism). Initial management e surgical evacuation recommended. Referral to a specialist Trophoblastic Centre for ongoing monitoring Monitoring process; blood tests and urine samples that can be done locally and posted to the Trophoblastic Centre. Difference between GTD and malignant conversion into GTN. Give approximate rates of requiring further treatment (additional surgery/ chemotherapy). Overall cure rate if additional treatment is required. Risk of GTD in a subsequent pregnancy. Contraception advice and avoidance of pregnancy until advised by Trophoblastic Centre. Explore patient’s ideas, concerns and expectations. Offer support and further face-to-face visits locally or at the Trophoblastic Centre. Provide contact numbers in case of emergency both in and out-of-hours (heavy bleeding, pain).
Table 2
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Indications for commencing chemotherapy in U.K Trophoblastic Centres
C C
C
C C C C
hCG levels 20,000 IU/L after one or two uterine evacuations e risk of uterine perforation. Static or rising hCG after one or two uterine evacuations. Static levels are defined as four or more equivalent values of hCG over at least 3 weeks (days 1, 7, 14, 21). Rising hCG is defined as two consecutive rises in hCG of 10% over at least 2 weeks (days 1, 7 and 14). Persistent elevation of hCG levels six months following uterine evacuation e Review patient at Trophoblastic Centre. If hCG levels are falling, can monitor for up to 1 year. Histological diagnosis of choriocarcinoma, Placental Site Trophoblastic Tumour (PSTT) or Epithelioid Trophoblastic Tumour (ETT) Heavy vaginal bleeding, evidence of gastrointestinal or intraperitoneal haemorrhage in the presence of raised hCG levels. Metastases in the liver, gastrointestinal tract or brain Pulmonary metastases with static or rising hCG levels.
Table 3
management (hysterectomy), followed by adjuvant chemotherapy if required.
40%, particularly in low-risk patients where the hCG level is <5000 IU/L. This evidence originates from the multicentre, phase II GOG 242 trial, which examined sixty-four women with low-risk, non metastatic GTN. Surgical success was independent of hCG burden, tumour size and depth of invasion, however only patients with a FIGO/WHO score 4 were cured by a second evacuation, suggesting chemotherapy is required in the low-risk patient subgroup who score 5e6. Ideally, regional centres should always consult the Trophoblastic Centres before performing a second evacuation, yet this may not be possible in the case of heavy vaginal bleeding.
Second uterine evacuation Second uterine evacuations for persistent trophoblastic disease detected on ultrasound imaging are indicated in some circumstances, and can reduce the requirement for chemotherapy by
The Combined FIGO/WHO prognostic classification system (2000)
Primary chemotherapy resistance Overall, approximately 25e35% of patients are resistant to first line chemotherapy, yet this rises to 75e85% amongst low-risk women who score 5 or 6. This may have detrimental psychological consequences for the patient and their family, as more potent single or combination agent chemotherapy is subsequently required, with an increased side effect profile. Interestingly, the time to achieve remission does not appear to be affected by this switch. In the Sheffield Trophoblastic centre, low-risk patients with primary chemotherapy resistance and hCG levels <300 IU/L are switched to intravenous Dactinomycin repeated every two weeks, whereas patients with levels 300 IU/ L receive intravenous Carboplatin every three weeks. At the Trophoblastic Centre in London, patients with first-line chemotherapy resistance and levels >1000 IU/L are commenced on combination chemotherapy (high-risk EMA/CO). High-risk patients who display primary resistance to combination chemotherapy are given different combination regimens (EP/EMA [etoposide and cisplatin alternating with Dactinomycin, etoposide and methotrexate] or TP/TE [paclitaxel and cisplatin alternating with paclitaxel and etoposide). Salvage hysterectomy may additionally be required.
FIGO anatomical stage Stage I II
III IV
Disease confined to the uterus GTN extends outside of the uterus but is limited to the genital structures (adnexae, vagina, broad ligament) GTN extends to the lungs, with or without known genital tract involvement All other metastatic sites
Modified WHO prognostic classification system, as adapted by FIGO Score
0
Age (years) Antecedent pregnancy Interval months from index pregnancy Pre-treatment hCG (IU/L) Largest tumour size including uterus (cm) Site of metastases
<40 40 e Mole Abortion Term <4 4e6 7e12
e e >12
<103 103e104 104e105 <3 3e4 5
>105 e
Number of metastases Previous failed chemotherapy
1
Lung Spleen, kidney e 1e4 e e
2
4
Gastrointestinal Liver, brain 5e8 >8 Single drug 2 drugs
Side effect profile Most young women are understandably very anxious about commencing chemotherapy, and the immediate questions commonly encountered include the effect on hair loss and future fertility. Low-risk chemotherapy regimens (methotrexate and dactinomycin) are generally well tolerated and are not associated with hair loss. Instead, emesis, stomatitis, mouth sores,
Score <6 ¼ Low-risk, Score 7 ¼ High-risk.
Table 4
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weeks later. By discontinuing monitoring after two normal urine samples, there is a 1:300 risk of missing GTN. Following any further pregnancy, irrespective of the outcome (miscarriage, live birth, ectopic), women should contact the Trophoblastic centre who will arrange for a urinary hCG sample to be checked six to eight weeks following the end of the pregnancy to exclude disease recurrence. Trophoblastic disease can recur after any pregnancy, and some subtypes in particular can recur even when separated by a normal, healthy pregnancy.
diarrhoea and abdominal pain are most commonly experienced. Carboplatin may cause nausea, vomiting and myelosuppression, whilst etoposide within the high-risk combination chemotherapy is predominantly associated with hair loss and higher rates of bone marrow toxicity. Combination chemotherapy with EMA/ CO significantly increases the risk of secondary leukaemia in a dose dependent manner and brings forward the age of menopause by three years. Aside from this, patients can be reassured that low- or high-risk chemotherapy regimens do not otherwise affect fertility. Evidence suggests that there is no increased risk of congenital abnormalities, miscarriage, ectopic pregnancy or stillbirth in future pregnancies compared to the general population. Patients are advised not to conceive for a year following the completion of chemotherapy, due to the risk of fetal teratogenicity secondary to the chemotherapeutic agents. Furthermore, recurrence risk is also highest during this period.
Concluding remarks Trophoblastic disease is a rare but extremely important condition that most clinicians will encounter during their training. Women who are affected by the disease are extremely anxious and upset, not only having to face losing their baby and having an unsuccessful pregnancy, but being diagnosed with a condition that the majority will not have heard of. The mention of chemotherapy should the condition fail to clear spontaneously, can induce additional concern. It is therefore essential that clinicians who initially encounter these patients in non-specialised centres are well informed and deal with patient’s concerns and questions in a sensitive and considerate manner. A
Contraception Contraceptive guidance following a molar pregnancy has now changed. The combined oral contraceptive pill can be used following uterine evacuation, whilst awaiting histological review, even if the hCG levels remains elevated. Progesterones are not considered to increase the risk of GTN and are safe to use. Intrauterine contraceptive coils should not be inserted at the time of uterine evacuation or indeed until hCG levels have returned to normal due to the risk of uterine perforation.
FURTHER READING Berkowitz RS, Goldstein DP. Current management of gestational trophoblastic diseases. Gynecol Oncol 2009; 112: 654e62. Hancock BW, Seckl MJ, Berkowitz RS. Gestational trophoblastic disease. Chapman & Hall Medical, 2015. http://isstd.org/gtd-book/ front-page/. Osborne RJ, Filiaci VL, Shink JC, et al. Second curettage for low-risk nonmetastatic gestational trophoblastic neoplasia. Obstet Gynecol 2016; 128: 535e42. RCOG. Green top guideline number 38, The management of gestational trophoblastic disease. 2010, https://www.rcog.org.uk/ globalassets/documents/guidelines/gtg_38.pdf. Savage PM, Sita-Lumsden A, Dickson S, et al. The relationship of maternal age to molar pregnancy incidence, risks for chemotherapy and subsequent pregnancy outcome. J Obstet Gynaecol 2013; 33: 406e11. Savage P, Williams J, Wong SL, et al. The demographics of molar pregnancies in England and Wales from 2000e2009. J Reprod Med 2010; 55: 341e5. Seckl MJ, Sebire NJ, Fisher RA, Golfier F, Massuger L, Sessa C. Gestational trophoblastic disease: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2013; 24(suppl 6). vi:39e50. Tidy J, Winter M, Singh K, Hancock B.W. Gestational trophoblastic neoplasia: a guide to management at Weston Park hospital, Sheffield teaching hospitals foundation trust. http://stdc.group. shef.ac.uk/resources/gtngm2014.pdf2014. WHO. WHO classification of tumours of female reproductive organs (IARC WHO classification of tumours). International Agency for Research on Cancer, 2014.
Recurrence Compared to the general population, women with a history of molar pregnancy have a higher risk of a recurrent mole, yet the absolute risk is low (1:100). However, women with a history of 2 molar pregnancies, have a risk of 1:6 in their third pregnancy. A specialist geneticist within the Trophoblastic Centres should review women with clusters of trophoblastic disease, as a condition called familial recurrent hydatidiform mole is now known to exist. This autosomal recessive condition involves a mutation in two genes, namely NLRP7 and more rarely, KHDC3L. Follow-up Patients diagnosed with a partial or complete hydatidiform mole have their urinary hCG levels monitored on a two weekly basis by the specialist Trophoblastic Centre. If their hCG level returns to normal within 56 days of the end of the molar pregnancy, patients are monitored for six months from the end of the pregnancy. However, if the hCG level does not return to normal within 56 days, the patient continues to be monitored for six months from the date of the first normal result. This monitoring regime carries a 1:2000 risk of missing disease, and during this time, patients should avoid a new pregnancy. These recommendations must be followed for a complete hydatidiform mole, but experience has shown that the follow-up for partial mole can be shortened without exposing the patient to significantly increased risk, due to the lower risk of malignant conversion. Partial moles are now commonly followed up until the urine hCG levels return to normal, followed by a confirmatory level four
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