Best Practice & Research Clinical Obstetrics and Gynaecology xxx (xxxx) xxx

Contents lists available at ScienceDirect

Best Practice & Research Clinical

Obstetrics and Gynaecology
journal homepage: www.elsevier.com/locate/bpobgyn

Clinical presentation and diagnosis of

Gestational Trophoblastic Disease
Christianne Lok, Minke Frijstein, Nienke van Trommel*
Department of Gynaecologic Oncology, Center of Gynecologic Oncology Amsterdam, The Netherlands Cancer
Institute-Antoni van Leeuwenhoek, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands

a b s t r a c t
Keywords:
Gestational trophoblastic disease Gestational trophoblastic disease (GTD) is a heterogeneous group
Symptoms of pregnancy-related disorders characterized by abnormal prolif-
Diagnosis eration of trophoblastic tissue. It encompasses the premalignant
Imaging partial and complete hydatidiform mole but also the malignant
invasive mole, choriocarcinoma, placental-site trophoblastic
tumor, and epithelioid trophoblastic tumor. The clinical presenta-
tion changed to earlier detection after the introduction of first
trimester ultrasounds. Patients are often asymptomatic, but
vaginal bleeding continues to be the most common presenting
symptom. Other symptoms can develop in the case of metastatic
disease. Ultrasound, serum human chorionic gonadotrophin, and
sometimes additional imaging such as CT, MRI, or PET can confirm
the diagnosis and stage of disease. Familiarity with the patho-
genesis, classification, imaging features, and treatment of GTD fa-
cilitates diagnosis and appropriate management.
© 2020 Published by Elsevier Ltd.

Gestational Trophoblastic Disease

Gestational trophoblastic disease (GTD) is a heterogeneous group of pregnancy-related disorders

characterized by abnormal proliferation of trophoblastic tissue. It encompasses premalignant hydati-
diform moles (HMs) but also malignant invasive mole, choriocarcinoma, placental-site trophoblastic
tumor (PSTT), and epithelioid trophoblastic tumor (ETT) (Fig. 1) [1,2]. The malignant forms of the
disease are also collectively known as gestational trophoblastic neoplasia (GTN) [3]. The basis of

* Corresponding author.
E-mail addresses: c.lok@nki.nl (C. Lok), m.frijstein@nki.nl (M. Frijstein), n.v.trommel@nki.nl (N. van Trommel).

https://doi.org/10.1016/j.bpobgyn.2020.12.001
1521-6934/© 2020 Published by Elsevier Ltd.

Please cite this article as: C. Lok, M. Frijstein and N. van Trommel, Clinical presentation and diagnosis of
Gestational Trophoblastic Disease, Best Practice & Research Clinical Obstetrics and Gynaecology, https://
doi.org/10.1016/j.bpobgyn.2020.12.001
C. Lok, M. Frijstein and N. van Trommel Best Practice & Research Clinical Obstetrics and Gynaecology xxx (xxxx) xxx

modern classifications for GTD and GTN was provided by Ewing et al., in 1910 as he was the first
investigator to differentiate the various types of trophoblastic neoplasm [4,5]. The recent description of
two previously not recognized benign trophoblastic diseases, exaggerated placental site (EPS), and
placental site nodule (PSN) shows that the field is still in development [6]. HMs and choriocarcinoma
originate in the cytotrophoblast and syncytiotrophoblast, whereas PSTTs, ETTs, EPSs, and PSNs develop
in the intermediate trophoblast [7]. As all these different entities of GTD are very rare and share
similarities in histology, expert review is often needed to avoid misdiagnosis.
There are two types of molar pregnancy: complete hydatidiform mole (CHM) and partial hydati-
diform mole (PHM). CHM is diploid and androgenic in origin, with no evidence of fetal tissue. CHM
develops after the monospermic or dispermic fertilization of an ovum. Maternal chromosomes are lost
before or just after conception, resulting in a diploid karyotype with an entirely paternal nuclear DNA.
In contrast, PHM results from dispermic fertilization of a normal ovum, usually resulting in a triploid
karyotype. In a PHM, fetal parts or fetal red blood cells can be present [1,8].
HM is the most common type of GTD. Worldwide incidence rates differ, but in Europe, HMs have an
incidence of 0.5e3.0 per 1000 pregnancies [7,9e11]. Higher frequencies have been reported in Asia
with rates ranging from 1 to 10 per 1000 pregnancies [9]. The variation in worldwide incidence rates
may be due to heterogeneity in case definition, inability to describe the population at risk and the lack
of centralized databases [9]. Dietary and genetic causes may also contribute.

Gestational trophoblastic neoplasia

In most patients, HMs regresses spontaneously after suction curettage. In approximately 15%e20%
of CHMs and 0.5%e1% of PHMs, trophoblastic tissue remains active after the evacuation of the molar
tissue with plateauing or rising human chorionic gonadotrophin (hCG) concentrations in blood [2,7].
This postmolar GTN is diagnosed according to the criteria of the International Federation of Gynecology
and Obstetrics (FIGO, Table 1), if one of the following is present: 1) A plateau of at least 4 persistently
elevated hCG values during 3 weeks or longer, 2) A sequential rise of 3 consecutive weekly hCG values
for two weeks or longer, and 3) the histological diagnosis of choriocarcinoma [12e14].
GTN usually occurs after the evacuation of a HM (post-molar GTN). However, GTN may follow any
type of antecedent pregnancy, including nonmolar abortion, ectopic pregnancy, and term pregnancy
[1,13]. Invasive mole describes the condition where a CHM or PHM invades the myometrium and this
type of mole can only be diagnosed after hysterectomy [3]. Histologically, postmolar and nonmolar
choriocarcinomas are characterized by the invasion of the myometrium, but in contrast to invasive HM
there is an absence of chorionic villi, abnormal syncytiotrophoblast, and cytotrophoblast, necrosis, and
hemorrhage. In several studies, antecedent term pregnancy is considered a risk factor for prognosis in
choriocarcinoma patients [15e17], although current survival is comparable to the general survival in
high-risk GTN patients [16,18,19]. Most GTDs secrete hCG, which is therefore a sensitive tumor marker
[2,3,20]. A pathological diagnosis, sometimes completed with genetic tests, provides useful informa-
tion about the causative pregnancy and confirms gestational choriocarcinoma rather than nongesta-
tional tumors such as gastric or lung cancers, which can occasionally present as choriocarcinoma with
increased serum hCG concentration [21].

Rare GTN: PSTT and ETT

PSTT originates from the intermediate trophoblast on the maternal side of the placental bed and
invades the myometrium. Chorionic villi are absent and there is a sheet-like and infiltrative growth
pattern. In contrast to choriocarcinoma, PSTT forms uterine lesions with less hemorrhage and necrosis
and with lower hCG concentrations [20,22]. An interval of >48 months since antecedent pregnancy
was reported to be a poor prognostic factor for patients with PSTT [25]. The even rarer ETT was first
described in 1998 by Shih and Kurman [23]. ETT develops from the chorionic leave type intermediate
trophoblast and is histologically distinguished from PSTT by its nested well-circumscribed nodular
growth [24e26]. PSTTs and ETTs can be difficult to diagnose as they can develop many years after the
antecedent pregnancy. ETT and PSTT share several overlapping features and similarities in behavior
with less hCG production, slow growth, and sometimes late metastases. ETT and PSTT are usually

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C. Lok, M. Frijstein and N. van Trommel Best Practice & Research Clinical Obstetrics and Gynaecology xxx (xxxx) xxx

Fig. 1. Entities of GTD and incidence rates.

treated in the same way, as both tumors have limited chemosensitivity making surgery the cornerstone
of treatment [26,27]. Mixed tumors composed of choriocarcinoma and PSTT or choriocarcinoma and
ETT or PSTT and ETT are described in literature.

Staging and scoring system

FIGO developed a prognostic scoring system (Table 1) and an anatomical staging system (Table 2)
[28e30]. The prognostic scoring system predicts the risk of single-agent chemotherapy resistance in
case of GTN. A total score of 0e6 indicates the low risk of resistance and a score of 7 or more indicates a
high-risk [12,28e31]. For ETT and PSTT, which have a different biological behavior, this scoring system
is not helpful and the FIGO anatomical staging should be used (Table 2) [1,3].
To determine the FIGO score and stage, all post-molar GTN patients need patient review, hCG
measurement and staging with (Doppler) ultrasonography (US) pelvis, and chest X-ray (CXR). For the
FIGO scoring system, a CXR is used to count the number of metastases. Staging with computer

Table 1
Modified WHO scoring system based on prognostic factors as adapted by FIGO.a

Score 0 1 2 4

Age (years) <40
40 e e

Antecedent pregnancy Mole Abortion Term e
Interval from index pregnancy, months <4 4e6 7e12 >12
Pre-treatment serum hCG (IU/L) <103 103-<104 104<105
105
Largest tumor size including uterus (cm) e 3 - <5
5 e
Site of metastases Lung Spleen and kidney Gastrointestinal Liver and brain
Number of metastases e 1e4 5e8 >8
Previous failed chemotherapy e e Single drug Two or more drugs

FIGO ¼ Fede
ration Internationale de Gyne
cologie et d’Obste
trique; hCG ¼ human chorionic gonadotropin; iu ¼ international
unit; and WHO ¼ World Health Organization.
a
Adapted from FIGO Committee on Gynecologic Oncology.

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C. Lok, M. Frijstein and N. van Trommel Best Practice & Research Clinical Obstetrics and Gynaecology xxx (xxxx) xxx

Table 2
FIGO staging and classification for gestational trophoblastic neoplasia.a,b

FIGO stage Description

I Gestational trophoblastic neoplasia strictly confined to the uterus corpus

II Gestational trophoblastic neoplasia extending to the adnexae or the vagina, but limited to the genital
structures
III Gestational trophoblastic neoplasia extending to the lungs, with or without genital tract involvement
IV All other metastatic sites
a
Adapted from FIGO Committee on Gynecologic Oncology.
b
To stage and allot a risk factor score, a patient's diagnosis is allocated to a stage as represented by a Roman numeral I, II, III,
and IV. This is then separated by a colon from the sum of all the actual risk factor scores expressed in Arabic numerals, i.e., stage
II:4 and stage IV:9. This stage and score will be allotted for each patient.

tomography (CT) chest/abdomen and magnetic resonance imaging (MRI) of the brain can be indicated
to exclude the disease that is more widespread [1,14,32].

Clinical signs and symptoms of hydatidiform mole

The clinical presentation of HM has changed considerably over the last decades. In the 1960e1970s,
the mean gestational age at diagnosis was 16 weeks [33] and classic presentations were, in declining
frequency, vaginal bleeding (89%e97%), uterine enlargement (38%e51%), and theca-lutein cysts due to
ovarian hyperstimulation by high serum hCG concentrations (20%e46%). Preeclampsia and hyper-
emesis occurred in 12%e27% and 20%e26% of patients, respectively [34,35], and 2% of patients pre-
sented with signs of hyperthyroidism [35]. The clinical presentation changed to earlier detection at a
mean gestational age of 10e12 weeks after the introduction of first trimester ultrasounds. Nowadays,
many patients are asymptomatic at diagnosis due to the wide availability of ultrasound. Vaginal
bleeding continues to be the most common presenting symptom occurring in 58%e84% of patients
presenting with HMs [36e38]. Heavy blood loss can lead to anemia with complaints of dizziness and
fatigue. Preeclampsia is hardly seen anymore. The exact frequency of presenting symptoms is difficult
to extrapolate from literature because symptoms of patients are not systematically reported in studies.
Moreover, symptoms can be vague and resemble complaints often present in normal pregnancy. In
Table 3, symptoms that are reported in GTD are listed. Some of the symptoms can also be caused by
anemia and hyperthyroidism.

Table 3
Clinical signs and symptoms of hydatidiform mole.

HM (possible) symptoms

History Abdominal pain

Vaginal bleeding
Nausea
Vomiting
Dyspnea
Palpitations
Preeclampsia
Physical examination Enlarged uterus
Vaginal blood (and sometimes tissue) loss
Theca lutein cysts
Tachypnea
Tachycardia
Laboratory examination Increased hCG
Abnormal thyroid function tests
Anemia

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C. Lok, M. Frijstein and N. van Trommel Best Practice & Research Clinical Obstetrics and Gynaecology xxx (xxxx) xxx

Clinical signs and symptoms of metastases of gestational trophoblastic disease

Patients can also present with symptoms from metastatic disease (Table 3). Dyspnea, coughing,
chest pain, tachypnea, and hemoptysis can be signs of the presence of trophoblastic emboli in the
lungs. Choriocarcinomas can present with widespread dissemination. The most common metastatic
sites for metastatic disease are the lungs, but other well-known sites are the vagina, liver, brain, spleen,
kidneys and/or bowel [20,39,40]. Vaginal metastases can present with bleeding, which cannot be
distinguished from uterine blood loss. A gynecological examination upon presentation is therefore
important. Vaginal metastases are often single lesions at the anterior wall [41]. These metastases are
very vascular and biopsies can potentially cause profuse bleeding. Even without biopsy, patients with
vaginal metastases regularly need blood transfusion or even embolization.
Liver metastases are rare and often have a poor prognosis [42]. The majority of the patients with
liver metastases also have lung metastases. In addition, liver metastases are vascular lesions and pa-
tients may present with life-threatening profuse intra-abdominal bleeding and hemorrhagic shock.
Emergency treatment with transcatheter angiographic embolization of the hepatic artery can be a
lifesaving procedure to stop bleeding [43].
More than half of patients with brain metastases present with central nervous system symptoms
but asymptomatic brain metastases can be found without symptoms during treatment or at relapsed
disease. The symptom reported is headache [44]. Symptoms can be so severe, that patients die before
treatment could have been started. Patients who die of brain metastases have symptoms of intracranial
hemorrhage or with concurrent herniation and multiple organ failure. In addition, shock resulting from
myelosuppression during treatments and respiratory failure has been described [45].
Pelvic metastases are not unequivocally described in literature. The symptoms depend on their
localization in the pelvis and whether they exert local pressure or invade into surrounding organs
leading to pain and bleeding.
PSTT and ETT often present with irregular bleeding or with symptoms related to metastatic disease.

Human chorionic gonadotropin (hCG)

Crucial for diagnosis of GTD or GTN is the measurement of Human Chorionic Gonadotropin (hCG)
which is a disease-specific tumor marker produced by HMs and GTN. It is easily measured quantita-
tively in both urine and blood, and hCG levels have been shown to correlate with the burden of disease
[2]. hCG is a glycoprotein hormone produced by trophoblastic tissue and therefore a key marker in
pregnancy and GTD. hCG is composed of two noncovalently bound subunits (i.e., the a- and b-subunit).
The a-subunit of hCG is identical to the a-subunit of the pituitary glycoprotein hormones follicle-
stimulating hormone (FSH), thyroid-stimulating hormone (TSH) and luteinizing hormone (LH). The
hCG b-subunit is composed of 145 amino acids, which distinguishes hCG from these other glycopro-
teins [46]. If hCG is abundantly present, the a-subunit can mimic the a-subunit of the other glyco-
protein hormones and therefore cause other symptoms, which can be seen in hyperthyroidism [47].
The main functions of serum hCG in uneventful pregnancy are antigonadotrophic (by inhibiting LH
and FSH avoiding ovulation during pregnancy) and steroidogenic (by stimulating progesterone pro-
duction of the corpus luteum in early pregnancy and the trophoblast at a later stage) [48]. Several forms
of hCG exist, like intact hCG (i.e., a hCG a-subunit attached to a hCG b-subunit), free hCG a-subunit,
nonnicked free hCG b-subunit, nicked free hCG b-subunit, and the hCG b-subunit core fragment. These
heterogeneous hCG molecules are more abundantly present in GTD than in normal pregnancy,
therefore, an assay that will detect all main forms of hCG and its multiple fragments should be used to
follow up patients with GTD [2].

hCG tests

The first pregnancy test measuring hCG was developed by Selmar Aschheim and Bernard Zondek.
In 1928, they described a bioassay in which young female mice were injected abdominally with the
urine of a suspected pregnant woman. If 48 h later on autopsy, the ovaries of the mice were enlarged,
the woman was pregnant [49]. This test was considered to have a good accuracy. In 1956, Solomon

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C. Lok, M. Frijstein and N. van Trommel Best Practice & Research Clinical Obstetrics and Gynaecology xxx (xxxx) xxx

Berson and Rosalyn Yalow introduced the concept of radioimmunoassay [50]. The principle of this
new technique was based on the reaction of radioactive labeled analyte with an antibody directed
against that analyte. The urine or serum sample in which the analyte (e.g., hCG) needs to be
measured is added to this mixture. The more analyte is present in the sample, the less radioactive
analyte is captured by the antibodies, and this leads to the quantification of the analyte in a
competitive setting. To date, these assays use an antiserum directed against the free hCG b-subunit as
first described by Vaitukaitis et al. [51].
More recently, in the 1980s, the concept of double-antibody “sandwich”-type immunoassays was
developed, which now are widely used for many purposes. In this type of assay, two antibodies are
used to bind the hCG molecule serving as the analyte; one antibody is bound to a solid surface of the
reaction tube and captures the hCG analyte (“capture antibody”) while the other antibody (binding the
hCG analyte as well) is labeled with a (radioactive) tracer (“signal antibody”). The principle is based on
an increase of signal with increasing concentrations of analyte (“proportional assay”). The application
of “sandwich”-type assay formats are primarily suited for pregnancy detection, and these type of as-
says do not necessarily detect the aberrant hCG molecules found in trophoblastic disease [52].

Pitfalls in hCG measurements

Both false-positive and false-negative hCG test can occur. A false-positive hCG test can occur due to
heterophile (human antimouse) antibodies [53]. A practical work around is proposed by Lurain if
falsely elevated hCG is suspected: (1) determine a urine hCG level, which should be negative because
the interfering substances are not excreted in urine; (2) request serial dilution of the serum, which
should not show a parallel decrease with dilution; and (3) send the serum (and urine) of the patient to
an hCG reference laboratory [2].
The presence of pituitary hCG may impose a clinical challenge if hCG is measured but no source or
histological proof of disease is found. If no histological proof of GTD can be found, one should consider
the option that pituitary secretes small amounts of hCG [54,55]. If this is suspected, the suppression of
the pituitary, e.g., by a 2 week trial with an oral contraceptive, should significantly lower the level of
hCG measured. This will prove that the hCG was produced by the pituitary and not by GTD. Finally, a
familial hCG syndrome has been described in several families. Because of a genetic defect, multiple
members in these families produce inactive hCG products. These hCG products are biologically inactive
and do not interfere with fertility [56]. If more women in a family have a history of false-positive
pregnancy tests, this condition may be suspected.
A false-negative hCG test can occur due to the high-dose hook effect. The high-dose hook effect is a
well-known phenomenon for which “sandwich” immunoassays are prone. The mechanism behind this
phenomenon is that if the analyte concentration (hCG) exceeds the binding capacity of both the
capture and the labeled antibodies in the assay reagents, an incomplete formation of the immune
complexes required for signal creation occurs. This gives falsely low results, which may have severe
implications for patient care [57]. If a false-negative hCG result due to high-dose hook effect is sus-
pected, dilution of the analyte can be applied to restore the disbalance between analyte and antibodies.

Genetics

The majority of CHM has a 46XX diploid chromosomal pattern and occurs most commonly when a
single haploid sperm fertilizes an ovum lacking maternal genes, and then undergoes duplication.
PHMs are genetically triploid, most commonly the result of the fertilization of a normal egg by two
sperms.
Genetics are not only helpful in differentiating CHM and PHM but can define which pregnancy is the
causative pregnancy, thereby determining the interval from the end of pregnancy until the start of
treatment, which a prognostic factor in the FIGO is scoring system. A genetic test can differentiate a
gestational origin from a nongestational tumor [21].
Amniocentesis or chorionic villus biopsy for antenatal karyotyping can also help in the rare situ-
ation of a viable fetus with an abnormal/enlarged placenta to differentiate between a PHM with a
viable or a digynic triploid fetus with a very poor prognosis.

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C. Lok, M. Frijstein and N. van Trommel Best Practice & Research Clinical Obstetrics and Gynaecology xxx (xxxx) xxx

Imaging in gestational trophoblastic disease

Ultrasound

US is the modality of choice for the initial diagnosis of molar pregnancy. Often, molar pregnancies
are diagnosed during routine first-trimester US. CHM is characterized by an enlarged uterus filled with
a heterogeneous echogenic mass with several hypoechoic foci multiple small cystic spaces. Hydropic
chorionic villi form the image of so-called “cluster of grapes” appearance. Larger irregular fluid col-
lections can be seen in pregnancies of more advanced gestational age [58]. In CHM, a fetus is absent,
unless there is a coexisting diploid twin. Multiple theca lutein cysts can be present in the ovaries caused
by ovarian stimulation by high levels of b-hCG.
In PHM, an elongated empty gestational sac or (mostly nonviable) fetal parts can be found. In
rare pregnancies with higher gestational age, growth retardation, oligohydramnios, and an enlarged
placenta with multiple diffuse anechoic lesions consistent with cystic degeneration can be found
[59]. Differentiation from other placenta anomalies or triploidy can be difficult. The performance of
US in differentiating PHM from nonmolar miscarriage is poor. Sebire et al. described that in 91
patients with a histological diagnosis of PHM, 16 were diagnosed as miscarriage or anembryonic
pregnancy [60]. This is confirmed in other studies [61], but more recent data suggest an increase in
the sensitivity and specificity over time [62]. In general, less than 50% of all molar pregnancies are
detected at routine US.
US alone is often not sufficient to diagnose HM and hCG and histological examinations
have to confirm the suspicion. After treatment, some patients still show intrauterine (vascular)
abnormalities, but this often normalizes with time. Arteriovenous malformations can remain
in utero [63] after treatment and can be diagnosed with ultrasound and color flow Doppler
studies [64]. In some clinics, the uterine artery pulsatility index is used to predict the response
to chemotherapy in GTN. Currently, studies are performed to further investigate this [65].
Choriocarcinoma may appear as heterogeneous, echogenic, vascular masses with necrosis, and
hemorrhage, but differentiation from PSTT or ETT is not possible by US. In case of vaginal metastases,
abdominal US is preferred to prevent hemorrhage [66].

Chest X-ray

CXR is used to determine the presence and number of lung metastases. Although, it is known that
many patients with a negative CXR have micrometastasis, this is not influencing treatment and
outcome. Therefore, CXR is still used to determine the FIGO score.

Computer tomography scan

Although intrauterine mass and enlarged ovaries can be seen on the CT scan, this imaging
technique does not help in the diagnosis of molar pregnancy. However, CT can be used to evaluate
metastatic disease in GTN. Up to 30% of patients with GTN have metastatic disease at the time of
diagnosis [67]. As the presence of metastatic disease affects prognosis and is incorporated in the
FIGO scoring system which directs treatment, evaluation for metastatic disease is essential. If me-
tastases are present, they are mostly found in the lungs (80%), vagina (30%) and liver and/or brain
(10%) [68]. There is an ongoing debate whether chest radiography is sufficient for staging or that a
chest CT is mandatory for the evaluation of pulmonary metastases. Chest CT is more sensitive for the
detection of pulmonary metastases than chest radiography. However, it was shown that there was
no significant difference in the need to change to second-line chemotherapy or in time to remission
in those patients with metastatic GTN whose score or risk was changed when CT scan was used in
place of CXR [67,69].
CT can help to evaluate rare pelvic metastases and intra-abdominal metastases of choriocarci-
noma, PSTT, and ETT. Although, lymph node metastases can be visualized, their occurrence is very
rare [70].

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C. Lok, M. Frijstein and N. van Trommel Best Practice & Research Clinical Obstetrics and Gynaecology xxx (xxxx) xxx

MRI

MRI does not contribute to the diagnosis of CHM or PHM. The general MRI findings are nonspecific
for HM. They appear as intrauterine heterogeneous tissue with multicystic spaces representing the
hydropic villi, with focal areas of hemorrhage. MRI of the pelvis may help to diagnose invasive moles, as
MRI is sensitive to visualize the invasion of the myometrium or adjacent pelvic organs. The intact
normal myometrium in HMs appears as a hypointense layer surrounding the molar tissue in the
uterine cavity. In invasive moles, this clearly visible border is interrupted [71].
On MRI, invasive moles and choriocarcinomas appear similar. Sometimes choriocarcinoma show
more areas of necrosis, hemorrhage, and solid soft-tissue components that enhance avidly with
contrast due to their increased vascularity. This increased vascularity may manifest as focal signal
voids [72].
Also newer MRI techniques such as diffusion-weighted MRI are not useful for predicting the
development into GTN [73].
MRI is very helpful in evaluating metastases in the liver or brain in (ultra) high-risk disease. As the
reported incidence of brain metastases is low and over 80% of patients with brain metastases do have
pulmonary metastases [74], it is recommended to perform an MRI of the brain in case of pulmonary
metastases [1]. An MRI of the liver is often performed if there is a suspicion of metastases based on US
or abdominal CT-scan.
Sometimes US is inconclusive in the diagnosis of placental abnormalities in pregnancies with a
viable fetus. Some radiologists have obtained expertise in evaluating the placenta with MRI. The ad-
vantages of MRI are that unlike US, MRI is not affected by fetal orientation, oligohydramnios, overlying
bones, or obesity. MRI provides better soft-tissue contrast and multiplanar imaging with a wider field
of view. MRI is limited by artifacts caused by the moving fetus and maternal breathing. Although MRI
can be used in pregnancy, a lower magnetic field (1.5T) is often used for scanning pregnant patients
whenever possible [75]. Gadolinium-based contrast agents are not used in pregnancy unless really
necessary because of rare adverse short and unknown long-term effects on the human fetus.

Positron emission tomography

In general, positron emission tomography with 18-fluorodeoxyglucose (18FDG-PET) can demon-

strate sites of metastatic disease by pointing out areas with increased metabolic activity. When
comparing 18FDG-PET to conventional imaging techniques in GTN (transvaginal US, CXR, and chest
CT), 18FDG-PET did not have a greater diagnostic accuracy [76]. In a series of 16 GTN patients, 18FDG-
PET changed treatment planning in only 3 patients.
It has been argued that there is a place for 18FDG-PET in settings of elevated hCG without suspicious
lesions on conventional imaging techniques [77]. Theoretically, 18FDG-PET can be useful to determine
if residual lesions are still metabolically active, although hCG concentrations should be sufficient [77].
18FDG-PET can aid in identifying residual disease sites in women relapsed from previously treated
GTN, but false positive and negative results have been described, thus careful evaluation and combi-
nations with other imaging modalities is indispensable [78].

Practice points
Patients with GTD are often asymptomatic, but vaginal bleeding continues to be the most
common presenting symptom. US, serum hCG, and sometimes additional imaging such as CT,
MRI, or PET can confirm the diagnosis and stage of disease. Familiarity with the pathogenesis,
classification, imaging features, and treatment of GTD facilitates diagnosis and appropriate
management.

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C. Lok, M. Frijstein and N. van Trommel Best Practice & Research Clinical Obstetrics and Gynaecology xxx (xxxx) xxx

Research agenda

* Core outcomes for GTD/GTN research have not been reported in the literature.
* International database for fine tuning of the diagnosis of high-risk GTN should be
established.

Conflict of interest

I hereby declare that C Lok, M Frijstein, and N van Trommel have no conflicts of interest for the
publication of our manuscript entitled “Clinical presentation and diagnosis of Gestational
Trophoblastic Disease” for Best Practice & Research Clinical Obstetrics & Gynaecology: an invited
Review for Issue 35.5/Volume 74.

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