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Radiol Oncol 2022; 56(4): 430-439. doi: 10.2478/raon-2022-0038
430
review article
Advances in diagnostics and management of 
gestational trophoblastic disease 
Nusa Lukinovic
1
, Eva Pavla Malovrh
1
, Iztok Takac
1,2
, Monika Sobocan
1,2
, Jure Knez
1,2 
1 
Faculty of Medicine, University of Maribor, Maribor, Slovenia
2 
Divison of Gynecology and Perinatology, University Medical Centre Maribor, Maribor, Slovenia
Radiol Oncol 2022; 56(4): 430-439.
Received 13 May 2022
Accepted 30 August 2022
Correspondence to: Assist. Monika Sobo čan, M.D., Division for Gynecology and Perinatology, University Medical Centre Maribor, 
Ljubljanska ulica 5, SI-2000 Maribor, Slovenia. E-mail: monika.sobocan@gmail.com 
Disclosure: No potential conflicts of interest were disclosed. 
This is an open access article distributed under the terms of the CC-BY license (https://creativecommons.org/licenses/by/4.0/).
Background. Gestational trophoblastic disease (GTD) is a heterogeneous group of rare tumours characterised by 
abnormal proliferation of trophoblastic tissue. It consists of benign or premalignant conditions, such as complete and 
partial molar pregnancy and variants of malignant diseases. The malignant tumours specifically are commonly re-
ferred to as gestational trophoblastic neoplasia (GTN). They consist of invasive mole, choriocarcinoma, placental-site 
trophoblastic tumour (PSTT) and epithelioid trophoblastic tumour (ETT). 
Conclusions. Patients with GTD are often asymptomatic, although vaginal bleeding is a common presenting symp-
tom. With the advances in ultrasound imaging in early pregnancy, the diagnosis of molar pregnancy is most com-
monly made in the first trimester of pregnancy. Sometimes, additional imaging such as chest X-ray, CT or MRI can 
help detect metastatic disease. Most women can be cured, and their reproductive function can be preserved. In this 
review, we focus on the advances in management strategies for gestational trophoblastic disease as well as possible 
future research directions.
Key words: gestational trophoblastic disease; hydatidiform mole; molar pregnancy; gestational trophoblastic neo-
plasia; human chorionic gonadotropin; invasive mole; choriocarcinoma 
Introduction
Gestational trophoblastic disease (GTD) is a het-
erogeneous group of rare tumours characterised 
by abnormal proliferation of trophoblastic tissue. 
Complete and partial molar pregnancy are the 
most common GTDs. They are generally consid-
ered to be benign disorders, but they can develop 
into gestational trophoblastic neoplasia and can 
b e c o n s i d e r e d a s p r e m a l i gn a n t c o n d i t i o n s . T h e 
malignant tumours specifically are commonly 
referred to as gestational trophoblastic neoplasia 
(GTN). They consist of invasive mole, choriocarci-
noma, placental-site trophoblastic tumour (PSTT) 
and epithelioid trophoblastic tumour (ETT).
1
 The 
malignant trophoblastic disorders are collectively 
known as gestational trophoblastic neoplasia.
2
 
GTD and GTN may both arise after normal preg-
nancies, miscarriage, ectopic pregnancies, or abor-
tion, but most GTNs will develop from complete 
molar pregnancies.
3
 H y datidiform mole (HM) is 
the most common type of GTD. In most parts of 
the world, the incidence of hydatidiform mole is 
1 per 1000 pregnancies, although higher frequen-
cies have been reported.
1,4
 A classification of GTD 
with incidences is presented in Figure 1. The aim 
of this review is to provide up-to-date information 
on current evaluation and management strategies 
for gestational trophoblastic disease. 
Hydatidiform mole
Our understanding of HM has changed consider-
ably over the last decades. It wasn’t until the late 
1970s that a partial mole was distinguished from 

Radiol Oncol 2022; 56(4): 430-439.
Lukinovic N et al. / Gestational trophoblastic disease 431
a complete mole.
6
 Clinical presentation of HM also 
changed dramatically over the years. In the 1960–
1970s, the mean gestational age at diagnosis was 16 
weeks and classic clinical signs were vaginal bleed-
ing, uterine enlargement greater than expected for 
gestational age, theca-lutein cysts due to ovarian 
hyperstimulation by high serum hCG values, hy-
peremesis, preeclampsia, hyperthyroidism, and 
respiratory insufficiency.
1,6,7
 Nowadays, many pa-
tients are asymptomatic at diagnosis due to wide 
use of ultrasound scans in early pregnancy.
1
 At 
present, mean gestational age at diagnosis is 10–12 
weeks. A HM is therefore detected before the onset 
of classic clinical signs. However, vaginal bleed-
ing continues to be the most common presenting 
symptom and it can occasionally present with pas-
sage of hydropic villi.
1,7
 Because bleeding may be 
prolonged and occult, patients may be anaemic at 
presentation.
6
 Symptoms can be vague and resem-
ble complaints often present in normal pregnancy.
1
Classification of hydatidiform moles
HM can be classified as a complete hydatidiform 
mole (CHM) or partial hydatidiform mole (PHM) 
based on histopathological exam and genetics.
8
 
The common pathology of these lesions is excessive 
proliferation of trophoblast.
6
 In both conditions, the 
placental villi become oedematous, forming hyda-
tidiform structures.
7
 In CHM hydrops is fully de-
veloped and most villi are involved. In PHM how-
ever, the hydrops remains characteristically focal.
6
 
In CHM foetal parts are absent.
9
 In PHM evidence 
of foetal development, such as amnion vessels with 
foetal red blood cells, is a prominent pathologic 
feature.
7
 HMs are genetically characterised with 
two copies of the paternal genome. Typical CHMs 
are diploid and androgenetic with both sets of 
chromosomes derived from the paternal genome 
and no contribution to the nuclear genome from 
the mother.
8
 The monospermic 46, XX karyotype 
i s m o s t c o m m o n , r e s u l ti n g f r o m f e r ti l i s a ti o n o f 
an ovum by a single sperm that then duplicates 
its DNA.
8,10
 About 10% of CHMs are 46, XY, aris-
ing by dispermy. 46, YY embryos are presumed to 
be non-viable.
8
 PHMs are almost always triploid, 
having an additional set of chromosomes from the 
father of the embryo. Most have a 69, XXX or 69, 
XXY karyotype usually resulting from fertilisation 
of an ovum by two sperms, or less frequently a dip-
loid sperm.
7, 8
 Trisomy with XYY karyotype is rarely 
seen and YYY karyotype has not been observed.
7
 
Most molar pregnancies are sporadic. A small sub-
set of women has an inherited predisposition to re-
current molar pregnancies, referred to as familiar 
recurrent hydatidiform mole (FRHM).
8,9
Diagnosis of hydatidiform mole
The diagnosis of HM is usually suspected on ul-
trasound imaging. Clinical signs, symptoms, and 
human chorionic gonadotropin (hCG) levels can 
be helpful in the diagnostic process.
11
 Diagnosis 
should always be confirmed by histology with or 
without ancillary techniques such as genotyping 
and p57kip2 staining.
12
Ultrasound
Ultrasound (US) is the imaging modality of choice 
for an initial diagnostic suspicion of GTD.
13
 The ad-
vances of ultrasound imaging in the last decades 
and the wide availability of high-resolution trans-
vaginal ultrasound (TVUS) in early pregnancy 
have shifted the diagnosis of HMs from the second 
to the first trimester of pregnancy.
14,15
 This allows 
the detection of HM before the onset of systemic 
m a n i f e s t a t i o n s s u c h a s a n a e m i a , h y p e r e m e s i s , 
preeclampsia, hyperthyroidism or even signs of 
metastatic disease.
16
In the first trimester, accurate US diagnosis of 
a CHM is more frequent than that of a PHM, be-
cause the latter has subtler US changes.
13
 In a co-
hort study of 295 women
14
 US imaging diagnosed 
*  Incidence rates per 1000 deliveries per year in Netherlands between 1994–2013
5
;
 
ETT = epithelioid type trophoblastic tumour; PSTT = placental-site trophoblastic tumour
FIGURE 1. Classification of GTD with incidence rates. 

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Lukinovic N et al. / Gestational trophoblastic disease 432
a significantly (p < 0.001) higher number of CHM 
(74.2%) than PHM (40.7%). These data show that 
for PHM the diagnosis is more difficult. Hydropic 
villi in PHM are only focal and difficult to differ-
entiate from the hydropic changes associated with 
prolonged retention after foetal demise often seen 
in missed abortions.
18
Ultrasound feature suggestive of a complete 
molar pregnancy is thick, cystic tissue within 
the uterine cavity without a visible gestational 
sac. Partial hydatidiform mole is often suspected 
in women with intact gestational sac with cystic 
placental changes. The accuracy of ultrasound to 
diagnose molar pregnancy is difficult to assess in 
modern practice as the majority of miscarriages 
are managed conservatively and histological con-
firmation of diagnosis is available only in a minor-
ity of women.
19
 The available data show that ul-
trasound diagnosis of complete molar pregnancy 
is very sensitive with the reported detection rates 
between 80% and 95%.
16,17
 The diagnosis of partial 
molar pregnancy is less accurate with the detec-
tion rates between 20% and 30%. The accuracy of 
US diagnosis is also operator dependent, therefore 
a broader awareness of the early US signs of HM 
should improve the detection rate of molar preg-
nancy in women presenting with early pregnancy 
complications.
15
Doppler US does not seem to differentiate be-
tween CHM and PHM. However, it is a useful tool 
in the diagnosis of GTN because abnormal myo-
metrial vascularisation and lower uterine artery 
Doppler indices seem to be correlated with inva-
sive disease.
20
Human chorionic gonadotropin (hCG)
Most GTDs secrete hCG which is therefore a sen-
sitive tumour marker.
1
 HCG is a glycoprotein hor-
mone produced by trophoblastic tissue. It compris-
es an α and a β subunit. The α subunit is shared 
with other members of the glycoprotein hormones, 
including thyroid-stimulating hormone (TSH), lu-
teinizing hormone (LH) and follicle-stimulating 
hormone (FSH). In hCG, the α subunit can mimic 
the α subunit of the other glycoprotein hormones 
and therefore cause symptoms seen in hyperthy-
roidism.
1,10
 The β subunit is a unique part of the 
hCG structure that allows the production of highly 
specific antibodies and the utilisation of highly spe-
cific immunologic assays.
21
 In a healthy pregnancy, 
intact hCG is the predominant protein, whereas in 
cancer patients various hCG isoforms can be pre-
sent. These include intact hCG ( α & β), the partially 
degraded or nicked forms of hCG (hCGn) and hCG β 
(hCG βn) and the β-core fragment (hCG βcf)).
22
 The 
combination of US findings with elevation of hCG 
above expected for gestational age is highly sug-
gestive of molar pregnancy
7
 and is crucial in diag-
nosis of GTD or GTN.
1
 Due to hyperplastic troph-
oblastic cells in CHM, patients will have marked 
elevations in hCG, sometimes greater than 100.000 
IU/L. However, such elevations are seen in fewer 
than 10% of patients with PHM.
11
Histological confirmation of diagnosis
HM is sometimes diagnosed only by pathology 
after suction dilation and curettage (D&C) is per-
formed for a suspected early embryonic demise. 
When HM is suspected beforehand, it should be 
evacuated as soon as possible.
7
 Histological confir-
mation of GTD after evacuation is mandatory.
12
Treatment of hydatidiform mole
The initial treatment of HM in women who wish 
to preserve fertility is D&C.
23
 Pre-treatment evalu-
ation consists of measurement of serum quantita-
tive beta-hCG, complete blood count, clotting stud-
TABLE 1. Ultrasound characteristics of partial hydatidiform mole (PHM) versus complete hydatidiform mole (CHM)
13,16,18
Feature CHM PHM
US characteristics Enlarged uterus filled with a heterogeneous predominantly 
echogenic mass with several hypoechoic foci (snowstorm 
appearance), multiple small anechoic cystic spaces 
varying in size from 1 to 30 mm (cluster of grapes). Theca 
lutein cysts presenting as multiple large, bilateral, functional 
ovarian cysts can be present.
Subtler US changes. Hydropic changes of some villi 
are often not visible before 10 weeks of gestation. 
Enlarged placenta relative to the size of the uterine 
cavity with internal cystic changes producing a 
“Swiss cheese pattern” is often seen. Theca lutein 
cysts are infrequent.
Foetal parts
Absent, except in the rare event of a CHM with a coexisting 
diploid twin.
Present as amorphous echoes. If a foetus is formed, 
it carries a typical spectrum of severe abnormalities. 
Growth retardation is common.
Colour-power 
Doppler of the uterus
Variable Variable

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Lukinovic N et al. / Gestational trophoblastic disease 433
ies (PT, PTT), renal and liver functions, blood type 
and screen, pelvic ultrasound examination, chest 
X-ray and thyroid function test if hyperthyroidism 
is suspected.
7
 Where available, D&C is performed 
under ultrasound guidance which helps to remove 
all molar tissue and avoid uterine perforation.
11,24
 
Usually, it is performed under general anaesthe-
sia.
7
 Intravenous oxytocin infusion may be started 
at the onset of suction D&C and may be continued 
for several hours after operation. Oxytocin enhanc-
es uterine contractility and decreases blood loss.
24
 
There is theoretical concern over the routine use of 
oxytocic agents, because of the potential to embo-
lise and disseminate trophoblastic tissue through 
the venous system.
25
 However, the authors recom-
mend the use of oxytocin in management of molar 
pregnancy.
2,7,24
 The risk of bleeding after suction 
D&C increases with uterine size. When the uterus 
is greater than 16 weeks in gestational size, blood 
transfusion should be available.
24
 Because RhD 
factor is expressed on trophoblastic tissue, RhD 
immunoglobulin should be administered at the 
time of uterine evacuation in Rh negative women. 
If HM is diagnosed at early gestational age, com-
plications during or after evacuation are uncom-
mon.
26
 Most common complications are excessive 
bleeding, uterine perforation, and respiratory dis-
tress syndrome.
27
 Respiratory distress syndrome 
may be caused by trophoblastic embolization, 
high-output congestive heart failure caused by 
anaemia, hyperthyroidism, preeclampsia, or iatro-
genic fluid overload.
7
 At the end of suction D&C, 
the evacuated tissues should be inspected and sent 
for histological examination.
27
 Uterine evacuation 
by medication only method is not recommended 
due to high failure rates, risk of haemorrhage, in-
creased risk of post-molar GTN and increased ma-
ternal morbidity.
7, 2 3
Hysterectomy with salpingectomy is an alter-
native method to suction D&C if molar pregnan-
cy is presumed and childbearing is complete.
24,28
 
Hysterectomy is especially used in women older 
than 40 years, because these patients have a higher 
risk of post molar GTN. Hysterectomy eliminates 
the possibility of local myometrial invasion as a 
source of persistent disease and hence reduces the 
need for subsequent chemotherapy.
7, 2 7, 2 8
 Usually 
the adnexa may be preserved, even if theca lutein 
cysts are present. Theca lutein cysts usually re-
gress over few months after uterine evacuation as 
hCG levels decrease.
7, 2 7
 Hysterectomy, compared to 
uterine evacuation, has a significant advantage in 
preventing post-molar GTN with an approximate-
ly 80% reduction in risk.
26,28
 Because hysterectomy 
does not eliminate the possibility of post molar 
gestational trophoblastic neoplasia these patients 
should also be monitored postoperatively with se-
rial hCG measurements.
7
Prophylactic administration of either metho-
trexate or actinomycin D chemotherapy at the time 
of or immediately following molar evacuation is 
associated with a reduction in the incidence of 
post molar GTN to 3%-8%. However, it should be 
limited to special situations where adequate hCG 
follow-up is not possible and the risk of post molar 
GTN is much greater than normal.
24
 
Surveillance after molar evacuation
The gold standard for clinical management of 
women diagnosed with a HM is to monitor the 
hCG levels in urine or serum.
22
 Following evacu-
ation of molar pregnancy, monitoring of hCG 
levels postoperatively is mandatory to identify 
and manage post-molar GTN.
27
 HCG is used as a 
marker in post molar monitoring because of the 
correlation between hCG levels and trophoblas-
tic tumour burden, allowing early diagnosis and 
treatment of GTN.
29
 The mean time to hCG nor-
malization in case of partial HM is 6 weeks and in 
case of complete HM 7 weeks.  For both complete 
and partial HM, 95% of patients reached normal 
serum hCG concentrations within 14 weeks after 
evacuation.
30
 FIGO recommends hCG monitoring 
every 1-2 weeks until hCG is normalised, and then 
on monthly intervals. For PHM, one additional 
confirmatory normal hCG measurement 1 month 
after first hCG normalisation is recommended. For 
CHM, monthly hCG measurements are required 
for 6 months after hCG normalisation.
27,31
 After 
evacuation of a HM effective contraception is cru-
cial because a new pregnancy may confound the 
interpretation of hCG levels.
29
Gestational trophoblastic 
neoplasia (GTN)
GTN includes invasive mole, choriocarcinoma, 
placental site trophoblastic tumour (PSTT), and 
epithelioid trophoblastic tumour (ETT). Recently, 
atypical placental site nodule (APSN) has been 
added to the GTD spectrum.
24
The reported incidence of GTN after molar preg-
nancy is 18% to 29%. This rate appears to be stable 
despite the progressively earlier diagnosis of HM.
11
 
Choriocarcinoma affects approximately 1 in 40.000 
pregnancies and 1 in 40 HMs. It is 1000 times more 

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Lukinovic N et al. / Gestational trophoblastic disease 434
likely after a CHM than another pregnancy event. 
50% of choriocarcinoma cases arise from HMs, 
25% follow abortion or tubal pregnancy and 25% 
are associated with other gestational events.
11,32
 
PSTT and ETT are rare subtypes of GTN with an 
incidence of 1 in 100.000 pregnancies. They repre-
sent approximately 1% of all GTN cases.
11
Post-molar GTN
Most GTN will arise after the evacuation of a HM.
1
 
GTN following a HM is referred to as post-molar 
GTN.
24
 Post-molar GTN includes invasive mole 
and choriocarcinoma.
11
 In contrast, PSTT and ETT 
can develop after any type of antecedent pregnan-
cy, including normal pregnancy, non-molar abor-
tion, or ectopic pregnancy.
7
 Risk factors for post 
molar GTN include age 40 years, hCG levels more 
than 100.000 IU/L, excessive uterine enlargement, 
and/or theca lutein cysts larger than 6 cm.
11
 In most 
patients, HMs regress spontaneously after evacua-
tion of the molar tissue, but in approximately 15% 
- 20% of CHMs and 0.5% - 1% PHMs, trophoblastic 
tissue remains active. Consequently, hCG levels 
have a sustained rise or plateau, which indicates 
the need for evaluation and treatment.
7
 At the 
FIGO Gynaecology Oncology Committee meeting 
in 2000, the definition of postmolar GTN based on 
hCG level changes were agreed (Figure 2).
2,24,33
Invasive mole
In v as i v e m o l e arise s fr o m in v as i o n o f C HM o r 
PHM into the myometrium and/or uterine blood 
vessels.
9,11
 The tendency of invasive mole to invade 
myometrium can result in uterine perforation and 
extension to adjacent organs. However, some de-
gree of myometrial invasion of the trophoblast is 
probably present in most moles.
9
 The diagnosis of 
invasive mole can only be histologically confirmed 
after hysterectomy.
1
 As hysterectomy is nowadays 
rarely performed, chemotherapy is usually started 
without histologic confirmation of the diagnosis. 
Chemotherapy is essential to prevent further com-
plications, although invasive moles rarely metasta-
size and are usually self-limited.
7,9
Choriocarcinoma
Choriocarcinoma is the most common malignant 
GTN. It is characterised by abnormal trophoblas-
tic hyperplasia and anaplasia, absence of chorionic 
villi with varying degrees of haemorrhage and ne-
crosis.
9,34
 The tumour is mainly uterine but extrau-
terine sites such as fallopian tubes and ovaries can 
also be involved. Patients with gestational chorio-
carcinomas tend to develop early systemic metas-
tasis.
7
 Metastases have been reported in the lung, 
liver, spleen, kidney, bowel, or brain.
9,24
 In contrast 
to ectopic tubal or ovarian choriocarcinoma, pri-
mary choriocarcinoma in other organs is likely to 
represent non-gestational carcinoma with tropho-
blastic differentiation.
9
Placental-site trophoblastic 
tumour (PSTT) and epithelioid 
trophoblastic tumour (ETT)
PSTT and ETT are the rarest subtypes of GTN. 
PSTT originates from the intermediate trophoblast 
on the maternal side of the placental bed with half 
of the cases invading deep into the myometrium. 
Chorionic villi are absent.
1,24
 In contrast to chorio-
carcinoma, PSTT forms uterine lesions with less 
haemorrhage. Tumour necrosis is often extensive.
35
 
ET T i s eve n ra rer, a nd it develops f rom t he c hor ion ic 
type of intermediate trophoblast.
1
 Nearly half arise 
in the cervix or lower segment of the uterus and 
some in the fundus or broad ligament. The char-
acteristic nodular and expansive growth mimics 
cervical carcinoma.
24,25
 PSTT and ETT share several 
overlapping features. They are both slow growing 
FIGURE 2. FIGO criteria for diagnosis of postmolar gestational trophoblastic 
neoplasia (GTN).
24

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Lukinovic N et al. / Gestational trophoblastic disease 435
tumours and can occur months to years after any 
type of antecedent pregnancy.
35
 They both produce 
less hCG and metastasize in later stages. Typically, 
both tumours have limited chemosensitivity.
1,7
Clinical signs and symptoms
GTN has a varying presentation depending on 
the antecedent pregnancy event, disease type and 
extent. Post molar GTN can be associated with ir-
regular bleeding after initial treatment for molar 
pregnancy, an enlarged and irregular uterus, and 
bilateral ovarian enlargement. However, these 
signs may be absent.
11
 Patients often present with 
symptoms of metastatic disease. The most common 
metastatic sites are the lungs, but metastatic lesions 
can also be found in vagina, liver, brain, spleen, 
kidneys, and bowel. Characteristically, gestational 
choriocarcinoma forms a rapidly growing tumour 
with the ability to metastasize to virtually every 
body site and present with widespread dissemi-
nation. Metastatic lesions often produce abnormal 
bleeding because trophoblastic tumours have frag-
ile vessels.
9,11
 Embolization of trophoblastic tissue is 
also possible, and it can cause dyspnoea, coughing, 
chest pain, tachypnoea, and haemoptysis. Vaginal 
metastases can present with bleeding, which can-
not be distinguished from the uterine blood loss. 
A gynaecological examination upon presentation 
is therefore important.
1
 Liver metastases are rare 
and often have a poor prognosis, especially if they 
present with intra-abdominal bleeding, which is 
life-threatening. Central nervous system lesions 
may be asymptomatic or produce subtle neuro-
logic symptoms such as headache. Symptoms from 
brain metastases can also be very severe, even fa-
tal if they cause intracranial haemorrhage.
1,7
 PSTT 
and ETT often present with irregular bleeding after 
some time has passed from a previous pregnancy 
and there may also be signs of metastatic disease.
11
 
Other rare symptoms such as virilisation and ne-
phrotic syndrome have also been described.
34
Diagnosis of GTN
GTN is most frequently diagnosed based on hCG 
values as discussed above, most often without his-
tologic verification.
7
 It is essential to measure hCG 
in any woman of childbearing age who has unex-
plained metastatic disease.
36
 A serum hCG deter-
mination and exclusion of normal pregnancy is 
essential to diagnose GTN in these circumstances, 
which can spare the patient an unnecessary sur-
gery to establish the diagnosis.
7
When a GTN diagnosis is made or suspected, 
immediate evaluation for metastases is needed. 
Along with the history and physical examination, 
the following evaluation should be performed: 
complete blood count, clotting function studies, 
renal and liver function studies, blood type and 
determination of pre-treatment hCG concentra-
tion.
7, 3 7
 A gynaecological examination should 
be done to exclude vaginal or pelvic metastases. 
Biopsy of metastatic lesions without the ability 
to control bleeding is highly risky due to abun-
dant vascularisation of this type of tumours and 
is not essential before starting chemotherapy.
11,36
 
However, where complete excision is possible, his-
tologic confirmation of the diagnosis is also valu-
able.
36
Extensive radiographic evaluation should be 
performed. Chest X-ray is appropriate to diagnose 
lung metastases and can be used for counting the 
n umber of l ung metastases to ev al ua te the risk 
score. Lung CT may not be used in the risk score. 
Liver metastases may be diagnosed by US or CT. 
Brain metastases may be diagnosed by MRI or 
CT.
11,24
Classification and staging of GTN
To categorise patients with GTN, two different sys-
tems can be used. They both correlate with clinical 
outcomes and identify patients at risk for failure of 
treatment.
7
 Currently , the 2000 FIGO staging sys-
tem is the standard classification (Table 2).
Patients are also assigned a modified World 
Health Organisation (WHO) prognostic index 
score based on prognostic factors modified as 
FIGO score (Table 3). It comprises age, anteced-
ent pregnancy, interval from index pregnancy (in 
months), pre-treatment hCG (in mIU/mL), largest 
tumour size including uterus (in cm), site of me-
tastases including uterus, number of metastases 
identified and previous failed chemotherapy.
24
 A 
WHO risk score of 6 or lower is classified as low-
risk and scores higher than 6 are classified as high-
risk.
7, 2 4
 Staging notation uses a Roman numeral in-
dicating FIGO anatomical staging followed by an 
Arabic numeral that represents WHO prognostic 
scoring.
37
 FIGO risk scoring is not recommended 
in PSTT and ETT , although it may be of value in 
guiding management.
35
Treatment of low-risk GTN
Low-risk GTN (FIGO/WHO score 0–6) is primar-
ily treated with one of two single-agent drugs, 

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Lukinovic N et al. / Gestational trophoblastic disease 436
methotrexate (MTX) or actinomycin-D (Act-D). A 
variety of doses and infusion schedules for these 
drugs have been utilized.
24,26
 To date, there is not a 
clearly superior regimen between these two drugs. 
Treatment therefore is often determined by institu-
tional preference.
26
 In Europe and North America, 
the methotrexate with folinic acid (MTX-FA) 8-day 
and MTX 5-day regimens are favoured over Act-D 
as first-line treatment.
38
 Single-agent chemothera-
py induces complete remission in 83.5% patients 
with stage I GTN, 80% patients with low risk stage 
II GTN and 81.8% patients with low risk stage III 
GTN.
39
 Chemotherapy response is monitored by 
hCG measurements at least every 1 or 2 weeks. 
Chemotherapy resistance is indicated by plateau 
in hCG over 3 consecutive cycles or a rise in hCG 
over 2 consecutive cycles.
11
 Approximately 25–30% 
of low-risk patients develop resistance or exces-
sive toxicity to  initial single-agent chemotherapy.
38
 
Resistance to initial single-agent chemotherapy is 
up to 70–80% in patients with FIGO/WHO score 5 
or 6. Current challenge is whether these patients 
should be still considered low risk and initially 
treated with single-agent chemotherapy or treated 
with more intensive therapy from the onset.
38,40
 
Low-risk patients experiencing treatment failure 
with one single agent are treated with other.
41
 
P a t i e n t s w i t h l o w - r i s k G T N r e s i s t a n t t o e i t h e r 
single-agent chemotherapy or relapsed disease 
following complete response to initial single-
agent chemotherapy, are treated with multi-agent 
c h e m o t h e r a p y . M o s t c o m m o n l y w i t h E M A - C O 
regimen (etoposide, methotrexate, actinomycin D, 
cyclophosphamide, vincristine).
38,41
 Multi-agent 
chemotherapy is associated with increased short- 
and longer-term toxicities. For this reason, promis-
ing new strategies are being investigated. For ex-
ample, the use of carboplatin and immunotherapy 
agents (programmed death protein 1 (PD-1) in-
hibitors and programmed death ligand 1 (PD-L1) 
inhibitors).
38,42-44
 In women who no longer wish to 
retain their fertility, first-line hysterectomy can be 
considered as an alternative to chemotherapy for 
treatment of low-risk non-metastatic GTN.
27
 Once 
hCG has normalised treatment is continued for a 
minimum of four weeks, which represents at least 
two consolidation cycles.
12,38
Treatment of high-risk GTN
High-risk GTN (FIGO/WHO score > 6) is treated 
with multi-agent chemotherapy, with or without 
adjuvant surgery or radiotherapy. The most used 
chemotherapy protocol is EMA-CO.
24
 In EMA-CO 
failures, the most employed regimen is EMA-EP 
(substituting etoposide and cisplatin for cyclo-
phosphamide and vincristine in the EMA-CO reg-
imen).
26
 In high-risk GTN patients EMA-CO regi-
men induces complete response at rates of 71-78% 
and long-term survival rates of 85-94%.
45
 Unlike 
for patients with low-risk GTN, primary hysterec-
tomy is not effective in reducing requirement for 
chemotherapy or improving cure rates in patients 
with high-risk GTN.
27
 As wi th low -risk disease , 
chemotherapy for high-risk disease is continued 
for at least 2 to 3 consolidation courses after the 
TABLE 3. World Health Organization scoring system based on prognostic factors modified as FIGO score
24
F I G O s c o r e 0124
Age <40 >40 - -
Antecedent pregnancy Mole Abortion Term
Interval from index pregnancy, months <4 4–6 7–12 >12
Pretreatment hCG IU/L <10
3
 >10
3
–10
4
>10
4
–10
5
>10
5
Largest tumour size including uterus, cm - 3–4 ≥5-
Site of metastases including uterus Lung Spleen, kidney Gastrointestinal tract Brain, liver
Number of metastases identified - 1–4 5–8 >8
Previous failed chemotherapy - - Single drug Two or more drugs
TABLE 2. FIGO staging and classification for gestational trophoblastic neoplasia
24
FIGO stage Description
I
Gestational trophoblastic tumours strictly confined to the 
uterine corpus
II
Gestational trophoblastic tumours extending to the adnexa 
or to the vagina but limited to the genital structures
III
Gestational trophoblastic tumour extending to the lungs and 
may or may not involve the genital tract.
IV
Gestational trophoblastic tumours extending to all other 
metastatic sites

Radiol Oncol 2022; 56(4): 430-439.
Lukinovic N et al. / Gestational trophoblastic disease 437
first hCG normalization.
11,41
 A separate category of 
ultra-high-risk GTN, defined as WHO score 13 or 
more, identifies women at high risk of early death 
and poor outcome.
26,41
 These patients are treated 
with low dose induction chemotherapy before 
initiating multi-agent chemotherapy. Induction 
chemotherapy reduces the risk of life-threatening 
complications, predominantly haemorrhage from 
metastatic implants.
26
 For induction chemother-
apy combination of low dose etoposide (100 mg/
m
2
) and cisplatin (20 mg/m
2
) (EP on days 1 and 2 
every 7 day, one to three cycles) is used.
26,40
 Active 
areas of investigation include the utilization of 
high-dose chemotherapy with stem cell support, 
use of immunotherapy and other chemotherapy 
regimens.
11,26
Treatment of PSTT and ETT
Treatment of PSTT and ETT is determined by two 
independent poor prognostic factors: an inter-
val of ≥48 months from the causative pregnancy 
and stage IV disease. Stage I tumours (confined to 
the uterus) arising <48 months since the anteced-
ent pregnancy are treated with a total abdominal 
hysterectomy including removal of any suspicious 
pelvic and retroperitoneal lymph nodes. Adjuvant 
systemic therapy is not required. In contrast, if 
the PSTT/ETT originated from a pregnancy > 48 
months previously, then such stage I patients and  
stage II–IV patients should be offered aggressive 
platinum-based chemotherapy including the op-
ti o n f o r e x p e r i m e n t a l tr e a tm e n t s s u ch a s hi g h -
TABLE 4. Ongoing clinical trials involving treatment of gestational trophoblastic disease
Trial Drug Design Reg. Nr.
Recruitment 
status
Immunotherapy Camrelizumab combined with apatinib for recurrent resistant GTN NCT04047017 Completed
Pebrolizumab for resistant GTN NCT04303884 Not yet recruiting
Camrelizumab combined with apatinib in patients with high-risk GTN NCT05139095 Not yet recruiting
Avelumab combined with methotrexate for  low-risk GTN NCT04396223 Recruiting
Avelumab in chemo-resistant GTN NCT03135769 Completed
Camrelizumab combined with bevacizumab in high-risk GTN after combined 
chemotherapy
NCT04812002 Recruiting
TRC105 and/or bevacizumab in refractory GTN NCT02664961 Terminated
Chemotherapy Paclitaxel plus cisplatin vs EMA-CO in high-risk GTN NCT02639650 Unknown
Rescue regimen with MTX vs high-dose MTX protocol in persistent GTN NCT03280979 Unknown
Pemetrexed disodium as salvage therapy for failed low-risk GTN NCT00096187 Terminated
Dactinomycin in patients with persistent or recurrent low-risk GTN NCT00003688 Completed
Single dose MTX vs MTX and Actinomycin-D single dose vs MTX multiple courses NCT01823315 Unknow
Biweekly actinomycin-D treatment vs multi-day methotrexate in low-risk GTN NCT04562558 Recruiting
Methotrexate vs dactinomycin in low-risk GTN NCT00003702 Completed
Methotrexate for prevention of postmolar GTN NCT01984099 Completed 
Dactinomycin vs methotrexate in low-risk GTN NCT01535053 Completed
Chemotherapy vs follow up in hydatidiform mole with lung nodule NCT03785574 Recruiting
Pemetrexed in recurrent or persistent low-risk GTN NCT00190918 Completed
Methotrexate vs methotrexate plus actinomycin in low-risk GTN patients with 
score 5-6
NCT03885388 Recruiting
Surgical 
treatment
Hysteroscopic repeat curettage vs methotrexate in low-risk GTN NCT03703271 Recruiting
Total abdominal hysterectomy and methotrexate vs methotrexate plus folinic acid NCT02606539 Unknown
Second uterine evacuation vs chemotherapy in low-risk GTN NCT04756713 Recruiting
Second curettage in low-risk, non-metastatic GTN NCT00521118 Completed
Single evacuation vs double evacuation of mole NCT01630954 Unknown
* accurate date as of 22th January 2022; EMA-CO = etoposide, methotrexate, actinomycin D, vincristine, cyclophosphamide; GTN = gestatinal trophoblastic neoplasia; 
hCG = human chorionic gonadotropin; MTX = methotrexate

Radiol Oncol 2022; 56(4): 430-439.
Lukinovic N et al. / Gestational trophoblastic disease 438
dose chemotherapy or immunotherapy.
41
 Residual 
masses after treatment should be excised wherever 
possible to confirm no active cancer remains.
35,41
 
The survival rate is approximately 100% for non-
metastatic disease and 50-60% for metastatic dis-
ease.
45
The future in GTN management
Research in GTD is mainly focused on the de-
velopment of new treatment strategies (Table 4). 
Especially, finding alternatives to multi-agent 
chemotherapy and associated short- and longer-
term toxicities.
38
 The use of immunotherapy is 
an important development in the management 
o f G TN , p arti cular l y in dru g - resis tan t dise ase .
44
 
The programmed cell death ligand 1 (PD-L1) is 
expressed in all pre-malignant and malignant 
GTD and anti-PD-1 monoclonal antibodies, such 
as pembrolizumab, are becoming important part 
of the management of relapsed chemo-resistant 
GTB.
38,41,44
 The use of immunotherapy must be fur-
ther evaluated, particularly because of the high 
cost and lack of longer-term safety data.
38
Surveillance after GTN
Remission of GTN is defined as three consecutives 
normal hCG (hCG normalisation).
26
 Posttreatment 
surveillance for low and high-risk GTN consists 
of weekly hCG measurements for 6 weeks af-
ter normalisation, then monthly for at least 12 
months.
24,41,42
 Surveillance for ultra-high-risk GTN 
is longer and consists of monthly hCG measure-
ments for 24 months after completion of consoli-
dation chemotherapy.
26
 A minimum of 5-year-
follow-up is advised.
12
 Rising serum hCG in not 
sensitive for identifying recurrence of PSTT and 
ETT. Therefore, in cases of PSTT and ETT surveil-
lance with 6 monthly MRIs is recommended.
26
 
T h r o u g h o u t s u r v e i l l a n c e p e r i o d , p a t i e n t s m u s t 
use reliable contraception because a new pregnan-
cy may confound the interpretation of hCG levels 
[24]. Because of the 1–2% risk for a second mole in 
subsequent pregnancy, early ultrasound examina-
tion is recommended during all future pregnan-
cies in addition to histologic evaluation of the pla-
centa, and postdelivery hCG.
7
Roots for further investigation 
There is a need for possible future investigations to 
identify factors, predicting which molar pregnan-
cies will resolve spontaneously, persist as GTN or 
transform into choriocarcinoma, PSTT or ETT.
25
It has become evident, a redefinition of the 
FIGO/WHO scoring system to predict resistance 
to single-agent chemotherapy, is needed. With an 
“intermediate” risk group patients scoring WHO 
5 and 6 can be identified for more intensive multi-
agent chemotherapy from the outset.
25,38
 
Although medical outcomes of GTD have been 
widely explored, limited data are available regard-
ing the related psychological, sexual and fertility 
issues.
46
 Improved understanding of the impact of 
GTD on women and their families, and how they 
may suffer is warranted.
25
Conclusions
GTD is a rare disease and was historically asso-
ciated with significant morbidity and mortality. 
Nowadays, many patients are asymptomatic at 
diagnosis due to wide use of ultrasound in early 
pregnancy. Initial detection of suspected HM is 
usually made based on ultrasound imaging, clini-
cal signs, symptoms and hCG levels, which are 
above expected for gestational age. In a smaller 
proportion of patients, GTD leads to post molar 
GTN. This requires further systemic or surgi-
cal management. Posttreatment surveillance for 
GTN consists of regular hCG measurements. Most 
women with GTD can be successfully managed. 
One of the main future challenges in this regard 
is the optimization of treatment for patients with 
resistant GTN. 
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