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Gestational Trophoblastic Neoplasia


  • This manual is not a substitute for consultation with an appropriate specialist.
  • The contents of this manual have been developed through consensus of a Provincial Tumour Group. Please note the various update dates for each section as some of the content of the manual may not be up to date.


Gestational trophoblastic diseases (GTD) are characterized by abnormal proliferation of trophoblasts. When they cause local invasion or metastasize, they are called gestational trophoblastic neoplasia (GTN).

Diagnostic entities

Gestational trophoblastic disease:

  • Molar pregnancy
    • Complete mole
    • Partial mole
  • Placental site nodule
  • Exaggerated placental site reaction

Gestational trophoblastic neoplasia:

  • Invasive mole
  • Choriocarcinoma
  • Placental site trophoblastic tumour (PSTT)
  • Epithelioid trophoblastic tumour (ETT)

Risk factors

Commonly cited risk factors for development of GTD/GTN include ethnicity (increased risk for patients from Japan, South East Asia and South Africa), extremes of maternal age (<18 or >40 years old) and nutritional deficiencies (low protein diets, vitamin A and carotene deficiency). Patients who had a previous molar pregnancy are at increased risk of developing again a molar pregnancy in the future: after one molar pregnancy this risk is 1-2% (10 times the risk of the general population) and up to 28% if two prior molar pregnancies.

There are also some genetic mutations associated with an increased risk of developing molar pregnancies. The two genes identified are NLRP7 (on chromosome 19) and KHDC3L (on chromosome 6) which are inherited in an autosomal recessive fashion. NLRP7 mutation is present in approximately 60% of patients with a history of two molar pregnancies and is associated with other poor obstetrical outcomes (non-molar spontaneous abortions, stillbirths and intrauterine growth restriction).

Clinical presentation


  • Complete moles represent 70% of molar pregnancies. They have a diploid karyotype (most commonly 46,XX but also 46,XY) that contains only paternal genetic material and are p57 negative. p57 is paternally imprinted, maternally expressed gene. Complete moles do not contain any embryonal/fetal tissue. Complete moles will usually present with vaginal bleeding (95%) and uterine size larger than expected for the dates. Other presenting symptoms include preeclampsia, hyperemesis gravidarum, hyperthyroidism, theca lutein cysts and trophoblastic embolization.
  • Partial moles represent 30% of molar pregnancies. They have a triploid karyotype (more commonly 69, XXX or 69, XXY) and are p57 positive (they contain both maternal and paternal genes). They contain embryonal/fetal tissue. If a fetus develops, it will likely have triploidy. Partial moles usually present as missed abortion with abnormal vaginal bleeding. Often, the diagnosis will be made only on the pathology specimen of a D&C.


  • The diagnosis of GTN does not require histopathology. Diagnosis is made solely with serum testing of hCG levels. If GTN is not confirmed histopathologically (e.g. the uterine dilation and curettage only identified products of conception), a pre-treatment pelvic ultrasound is required to rule out a previously undetected viable ultra-uterine pregnancy.
  • The index pregnancy (last pregnancy before development of the GTN) is most often a molar pregnancy (50%) but can also be a spontaneous abortion/ectopic pregnancy (25%) or a term/preterm pregnancy (25%).
  • The diagnostic criteria for a GTN are:
    • A plateau (+/- 10%) in hCG levels over at least 3 weeks (i.e. 4 consecutive values);
    • A rise (≥ 10%) in hCG levels over at least 2 weeks (i.e. 3 consecutive values);
    • Persistence of hCG at ≥ 6 months after molar evacuation
    • Histologic evidence of choriocarcinoma
    • Presence of metastatic disease


FIGO 2000 Anatomical staging

Disease confined to the uterus
GTN extends outside of the uterus, but is limited to the genital structures (adnexa, vagina, broad ligament)
GTN extends to the lungs, with or without known genital tract involvement
All other metastatic sites

  • Staging for GTN is dynamic (i.e. patients need to be staged for each recurrence)


FIGO Scoring
< 40
≥ 40
Antecedent pregnancy
Interval months from index pregnancy
< 4
4 - < 7
7 - < 13
≥ 13
Pre-treatment serum hCG (IU/L)
< 103
103 - < 104
104 - < 105
≥ 105
Largest tumour size in cm (including uterus)
< 3
3 - < 5
≥ 5
Site of metastases
Spleen, kidney
Liver, brain
Number of metastases
> 8
Previous failed chemotherapy
Single drug
2 or more drugs

  • Score ≤ 6 --> low/moderate-risk GTN
  • Score ≥ 7 --> high-risk GTN
  • Patients with stage I are generally considered low-risk
  • Patients with stage IV are generally considered high-risk


Management GTD

The cornerstone of GTD management is surgery. Incomplete moles are usually diagnosed on pathology specimen after D&C for missed abortion. Complete moles are usually diagnosed by ultrasound and are then scheduled for surgery.

Patients with a GTD and no further fertility desire can have a hysterectomy. They do require hCG monitoring afterwards as with any other GTD since they can still develop metastatic disease after the hysterectomy.

Most patients will, however, want to maintain reproductive capacity and will elect to undergo a D&C.

Preoperative assessment:

  • Detailed history and complete physical examination
  • Group & Screen
  • CBC
  • Creatinine, electrolytes
  • LFTs
  • TSH (T4, T3 if TSH abnormal)
  • CXR
  • Pelvic ultrasound

Intraoperative considerations:

  • Oxytocin infusion (to be started before the D&C)
  • Large bore aspiration cannula
  • Access to ultrasound for guidance 

Postoperative considerations:

  • Rh immunoglobulin (Winrho) if Rh-
  • Adequate contraception (OCP is the best choice; avoid IUD until hCG negative because of risk of perforation)
  • hCG weekly until negative x 3, then monthly x 6 months
  • At next pregnancy, plan early US to rule out recurrence of molar pregnancy and repeat hCG 6 weeks postpartum to ensure normalization.

Management low/moderate-risk GTN

Patients with stage I and stage II-III GTN with a WHO score of ≤ 4 or HCG <10,000 IU in the setting of incomplete risk score data (e.g. missing pelvic examination to assess for vaginal metastases or no pelvic scan to assess primary site) are considered to have a low-risk GTN. Moderate risk is a score of 5-6. Diagnostic workup includes complete bloodwork, HCG, chest x-ray, a pelvic examination and pelvic ultrasound. If metastases on CXR,then add CT brain/chest/abdo/pelvis.


The role for surgery in the management of GTNs is limited. Hysterectomy may be warranted in cases of acute events such as hemorrhage and infection as well as for management of PSTT and ETT that are known to be chemo-resistant.

Second Uterine Evacuation:

Second uterine curettage is a reasonable option for women with low-risk (WHO score 0-4 and HCG < 100, 000 IU), non-metastatic disease and may avoid the use of chemotherapy to achieve cure. The efficacy and safety of a second procedure was studied prospectively by the GOG.  The type of procedure was not specified in the study (e.g. suction curettage, hysteroscopic resection, or intra-operative ultrasound localization). The overall cure rate following second curettage was 40%. Uncured patients required treatment with chemotherapy. There was a higher risk of failure in patients ≤ 19 or ≥ 40 years old. Importantly, there were no cases of hysterectomy and 1 patient had a perforation managed by observation (Osborne et al. Obstet Gynecol. 2016). Although some reports suggest up to 8% risk of uterine perforation, most publications report much lower risks. 

In well counselled patients, a second curettage could be considered to achieve cure and avoid chemotherapy. Post second curettage, patients require HCG monitoring. If the HCG does not return to, and remain, normal, chemotherapy will be required.


Hysterectomy can be offered to women with non-metastatic low-risk GTN who do not desire future fertility. However, this does not prevent metastatic disease and chemotherapy may still be warranted if there is evidence of distant disease or the hCG does not return to, and remain, normal post-hysterectomy. 


Management has traditionally been with either single agent methotrexate (MTX) or actinomycin-D (Act-D). Different regimens have been used with variable efficacy. Approximately 80% of patients will be cured with the single agent regimen; the remainder 20% will need combination treatment. A Cochrane review on the subject included 7 RCTs / 667 patients with low-risk GTN and concluded that patients were more likely to achieve primary cure with Act-D than with weekly IM MTX (RR 0.65and because of this higher initial failure rate we do not routinely recommend its use). Neither MTX or ActD are particular gonadotoxic and oocyte preservation is often not mandatory, although can be offered.

At BC Cancer, our preferred regimen consists of upfront doublet chemotherapy with Act-D and MTX (and leucovorin) (GOTDLR protocol) for moderate risk disease. This regimen has been associated with a higher primary cure rate (98%). The median number of cycles was 3. For low risk, we recommend pulse ACT-D (protocol UGOO).

Once hCG is negative, patients with either low or high-risk GTN will receive 2 further consolidation cycles of chemotherapy. A study looking at 2 versus 3 cycles of consolidation treatment for single agent treatment has shown that recurrences decreased by half when a third cycle was added (8.3% vs 4.0%; p=0.006). 

After chemotherapy is completed, patients continue ongoing follow-up of hCG levels every month for 12 months. Contraception is recommended during follow-up (see section on contraception).

Management high-risk GTN

Patients with stage IV and stage II-III GTN with a WHO score of ≥ 7 are considered to have a high-risk GTN. Diagnostic workup includes complete bloodwork, HCG and CT chest/abdomen/pelvis +/- CT or MR brain.

Urgent consultation with an oncologist experienced in the treatment of high-risk GTN is required, and when possible, immediate transfer to an appropriate care facility is needed. Treatment of high –risk GTN should be initiated as soon as possible, within 24-48 hrs of diagnosis whenever possible.

Patients with high-risk GTN are generally treated with combination chemotherapy. The most commonly used regimen is EMA-CO (etoposide, methotrexate/folinic acid, actinomycin-D / vincristine, cyclophosphamide) (GOTDEMACO protocol). Patients are admitted for days 1 and 2 (EMA) of each cycle and receive day 8 treatments (CO) as outpatients. Cycles are given every 2 weeks. EMA-CO is not particular gonadotoxic (in one study, 86% patients with a wish to get pregnant achieved normal pregnancy after EMA-CO) and oocyte preservation is often not mandatory, although can be offered.

Once hCG is negative, patients with either low or high-risk GTN will receive 2 or 3 consolidation cycles of chemotherapy.

After chemotherapy is completed, patients continue ongoing follow-up of hCG levels every month for 12 months (up to 24 months for patients with stage IV disease). Contraception is recommended during follow-up (see section on contraception).

In rare cases, patients having high disease burden, especially in the chest, are at high risk of bleeding (i.e. extensive pulmonary metastases with hemoptysis or hypoxia). Induction low-dose chemotherapy can be used first to stabilize the patient’s condition before embarking on curative intent therapy with conventional multi-drug regimens. Urgent consultation with an oncologist experienced in the treatment of high-risk GTN is required for patients who are medically unstable and are in need of emergent therapy. 
Brain metastases similarly are an emergency needing urgent consultation about optimal treatment and sequencing of therapy. 

Management resistant/relapsed GTN

If GTN is resistance to treatment (new metastasis or increase/plateau in 2 consecutive values over a 2 week period) or has relapsed, an alternative treatment is considered. If the patient initially received a single chemotherapy agent such as MTX or ActD, the other single agent can be used to treat relapsed disease. If the patient initially received doublet MTX and ActD and developed resistance/recurrence, EMA-CO should be tried. If the patient received EMA-CO and developed resistance/recurrence, alternative regimens include EMA-EP (etoposide, methotrexate, actinomycin-D / etoposide, cisplatin), TP-TE (paclitaxel, cisplatin / paclitaxel, etoposide), EP (etoposide, cisplatin) and BEP (bleomycin, etoposide, cisplatin). In some instances, high dose chemotherapy with bone marrow support is required.

Management PSTT and ETT

Since PSTT and ETT are relatively chemo-resistant, hysterectomy should be considered in the management of these tumours. These cases should be presented at the provincial tumour board round and/or referred urgently to the Gynecologic Oncology Surgery group.

Optimal chemotherapy is unclear for these two types of tumours but either EMA-EP (etoposide, methotrexate, actinomycin-D / etoposide, cisplatin) or TP-TE (paclitaxel, cisplatin / paclitaxel, etoposide) is usually recommended.

For ongoing treatment refractory disease, consider immune check point inhibitors.



During treatment and follow-up of either GTD or GTN, contraception is recommended since it would be difficult to distinguish between a new pregnancy or recurrent disease. If the patient does not have contraindications to hormonal treatments, OCPs are generally recommended. Intrauterine devices (IUDs) should be avoided at least until hCG is negative since there is a risk of uterine perforation.

Phantom hCG

Patients can sometimes have phantom (or false positive) hCG. In these cases, hCG can be elevated up to a few hundred but they are not secondary to a GTD/GTN. This has been described in patients who have heterophile antibodies that are detected by hCG assays as well as in postmenopausal women who have increased levels of LH that cross-reacts with hCG assays.

There are different strategies to determine whether the elevated hCG is a false positive result:

  1. Repeat the test in the same lab (to ensure correct reading);
  2. Repeat the test in a different lab;
  3. Do urinary pregnancy test (if it is a true elevation of hCG, the urine test should be positive);
  4. Proceed with serial dilutions of the serum (with serial dilutions, the hCG level should decrease);
  5. Test for heterophile antibodies;
  6. Trial of oral contraceptives (OCP) in postmenopausal women and repeat hCG test after (should suppress the production of hCG-like polypeptide by the pituitary).

Arteriovenous fistula

Up to 10-15% of patients will develop an arteriovenous fistula after GTD/GTN but only 2% will be symptomatic from it. Angiography represents gold standard procedure for diagnosis but it can also be diagnosed with Doppler ultrasound or MRI. If symptomatic, these can be managed by hormonal manoeuvres, embolization, surgery (hysterectomy, laparoscopic resection, uterine/internal iliac artery ligation).
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