What is Gestational Trophoblastic Disease?

Gestational Trophoblastic Disease (GTD) is a spectrum of pregnancy-related conditions characterised by abnormal proliferation of trophoblastic tissue ¹.

GTD includes both benign and malignant conditions. The most common benign entities are Complete Hydatidiform Mole (CHM) and Partial Hydatidiform Mole (PHM). Other benign entities are Exaggerated Placental Site, Placental Site Nodule and Atypical Placental Site Nodule (APSN). APSN is considered a non-malignant condition but may be a precursor to or co-exist with Placental Site Trophoblast Tumour (PSTT) or Epithelioid Trophoblast Tumour (ETT) (in 10-15% of cases ²). The malignant versions are—Persistent Disease or Invasive Mole, Choriocarcinoma (CC), PSTT, and ETT. Collectively they form Gestational Trophoblastic Neoplasia (GTN). GTN can occur following any pregnancy but is most commonly seen following a molar pregnancy.

Incidence and Risk Factors

Molar pregnancy rates vary worldwide; in Australia it affects approximately 1 in 1,000 pregnancies. Established risk factors include extremes of reproductive age and previous molar pregnancy. Molar pregnancies are also more common in women of Asian descent ². The majority of GTN cases arise following a molar pregnancy, the rest can occur following a term pregnancy, miscarriage or ectopic pregnancy.

Features of Molar Pregnancy

CHM are androgenetic diploid conceptions, characterised by hydropic villi, trophoblast proliferation and negative p57 expression. Ultrasound findings show no fetus, heterogenous material with anechoic spaces and ovarian theca lutein cysts. Human chorionic gonadotropin (hCG) levels are often >100,000 and hyperthyroidism may occur.

PHM are diandric triploid conceptions, characterised by occasional hydropic villi, minimal trophoblast proliferation and positive p57 expression. Ultrasound will show a fetus is present and the placenta may contain cystic spaces. hCG levels are usually lower.

Diagnosis

CHM is often suspected based on ultrasound findings showing cystic spaces within the endometrial cavity with no fetal pole or parts identified. In PHM, a fetus is present on ultrasound and the diagnosis is usually made during a curettage for a miscarriage or termination. Histological diagnosis is confirmed via suction curettage, which should be performed under ultrasound guidance—especially for suspected CHM—to ensure complete evacuation ³.

As ultrasound scans become more sensitive, curettage is occurring at earlier gestations, making histological diagnosis more challenging as the classic histologic features of molar pregnancies are not always present. Expert pathology review and molecular genotyping may be required for ambiguous cases. After review, the initial diagnosis can be changed in up to 26% of cases ⁴. Molecular genotyping helps distinguish between diandric triploids (PHM) and digynic triploids (non-molar triploids) as well as to diagnose other causes of abnormal villous morphology (e.g. trisomy).

Post molar GTN is usually diagnosed during hCG monitoring and does not require histological diagnosis. Performing a hCG level should be considered if a woman presents with abnormal vaginal bleeding following any pregnancy.

Monitoring and Follow Up

Once a molar pregnancy has been diagnosed, hCG levels are monitored until they return a negative result. Monitoring is typically weekly until negative but should occur at least every two weeks. Confirmatory negative testing includes weekly hCG checks for three consecutive weeks or a repeat test one month after hCG normalisation.

For CHM, patients undergo monthly hCG testing for six months (after normalisation). Patients should be advised not fall pregnant during that time. Emerging evidence suggests hCG monitoring may be discontinued once negative if it occurs within 56 days of evacuation ⁵. Patients diagnosed with a PHM do not require any further hCG testing (after normalisation) and can pursue pregnancy when desired.

The relapse risk after achieving negative hCG is less than 1%. Factors that increase relapse risk include advanced maternal age and delayed hCG normalisation (beyond 56 days).

Persistent Disease and GTN

Persistent disease occurs in 15% -20% of CHM and after 0.5 – 5% of PHM cases ^2. Persistence is defined as a hCG fall of less than 10% over 3 weeks or a hCG rise by more than 10% over two weeks.

If persistence occurs, imaging is required to exclude metastatic disease. This can include Chest X-Ray (CXR) and Pelvic ultrasound or a computed tomography (CT) scan of the head/neck/chest/abdomen and pelvis.

The World Health Organization (WHO)/International Federation of Gynecology and Obstetrics (FIGO) Prognostic Score is then calculated (see Table 1). A score of six or less is considered Low Risk disease and a score of 7 or more is considered High Risk disease. A score of 13 or higher indicates Ultra High-Risk disease. Whether the patient has low, high or ultra high-risk disease determines the chemotherapy agents used for treatment.

Table 1: WHO scoring system based on prognostic factors modified as FIGO score

Chemotherapy

Patients with Low-Risk disease requires single agent chemotherapy. This can include Actinomycin D or Methotrexate. The 2016 Cochrane Review and a 2021 meta-analysis report superior efficacy with Actinomycin D, with a higher primary remission rate (80.2% vs 65.1% for Methotrexate), with increased (although acceptable) dermatological and GIT toxicity ^6,7. Actinomycin D is administered every two weeks via an intravenous route. Alternatively, Methotrexate can be given as an intramuscular injection every second day on Days ^1,3,5,7 (with folinic acid rescue orally on Days ^2,4,6,8) or as an intravenous infusion over 12 hours. Queensland uses Actinomycin D as the preferred first line agent. The bi-weekly administration is more convenient for patients, particularly those living remotely where travel to a chemotherapy facility every second day is not practical.

Patients with high-risk disease require multi-agent chemotherapy. Etoposide, Methotrexate, Dactinomycin, Cyclophosphamide, Vincristine (EMA-CO) is the most used regimen. If patients are extremely unwell low dose induction etoposide-cisplatin (EP) may be commenced first and then changed to EMA-CO when the patient is able to tolerate it ³. Patients with ultra high-risk disease are commenced on EP/EMA. Immunotherapy agents (ie. Pembrolizumab) are being used in GTD, particularly in cases of resistance or relapse.

Chemotherapy is given in fortnightly cycles until the hCG has reached negative. Once the hCG has fallen to negative, a further three consolidation cycles of chemotherapy are given. hCG testing is performed monthly for 12 months and the patient is advised not to fall pregnant during that time. Any form of reliable contraception is acceptable.

Role of Surgery

Repeat curettage may be required for patients who experience ongoing bleeding with evidence of retained product (as detected on a pelvic ultrasound scan) or if hCG rises with no evidence of metastatic disease. In 60% of cases chemotherapy may be avoided ⁸. Repeat curettage (with hysteroscopic or ultrasound guidance) should be performed by an experienced clinician to avoid perforation of the uterus or Asherman’s Syndrome. Very rarely, even in the event of metastatic disease, curettage may be performed to decrease the burden of disease and the number of cycles of chemotherapy required.

In patients who have completed childbearing, hysterectomy may be performed at the time of diagnosis of a molar pregnancy or once persistence develops. Hysterectomy is the procedure of choice for PSTT and ETT as these entities are less sensitive to chemotherapy.

Resistance and Relapse

Resistance occurs in approximately 30% of patients with low-risk disease and 20% of patients with high-risk disease 1,9. Resistance is defined as a hCG fall by less than 10% over three weeks or a hCG rise by more than 10% over two weeks whilst undergoing chemotherapy. Patients may need to be re-scanned to assess for progression of metastatic disease. Alternative chemotherapy agents are utilised based on the beta-human chorionic gonadotropin (BhCG) level at the time of resistance. The cut-off value for changing to an alternative agent is constantly being updated.

Treatment adjustments depend on BhCG levels:

• For low-risk disease: if BhCG levels are below 1000 IU/L, a different single chemotherapy drug may be used. If BhCG levels are above 1000 IU/L, multiple chemotherapy drugs is recommended.
• For high-risk disease: different combinations of multiple chemotherapy drugs, such as EMA/EP or TE/TP, are used.

There is emerging evidence for the use of immunotherapy agents (i.e. Pembrolizumab) in treating resistant disease. Other treatments such as surgical intervention or radiation therapy may be utilised in cases that are refractory to chemotherapy to achieve remission. Patients with resistant or refractory disease have a poorer prognosis with a five-year survival of only 43% when compared with patients who relapse ¹⁰.

Relapse is defined as a rise in hCG after initial normalisation. Relapse can occur at any time following a GTN event. Despite relapse, salvage chemotherapy resulted in a 100% cure rate for low-risk disease and 84% for high-risk disease ¹⁰.

Common Pitfalls in the management of GTD and GTN

Histological Diagnosis: Early curettage can obscure classic molar features, necessitating expert pathology review and ancillary testing. After expert pathology review, the initial diagnosis can be changed in up to 26% of cases ⁴.

hCG monitoring: monitoring should be performed at least every two-weeks, but routinely weekly, to assess the trend of the hCG level. Performing the test more frequently than this leads to confusion in interpretation of the results. It is important to use the same hCG assay each week and patients are encouraged to attend the same laboratory for testing.

WHO Prognostic Score: errors are commonly made in calculating the Prognostic score which can lead to incorrect chemotherapy treatment.

• hCG level at the time of diagnosis of GTN should be used and not the patients initial hCG.
• Confusion with how the hCG is displayed (10 3, 10 4, 10 5) leads to an incorrect score.
• Lung metastases should be scored from a CXR. A CT scan may be used for scoring, but lung metastases should only be counted if they are 1cm or more in size.
• Largest tumour size includes the size of any uterine lesion. However, a uterine lesion is not included in the number of metastases.

PSTT and ETT – a Prognostic Score should not be calculated for these diagnoses. They are only assigned a FIGO Score. The mainstay of treatment for PSTT and ETT is hysterectomy as these are typically non metastatic and resistant to chemotherapy ². In the presence of metastatic disease or an interval >48 months from the index pregnancy, platinum-based chemotherapy is required.

Centralisation of care

Best practice is to register a molar pregnancy with a specialist GTD centre. Centralisation allows for a multi-disciplinary team approach to improve patient outcomes and develop consensus-based guidelines ¹. The type of GTD centre will depend on resources available. Queensland, Victoria, and Western Australia have established centralised care, and New South Wales is progressing towards this model. The International Society for the Study of Trophoblastic Disease (ISSTD) and the European Organisation for the Treatment of Trophoblastic Diseases (EOTTD) are organisations aimed at improving care of women diagnosed with GTD. These organisations can provide expert review of complex cases and allow for collaboration of research projects.

Conclusion

GTD is a diverse group of rare, but highly curable conditions. When possible, cases should be managed in specialised centres. Updated guidelines from FIGO and EOTTD for GTD management are expected in 2025.