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GTD management updates include definitive diagnosis, new risk groupings

Jairia Dela Cruz
04 Apr 2018
Professor Hextan Ngan from the University of Hong Kong

Updates on the management of gestational trophoblastic disease (GTD) shine a light on the importance of correct diagnosis, options for treatment and the need to better define risk groupings.

The update was presented at the Royal College of Obstetricians & Gynaecologists (RCOG) World Congress 2018 by Professor Hextan Ngan from the University of Hong Kong.

GTD has several histologically distinct entities, Ngan said. Those that are benign are categorized as molar pregnancy or hydatidiform mole, which is further classified as complete (CHM) or partial (PHM). Those that are malignant, such as choriocarcinoma, placental site trophoblastic tumour (PSTT) and epithelioid trophoblastic tumour (ETT), are all grouped under gestational trophoblastic neoplasia (GTN).

Molecular cytogenetics for definitive diagnosis

CHM is characterized by florid cistern formation, trophoblastic proliferation and absence of foetal parts. In contrast, such features are less pronounced in PHM while foetal parts are present. As some clinical and morphologic features of PHM overlap with hydropic spontaneous abortion, Ngan emphasized the importance of differentiating CHM and PHM from nonmolar pregnancy.

There are several reasons why a definitive diagnosis is crucial, she said. First, PHMs and CHMs require follow-up monitoring for the possible development of GTN. Second, there are cases where patients show abnormal villous lesions, which are suggestive but not diagnostic of a PHM.

Where abnormal villous morphology is concerned, short-term human chorionic gonadotropin (hCG; a reliable and specific tumour marker) monitoring is advised. This is in line with the new WHO classification defining such lesions to be nonmolar in nature but carrying a low risk of GTN, Ngan noted.

To help establish a definitive diagnosis, a molecular cytogenetic testing should be performed. “Selective molecular genotyping enables the comparison of alleles by evaluating molecular characteristics such as microsatellite instability. This allows for definitive diagnosis when histologic review is equivocal,” she explained.

Moreover, a molecular study can help identify defective genes associated with the risk of recurrent mole, which is very low at 1:60. [Front Immunol 2013;4:242; BJOG 2003;110:22-26]

Management options for moles, GTN

Hydatidiform moles are managed by uterine dilatation and evacuation. Subsequently, serum hCG levels are monitored for early diagnosis of postmolar GTN. Serum hCG has been shown to drop to normal levels after 14 weeks in most moles (90 percent), and the rate of normalization is about tenfold every 1–2 weeks.

New recommendations for UK centres shorten the duration of hCG surveillance after mole evacuation from 12 months for CHMs and from 6 months for PHMs. The new protocol for PHM entails a single additional confirmatory normal urine hCG measurement 1 month after first normalization of hCG levels. [Gynecol Oncol 2018;148:254-257]

For CHM, hCG surveillance continues for 6 months from the date of hCG normalization. However, if the normalization occurs within 56 days, surveillance is shortened to 6 months from the date of evacuation rather than from the date of hCG normalization.

“Stationary or rising serum hCG levels imply persistent trophoblastic activity and require additional investigations and treatment,” Ngan said.

Patients with low-risk GTN are treated with actinomycin D or methotrexate. While the best single agent and regimen for low-risk GTN has yet to be established, evidence suggests that cure is more likely to be achieved with actinomycin D vs a methotrexate regimen. However, it is uncertain whether actinomycin D carries a greater risk of severe adverse events. [Cochrane Database Syst Rev 2016;doi:10.1002/14651858.CD007102.pub4]

EMA-CO (etoposide, methotrexate and actinomycin D/cyclophosphamide and vincristine) is the preferred regimen for patients with high-risk GTN, while there are various treatment protocols available for resistant or recurrent GTN (eg, MBE [methotrexate, bleomycin and etoposide]), as Ngan pointed out.

Ultra-high-risk GTN, PSTT/ETT

“There seems to be an ultra-resistant trophoblastic neoplasia, which remains [an] occasional killer,” she said. The disease is characterized by cerebral and multiple metastases, high hCG levels over a long interval, and, although unclear, a risk score >12 or 13.

According to Ngan, this ultra-high-risk disease highlights a need to review risk groupings to define a new cutoff for low-risk GTN, as well as establish an intermediate-risk group and an ultra-high-risk group.

Patients with ultra-resistant or ultra-high-risk GTN are at risk of early death due to treatment complications including sudden tumour collapse with severe bleeding, metabolic acidosis myelosuppression, septicaemia and multiple-organ failure. 

Evidence shows that treatment with induction chemotherapy such as etoposide plus cisplatin (EP) for two cycles before commencing full EMA-EP or BEP (bleomycin plus EP) may reduce mortality in the ultra-high-risk population. [J Clin Oncol 2013;31:280-286]

Meanwhile, PSTT and ETT, rare forms of GTN, are less chemosensitive and should be treated primarily with hysterectomy, Ngan said. Nevertheless, “conservative treatment can be considered on an individual basis.”

Patients with advanced-stage or resistant disease are usually given a platinum-containing combination therapy such as EMA-EP or TE/TP (paclitaxel/cisplatin and paclitaxel/etoposide). This population has poor prognosis, and antecedent pregnancy >48 months is the most significant prognostic factor. [Gynecol Oncol 2017;144:208-214]

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