Gestational trophoblastic neoplasia treated with low-dose induction chemotherapy despite prognostic score < 13: a case report

Abstract

Background

Gestational trophoblastic neoplasia (GTN) can cause significant morbidity and mortality if not appropriately recognized and treated. Low-dose induction chemotherapy is recommended for “ultra-high risk” GTN– defined as prognostic score ≥ 13 - to prevent mortality from hemorrhage that occurs when tumors respond rapidly.

Case

A 22-year-old patient presented with hemoptysis due to pulmonary metastases from GTN, but with WHO score < 13. A multi-disciplinary care team began treatment with low-dose induction chemotherapy to prevent worsening pulmonary hemorrhage. While she required intubation to complete induction chemotherapy, she did not suffer further pulmonary hemorrhage during treatment.

Conclusion

Low-dose induction chemotherapy should be considered as treatment for patients with GTN and pulmonary metastasis causing hemorrhage even if WHO score is <13.

Highlights

• •Ultra high-risk gestational trophoblastic neoplasia (GTN) has high risk of mortality.
• •When prognostic score ≥13, low-dose induction chemotherapy can reduce mortality risk.
• •We describe a case of GTN with pulmonary hemorrhage and prognostic score < 13.
• •We successfully treated the patient with low-dose induction chemotherapy.
• •Regardless of score, induction chemotherapy can be considered when hemorrhage risk is high.

1. Introduction

Gestational trophoblastic neoplasia (GTN) is a rare and highly curable malignancy of the placenta, but it can carry significant morbidity and mortality if not diagnosed and treated promptly (Ngan et al., 2018). “Ultra-high risk” GTN –defined as those with World Health Organization (WHO) prognostic scores of 13 or greater – carries the highest mortality risk, with up to 30% of patients dying within 4 weeks (i.e. early death) of chemotherapy initiation (Albright et al., 2023; Bolze et al., 2016). Low-dose induction cisplatin/etoposide (EP) prior to standard multi-agent chemotherapy (EMA-CO: etoposide, methotrexate, actinomycin D; cyclophosphamide, vincristine) significantly reduces the risk of early death in this population and is recommended by GTN experts (Alifrangis et al., 2013; Braga et al., 2024). We describe a patient who presented with clinically-diagnosed GTN and life-threatening hemoptysis who was successfully treated with induction chemotherapy despite WHO score < 13. This case emphasizes considering the whole clinical picture and not just the WHO score when choosing the chemotherapeutic approach. This case also highlights the importance of prompt diagnosis and transfer to a tertiary care center with GTN expertise.

2. Case narrative

A 22-year-old gravida 1 para 0010 presented to our institution with a 1-week history of hemoptysis. She reported being told she had a molar pregnancy 2 years prior, when her β-hCG had been elevated to 230,000 mIU/mL. But when she transferred her care to another provider, she reported being diagnosed with a spontaneous abortion (SAB). She did not undergo a D&C, serial β-hCG monitoring, or receive chemotherapy. She did receive two doses of 150 mg intramuscular medroxyprogesterone. Since that time, she had continued to have irregular vaginal bleeding but did not seek medical attention. She had no other past medical history.

Upon presenting to our institution, the patient reported being recently discharged from an outside hospital on home oxygen after a 3-day stay for hemoptysis, during which she was told she had pulmonary metastasis, an elevated β-hCG, a large pelvic mass, and that she needed a lung biopsy and care at an institution with Gynecologic Oncology expertise.

On day of presentation to our institution 1, the patient's temperature was 38.2 °C, heart rate 128 bpm, blood pressure 100/60 mmHg, respiratory rate > 30 breaths/min, and she required 30 l/min oxygen via high flow nasal cannula at FiO₂ 50–55% to maintain SpO2 > 91%. β-hCG was 5841 mIU/mL. She received 2 units of packed red blood cells (PRBC's) for a hemoglobin of 7.3 g/dL with ongoing hemoptysis. Computed tomography (CT) chest/abdomen/pelvis showed a 7.3 cm myoinvasive endometrial mass as well as innumerable bilateral pulmonary nodules (Fig. 1). CT head was negative. A presumptive diagnosis of metastatic GTN was made.

Fig. 1.

Axial and Coronal section from CT angiography performed on Day of Presentation 1 (A_i, A_ii), and 12 days after (B_i, B_ii) initiation of induction chemotherapy with cisplatin and etoposide.

A multi-institutional virtual meeting was conducted with a larger tertiary care center within our hospital system to address several factors complicating her definitive diagnosis, e.g. her unclear history of molar pregnancy and her relatively low β-hCG in relation to burden of disease. The patient was assigned a WHO prognostic risk score of 11 vs. 12 (0 points = prior mole vs 1 = prior SAB, 0 = lung metastasis, 4 ≥12 months since pregnancy, 4 ≥8 metastasis; 0 = no prior chemo; 2 = largest tumor >5 cm; 1 = β-hCG 10^3). Biopsy was not recommended due to concern for hemorrhage and potential delay in chemotherapy initiation. Consensus recommendation was expeditious low-dose weekly induction EP instead of multi-agent EMA-CO given concern for worsening pulmonary hemorrhage, despite WHO score < 13 and therefore not classified as “ultra-high risk”. The patient initiated broad spectrum antibiotics for her fever and was counseled on the potential need for intubation due to fluid overload during treatment and was admitted to the intensive care unit (ICU) in anticipation of respiratory compromise. A chemotherapy pharmacist assisted in minimizing the fluid volume of the chemotherapy regimen. About 28 h after presentation to our institution, she initiated cisplatin (20 mg/m² IV) and etoposide (100 mg/m2 IV). Shortly thereafter, she was intubated due to worsening pulmonary edema in the setting of pulmonary metastasis and hemorrhage with anticipation of worsening hypoxic respiratory failure from ongoing chemotherapy infusions.

Once stable, on day of presentation 6 she was transferred to the larger tertiary care center on for continued care. She was given 3 total weekly treatments of induction EP. Her β-hCG initially increased before down-trending (Fig. 2). She remained intubated for 7 days, and was extubated on day of presentation 10. After 2 cycles of weekly induction EP, a CT angiography chest demonstrated significant improvement in disease burden (Fig. 1), though new bilateral pulmonary emboli and a left upper extremity deep vein thrombosis were identified, for which she was started on anticoagulation. She received a total of 3 weekly cycles of induction EP while admitted, on days of presentation 2–3, 9–10, and 16–17. On day of presentation18 patient transitioned to oral anticoagulation for her DVT and PE and was discharged home on room air.

Fig. 2.

β-hCG trend during induction EP (day 1 indicated by gray arrows) through the first day of EMA-CO (white arrow). Gray shaded area (day of presentation 3 to day of presentation 10) indicates period of intubation. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

On Day of presentation 25, the patient initiated EMA-CO. β-hCG normalized after 2 cycles of EMA-CO and she received 3 additional consolidation cycles. She has continued to get monthly β-hCG checks and has been without evidence of disease for 18 months.

3. Discussion

The favorable outcome for this case despite delays in care and the medically tenuous status of this patient upon arrival highlight not only the need for expeditious diagnosis and treatment of metastatic GTN, but also the high curability of GTN when effectively managed. Expert understanding of GTN and its pathophysiology are critical to 1) complete the appropriate workup, 2) ensure appropriate chemotherapeutic decision-making, 3) prepare a multidisciplinary team to manage potential complications.

Several aspects of this patient's presentation demonstrate the importance of prompt recognition of GTN and expeditious transfer to a center with appropriate expertise. The lack of follow-up after potential molar pregnancy was a missed opportunity for earlier detection of GTN. Then a 3 day delay resulted when she was admitted to a center without Gynecologic Oncology services reportedly awaiting lung biopsy which was ultimately not recommended by our multidisciplinary team. Immediate intra-hospital transfer or consultation likely would have expedited this patient's access to appropriate-level care. Our decision to hold a consensus multi-institutional virtual meeting emphasizes the real-world value of collaborative care and rapid mobilization of expertise in cases of high-risk GTN. In this case, several complicating factors – such as the relatively low β-hCG, unclear antecedent pregnancy, and WHO score < 13 – had to be carefully considered before reaching consensus recommendation. Ultimately, we recommended against lung biopsy due to concern for delay in treatment initiation and the potential for hemorrhage. GTN is a clinical diagnosis that can be made without histopathologic confirmation (Braga et al., 2024), and biopsies of metastatic sites can precipitate uncontrollable, life-threatening bleeding. In one case series of 3 patients with GTN who underwent lung biopsy, 2 had inconclusive pathology results and the third was diagnosed with choriocarcinoma but died of uncontrollable pulmonary hemorrhage 5 days following the biopsy (Zhang et al., 2017).

While most GTN is highly curable, mortality rates are as high as 35% in patients with high-risk disease, particularly with WHO scores ≥13 (Albright et al., 2023). In 2013, Alifrangis et al. published a practice-changing study which showed a significantly lower early death rate in ultra high-risk patients with low-dose induction EP vs. multiagent EMA-based regimens (7.2% vs 0.7%) (Alifrangis et al., 2013). They concluded that induction EP should be given to those patients with WHO score ≥ 13 or with β-hCG >1 million. This has led multiple guidelines – including the most recent global consensus guidelines published in May 2025 – to recommend induction EP in those with WHO score ≥ 13 (Lok et al., 2025). However, it is important to note that in Alifrangis' study, the decision to give induction chemotherapy was not based on WHO score alone, but rather it was given to patients for whom the physicians had a “clinical suspicion for early death” including those with “extensive disease in the chest, liver, brain; FIGO score >12; and/or major bleeding”. More than half of patients treated with induction chemotherapy had scores <13 and the decision to give induction chemotherapy was therefore largely based on clinical suspicion for early death (Alifrangis et al., 2013). Most of the deaths in patients receiving multi-agent chemotherapy were caused by hemorrhage – particularly pulmonary hemorrhage – which the authors theorized was due to rapid destruction of the tumor. Therefore, it is important that the pathophysiology of the disease – not just the WHO score - be considered when making chemotherapeutic decisions. In the case presented here, we believe the patient benefited from our decision to initiate treatment with induction EP due to her high risk of worsening pulmonary hemorrhage, despite WHO score < 13.

Our case also highlights the importance of multi-disciplinary care in these cases as the patients are at high risk of respiratory compromise from the disease burden and the chemotherapy itself. Patients with significant pulmonary disease burden are at risk of pneumothorax, pulmonary pseudoaneurysm, and respiratory compromise from chemotherapeutic injury (Khadraoui et al., 2023). Multidisciplinary care teams must be assembled and prepared for cardiopulmonary collapse in patients with significant burden of disease, and treatment should not be initiated until the patient is at a center with the ability to provide maximum cardiopulmonary support. Intubation – as in our case – or even extracorporeal membrane oxygenation as reported in others (Naji, 2017; Vaccarello et al., 1997) may be necessary to administer chemotherapy. Clear and consistent communication between the gynecologic oncology team and the intensivist team is critical, particularly to emphasize the high rates of cure despite widespread metastatic disease. As in our case, these patients often require a multi-disciplinary team and careful coordination of care with the pulmonary critical care team.

4. Conclusion

This case underscores the importance of prompt diagnosis and transfer to a specialized center in the management of high-risk GTN. In patients with extensive pulmonary involvement, induction EP chemotherapy should be considered even when WHO score is below the conventional “ultra high-risk” threshold. Care should be delivered at centers equipped for multidisciplinary and cardiopulmonary critical care support.

Statement of consent

Written informed consent was obtained from the patient for publication of this case report and accompanying images.

CRediT authorship contribution statement

Patrick Marta: Writing – review & editing, Writing – original draft, Investigation, Data curation, Conceptualization. Katelyn Furey: Conceptualization, Writing – review & editing. Hadi Erfani: Writing – review & editing, Conceptualization. Nathan Yee: Writing – review & editing, Conceptualization. Laila I. Muderspach: Conceptualization. Koji Matsuo: Writing – review & editing. Anna L. Beavis: Writing – review & editing, Writing – original draft, Supervision, Investigation, Conceptualization.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.