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Stage IV Gestational Choriocarcinoma Diagnosed in the Third Trimester

Jorgensen, Kirsten, MD; Roychowdhury, Monika, MD; da Cunha, Grace, NP; Kim, Young Bae, MD; Schorge, John O., MD

doi: 10.1097/AOG.0000000000003001
Contents: Gynecologic Oncology: Case Report

BACKGROUND: Gestational trophoblastic neoplasia rarely occurs in term pregnancies. Stage IV choriocarcinoma treated with conventional chemotherapy can result in death as a result of hemorrhagic sequelae at tumor sites.

CASE: A 30-year-old woman at 34 weeks of gestation presented with a persistent cough, worsening dyspnea, and vaginal bleeding. Chest radiograph demonstrated innumerable lung nodules, and quantitative β-hcg concentration exceeded 1.3 million milli-international units/mL. Cesarean delivery was performed for presumed abruption. Placental pathology demonstrated choriocarcinoma, and imaging confirmed stage IV disease with a World Health Organization score of 14. Remission was achieved after two courses of low-dose induction chemotherapy followed by 10 cycles of combination chemotherapy.

CONCLUSION: Gestational trophoblastic neoplasia should be considered in a pregnant or postpartum woman presenting with atypical vaginal bleeding. Coexistent pulmonary or neurologic findings may suggest advanced disease.

Progressive dyspnea in the third trimester may indicate the presence of enlarging pulmonary metastases from gestational choriocarcinoma.

Departments of Obstetrics and Gynecology and Pathology, Tufts Medical Center, Boston, Massachusetts.

Corresponding author: Kirsten Jorgensen, MD, Department of Obstetrics and Gynecology, 800 Washington Street, Boston, MA 02111; email:

Financial Disclosure The authors did not report any potential conflicts of interest.

Dr. Schorge, Associate Editor (Gynecology) for Obstetrics & Gynecology, was not involved in the review or decision to publish this article.

Each author has confirmed compliance with the journal's requirements for authorship.

Peer reviews and author correspondence are available at

Received July 22, 2018

Received in revised form September 19, 2018

Accepted September 27, 2018

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Teaching Points

  1. Gestational choriocarcinoma occurs very rarely near term but portends a worse prognosis. Early recognition is critical to reduce morbidity and achieve best outcomes.
  2. Very high-risk gestational trophoblastic neoplasia is associated with early death from treatment-induced hemorrhage. Use of a low-dose induction protocol decreases this risk 10-fold by reducing tumor bulk before initiation of conventional chemotherapy.

Gestational trophoblastic disease complicates approximately 1–2 of 1,000 pregnancies. The most common presentation is a partial or complete hydatidiform mole diagnosed in the first or early second trimester that resolves with uterine evacuation. Rising quantitative β-hCG titers after appropriate treatment may be indicative of malignant transformation into gestational trophoblastic neoplasia. Choriocarcinoma is an aggressive form of gestational trophoblastic neoplasia that can occur after any type of antecedent gestation. One fourth occur after a normal pregnancy, with worse outcomes observed when the presenting symptoms suggest liver or brain metastases. These patients have lower rates of remission and consequently are assigned adverse variables in the World Health Organization (WHO) prognostic score.1–3 Metastatic gestational choriocarcinomas coexistent with a term pregnancy have been reported rarely and tend to have higher WHO scores and historically high mortality rates for the mother and fetus.4

Patients with gestational trophoblastic neoplasia with WHO scores of 7 or greater are classified as high risk and require combination chemotherapy. More than one third of those having a score of 13 or greater will have an early death as a result of hemorrhagic sequelae of rapid tumor response.5 Use of a low-dose etoposide and cisplatin induction protocol before conventional etoposide, methotrexate, and dactinomycin alternating weekly with cyclophosphamide and vincristine has been shown to decrease rates of early death by 90%.6 We present the case of a symptomatic patient diagnosed with high-risk gestational choriocarcinoma metastatic to the lungs and liver who was treated initially with low-dose etoposide and cisplatin followed by conventional etoposide, methotrexate, and dactinomycin alternating weekly with cyclophosphamide and vincristine therapy until achieving remission.

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The patient is a 30-year-old woman, gravida 2 with one prior spontaneous abortion, who presented at 34 weeks of gestation with her second episode of vaginal bleeding in as many days. Her prenatal care had been provided by a lay midwife, because the patient preferred minimal intervention, and she had no prior ultrasonograms in the pregnancy. One day before delivery, her placenta was ultrasonographically noted to be anterior and without abnormalities. Both ovaries were enlarged and multicystic, later confirmed as theca-lutein cysts. She had noted a persistent cough and increasing shortness of breath for 1 month before presentation that had prompted a visit to an urgent care clinic, where she was given medication for asthma and was presumed to have a mild viral illness. Chest auscultation demonstrated wheezing, and a radiograph showed innumerable lung nodules. A computed tomography (CT) scan of the chest, abdomen, and pelvis demonstrated apparent metastases to the lungs and liver (Figs. 1 and 2). A quantitative β-hCG was drawn and exceeded 1,300,000 milli-international units/mL. Cesarean delivery was performed for presumed abruption owing to increasingly heavy vaginal bleeding, with observation of a grossly irregular section of the placenta. Choriocarcinoma was confirmed histologically (Fig. 3). The patient was transferred to our tertiary care center on postoperative day 2, dyspneic with a significant cough, on supplemental oxygen to maintain saturation greater than 92%. The newborn was transferred to our neonatal intensive care unit for respiratory distress and prematurity. His β-hCG level was originally 135 milli-international units/mL but decreased as expected after delivery; imaging revealed no evidence of metastases.

Fig. 1

Fig. 1

Fig. 2

Fig. 2

Fig. 3

Fig. 3

The patient's CT scan was consistent with International Federation of Gynecology and Obstetrics (FIGO) stage IV disease resulting from parenchymal liver metastases. The WHO score was calculated to be 14 (Table 1).3 Her symptomatic pulmonary disease burden was worrisome for risk of early death using conventional etoposide, methotrexate, and dactinomycin alternating weekly with cyclophosphamide and vincristine. Low-dose induction etoposide and cisplatin chemotherapy was initiated on postoperative day 3, with intravenous etoposide (100 mg/m2) and cisplatin (20 mg/m2) given on days 1 and 2. Within 72 hours, the patient noted clinical improvement, had a clear lung examination, and was comfortable breathing on room air. By day 8, her β-hCG level had decreased to 254,643 milli-international units/mL, and she received a second course of etoposide and cisplatin. Her day 15 β-hCG level dropped to 26,718 milli-international units/mL, and, owing clinical improvement with decreased disease burden, she was transitioned to conventional etoposide, methotrexate, and dactinomycin alternating weekly with cyclophosphamide and vincristine (day 1: 100 mg/m2 etoposide intravenously [IV] over 30 minutes, 300 mg/m2 methotrexate IV over 12 hours, 0.5 mg actinomycin D IV bolus; day 2 100 mg/m2 etoposide, 0.5 mg actinomycin D, folinic acid rescue; day 8 600 mg/m2 cyclophosphamide IV over 30 minutes, 1 mg/m2 Oncovin [vincristine] IV bolus) repeated on alternating weeks. Neutropenia during cycle 2 of conventional etoposide, methotrexate, and dactinomycin alternating weekly with cyclophosphamide and vincristine prompted initiation of 3 consecutive days of filgrastim each week through the end of treatment. Her β-hCG level normalized after 10 cycles of therapy, at which point she was briefly hospitalized for febrile neutropenia. After a 1-week delay, she completed two additional courses. A posttreatment CT scan demonstrated no further evidence of metastases. Her surveillance plan will consist of monthly β-hCG titers for the next 2 years.

Table 1

Table 1

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Metastatic gestational choriocarcinoma coexisting with an otherwise normal term pregnancy is exceedingly rare and generally portends a poor prognosis. Both maternal and fetal metastases have been reported with varying morbidity and mortality. Passive transfer of β-hCG to the fetus is expected and seen in normal pregnancies as well as gestational choriocarcinoma. In cases of fetal metastases, the β-hCG level would be expected to increase postpartum and the neonate may present with failure to thrive, hepatosplenomegaly, jaundice, or anemia and may have liver, lung, brain, or other metastases.7 Steigrad et al4 reviewed the world literature to identify 36 total cases in the 20th century. Both mother and fetus survived only one fourth of the time. Although the most common presenting symptom was vaginal bleeding, other presenting signs included neurologic changes from brain metastases or, as in our case, pulmonary symptoms (cough, shortness of breath). The differential diagnosis for bleeding in the third trimester is broad, to include abruption or previa, yet this case emphasizes the need for a high index of suspicion to consider gestational trophoblastic neoplasia-related diseases when a pregnant woman near term also has persistent unexplained respiratory or neurologic symptoms.

Gestational trophoblastic neoplasia is an uncommon malignancy that is staged anatomically—a unique FIGO system among gynecologic cancers. Further risk stratification is determined by calculating a complex WHO score.3 Because not every oncologist is familiar with these systems, much less the most appropriate sequence of treatment for high-risk patients, referral to a specialized trophoblastic disease center is recommended.5 Our patient had stage IV disease based on CT evidence of liver metastases with a WHO score of 14, placing her in the highest risk category. Patients with gestational trophoblastic neoplasia having a WHO score of 13 or greater had a 38% mortality rate at the French Center for Trophoblastic Diseases from 1999 to 2014 compared with a 5% death rate in high-risk patients with WHO scores of 7–12. High WHO scores were associated with poorer outcomes not necessarily resulting from chemoresistance, but mainly the result of severe complications of treatment. In patients with FIGO scores of 13 or greater, a high burden of disease contributed significantly to early death (occurring within 4 weeks of initiating chemotherapy) as a result of hemorrhagic metastases.5 To decrease the rate of early deaths, a low-dose induction protocol to precede conventional etoposide, methotrexate, and dactinomycin alternating weekly with cyclophosphamide and vincristine was developed at Charing Cross. This protocol consists of etoposide and cisplatin to allow for a gradual decrease in tumor bulk and has been used preferentially in patients having an antecedent term pregnancy, choriocarcinoma histology, higher serum β-hCG level, higher WHO score, and more extensive metastases. Incorporation of induction etoposide and cisplatin was associated with a reduction in the early death rate from 7.2% to 0.7% and is currently recommended for all patients with gestational trophoblastic neoplasia having a WHO score greater than 12, pretreatment β-hCG level greater than 1,000,000 international units/L, and high burden of disease.6 Our patient responded as expected to this low-dose induction protocol for two cycles with significant clinical and laboratory improvement before starting traditional conventional etoposide, methotrexate, and dactinomycin alternating weekly with cyclophosphamide and vincristine combination therapy.

High-risk gestational trophoblastic neoplasia requires combination chemotherapy, but, unlike other gynecologic malignancies, the duration of primary treatment is hard to estimate at the onset because it is unclear when, or whether, the β-hCG level will normalize. Our patient ultimately required 10 cycles of conventional etoposide, methotrexate, and dactinomycin alternating weekly with cyclophosphamide and vincristine before achieving serologic remission. Whether to stop treatment at that point, or give additional courses is an unresolved area of controversy without solid supporting data. We elected to treat for an additional two cycles for a total of 12 cycles over a 6-month period. This amount of continuous therapy led to cumulative menopausal-type symptoms. She did not have a menstrual cycle on treatment and it is unclear whether her ovarian function will fully recover from the damaging alkylating agent (cyclophosphamide). Etoposide in large cumulative doses or short-interval high doses has also been shown to lead to an increased risk of myelodysplastic syndromes or acute myeloid leukemia as soon as 5 years after therapy.8 Fortunately, the majority of the side effects related to our patient’s chemotherapy are expected to resolve completely.

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