A rare manifestation of choriocarcinoma syndrome in a child with primary intracranial germ cell tumorand extracranial metastases: a case report and review of the literature

Abstract

Choriocarcinoma syndrome is an uncommon, potentially fatal complication of germ cell tumors (GCTs) in adults,but it is not well documented in children. Pediatric central nervous system (CNS) GCTs comprise a rare group of malignancies not usually associated with extra-CNS metastatic disease.Here we report the case of a pediatric patient witha suprasellar mixed GCTand pulmonary metastases whopresented withintratumoral hemorrhage and stroke.Choriocarcinoma syndromedevelopedsoon after initiating chemotherapy. The primary tumor and pulmonary metastases were successfully treated using a multidisciplinary approach, including neurovascular intervention, chemotherapy and craniospinal irradiation.

Introduction

Pediatric germ cell tumors (GCTs) most commonly develop within the gonads, though extragonadal primary tumors can involve the anterior mediastinum, retroperitoneum, or the central nervous system (CNS),predominantly in the pineal or suprasellar regions.¹ Intracranial GCTs are subdivided into germinoma and non–germinomatous GCTs (NGGCTs), which include teratoma, endodermal sinus (yolk sac) tumor, embryonal carcinoma, choriocarcinoma, or mixed GCTs.^2,3 Treatment of pediatric intracranial GCTs involves the use of either radiation therapy (RT) alone for germinomas or a combination of chemotherapy and RT.^2–4

In extra-CNS GCTs with complete or partial components of choriocarcinoma, the hemorrhagic propensity of metastatic foci is described as choriocarcinoma syndrome. This complication has been reported in about 10% of gonadal and extragonadal advanced GCTs, mostly in adults, at various sites of metastasis.⁵ Choriocarcinoma syndrome typically develops soon after initiation of chemotherapy; however, this phenomenon can also occur at presentation.⁶ The hallmark of this syndrome is markedly elevated serum β-human chorionic gonadotropin (β-hCG)and hemorrhage at sites of metastatic disease. β-hCG levels >50,000 IU/L are associated with very poor prognosis.^5,6 Most reports of choriocarcinoma syndrome are in adults,aged 20 to 30 years, when GCTs are most common. The severity of hemorrhage in adults often leads to hemorrhagic shock and death, highlighting the importance of early detection and intervention.^6–9

Here we describe the case of a pediatric patient with a primary intracranial GCT and pulmonary metastases, complicated by intracranial and pulmonary hemorrhage after initiation of chemotherapy. This is the first report of choriocarcinoma syndrome in a pediatric patient with a metastatic CNS GCT successfully treated with chemotherapy and RT.

Clinical Report

This study was approved by the institutional review board of St. Jude Children’s Research Hospital, and informed consent was obtained from the patient’s family.

An 8-year-old previously healthy African American female presented with acute-onset right-sided hemiparesis, facial droop, left third nerve palsy, nausea, intermittent vomiting, and a week of progressive headache. Magnetic resonance imaging (MRI) and computed tomography (CT) angiography revealed a hypervascular, partially hemorrhagic suprasellar mass and left-sided intracranial arteriovenous (AV) shunting in the thalamic-midbrain area, with left anterior thalamoperforating artery infarction, resulting in ischemic stroke (Figures 1A–C and 2A–C).

Figure 1.

Computed tomography (CT) angiograms demonstrating the vascular anomaly and response to intervention. (A) Right internal carotid artery demonstrates a hypervascular lesion centered on the sellar and suprasellar regions. (B) Lateral left internal carotid artery demonstrates the mass and AV shunting toward the left orbit and cavernous sinus. Inset:A high-magnification view showing the site of erosion of the left posterior communicating artery (arrow) by the tumor: the erosion causedAV shunting and thalamic infarct. (C) Left vertebral artery also demonstrates retrograde filling of the left posterior communicating artery into the tumor and fistula (arrow) with AV shunting. (D) CT angiogram of the left vertebral artery after embolization of the fistula with coils and n-butyl cyanoacrylate glue, resulting in substantially reduced AV shunting. (E) Left internal carotid artery after the second embolization 7 days later demonstrates no further fistula from the posterior communicating artery, but increased tumor blush is present. (F) Left vertebral artery after the second embolization demonstrates no further fistula but new tumor blush superior to the posterior cerebral artery is present, again suggesting rapidly progressive malignancy.

Figure 2.

Imaging demonstrating the primary tumor in the suprasellar region and metastases in the chest. (A-D) Appearance of the tumor at presentation. (A) Axial T1-weighted MRI through the suprasellar region shows a heterogeneous mass with complex internal signal. Punctate areas of high signal at the periphery of the tumor (white arrow) are related to intratumoral hemorrhage. (B) Axial T2-weighted MRI through the same level shows that the mass has both solid and cystic components (black arrow). (C) Post-contrast coronal T1-weighted MRI through the tumor shows peripheral enhancement of the cyst and more homogeneous enhancement of the solid component. (D) Coronal reconstruction of the chest CT scan through the posterior lung (behind the heart) shows numerous lung nodules that are suggestive of lung metastases.(E-H) Appearance of the tumor at the most recent follow-up (30 months from presentation). (E) Axial T1-weighted MRI through the suprasellar region shows a mostly cystic small residual tumor (thin arrow). (F) Axial T2-weighted MRI through the same level better defines the cystic nature of the residual tumor (white arrow). (G) Post-contrast coronal T1-weighted MRI through the tumor shows peripheral enhancement of the cyst, which is much smaller than at presentation, and the absence of any solid component. (H) Coronal reconstruction of the chest CT scan through the posterior lung (behind the heart) at the most recent follow-up shows that all lung metastases have resolved.

The stroke was caused by erosion of the posterior communicating artery by the tumor and subsequent infarction of the anterior thalamoperforating artery branch. Transarterial embolization with coils and n-butyl cyanoacrylate glue of the left posterior communicating artery AV fistula was performed to prevent further tumoral hemorrhage and protect against subarachnoid hemorrhage from the fistula. A second embolization was required to completely close the fistula 7 days later(Figure 1D–F).

The CT angiogram incidentally noted multiple pulmonary nodules, but a CT-guided lung nodule biopsy was nondiagnostic with negative infectious workup. Open biopsy was deemed too highrisk, given the extensive vascularity of the primary CNS tumor.Elevated serum α-fetoprotein (AFP; 41 ng/mL) and serumβ-hCG (168,552 mIU/mL), along with an elevated cerebrospinal fluid (CSF) AFP (2.4 ng/mL) and β-hCG (>9000 mIU/mL) suggested the diagnosis of mixed GCT. Spine MRI and CSF cytologyruled outCNS metastatic disease. A chest/abdomen/pelvis CT confirmed multiple bilateral pulmonary nodules suggestive of metastatic disease (Figure 2D), and no identifiable tumors in the abdomen or pelvis.

Because GCTs preferentially arise from the suprasellar region, a diagnosis of primary intracranial mixed GCT with extracranial metastases was made. The patient began induction chemotherapy,per the Children’s Oncology Group clinical trial for CNS NGGCTs, ACNS1123 (Supplemental Table S1).³

On Day 3 of chemotherapy, she experienced respiratory distress with increased supplemental oxygen requirement by Day 5. After intubation for repeat disease evaluation on Day 6, she had blood in the endotracheal tube, confirmed as pulmonary hemorrhage by bronchoscopy.Pulmonary hypertension followed requiring inhaled nitric oxide. She developed a left-sided lung collapse and hemothorax but eventually improved and was extubated on Day 17.

Serum β-hCG increased further to 273,349 mIU/mL 7 days after initiation of chemotherapy, which suggested tumor lysis secondary to chemotherapy.Due to the metastatic disease, we chose not to dose reduce her chemotherapy despite the complications.Before course 2, she had an acute mental status change caused by a right parietal lobe hemorrhage with acute hydrocephalus requiring placement of a ventriculoperitoneal shunt (Supplemental Figure S1). She experienced another acute mental status change on Day 5 of course 2, with a small enlargement of previous intracranial hemorrhagic foci but stable ventricular size.

She completed six cycles of chemotherapy without further hemorrhagic complications, followed by craniospinal irradiation to 36 Gy and boost to 54 Gy to the primary site using proton therapy. Serum and CSF tumor markers normalized (Supplemental Figure S2) and pulmonary nodules resolved. She remains without evidence of tumor recurrence 21 months since completion of therapy and is currently 2.5 years from diagnosis (Figure 2E–H). Her right-sided weakness has improved to near normal.

Discussion

This report highlights several rare and interesting details from a pediatric case of CNS GCT: intratumoral hemorrhage, ischemic stroke due to tumoral erosion of an intracranial artery,the presence of an AV fistula, extracranial metastases, and choriocarcinoma syndrome. The severity of initialserum β-hCG had not been previously reported in a child with metastatic intracranial GCT.^3,4,10–12 Also, the patient’s response to chemotherapy and craniospinal irradiation, despite the presence of pulmonary metastases, was excellent.

Although intracranial hemorrhage has been reported with choriocarcinoma syndrome in the setting of extragonadal mixed GCTs, those cases have primarily been in adult patients with either CNS metastases or infarcts presumably secondary to tumor emboli.¹³ Most reports of choriocarcinoma syndrome with pulmonary hemorrhage are of adult patients with primary gonadal disease and hemorrhagic manifestations at presentation or soon after starting systemic therapy^5,14,15, or with gestational choriocarcinoma,¹⁶ barring one report by Peng and colleagues describing a pediatric patient with nongestational ovarian carcinoma.⁹ In that report, a 12-year-old female had a presentation similar to our patient’s, with choriocarcinoma syndrome manifesting soon after the initiation of chemotherapy. The clinical course of our patient aligns with the description of choriocarcinoma syndrome with pulmonary hemorrhage after initiation of chemotherapy in the setting of extremely elevated β-hCG. The pathogenesis of choriocarcinoma syndrome is not well described butis hypothesized to involve tumor invasion into adjacent blood vessels or development of aneurysms secondary to necrotic tumor emboli, which perhaps occurred in our patient.^5,13This highlights the importance of considering rare but life-threatening complications like choriocarcinoma syndrome in pediatric patients with GCTs, while providing aggressive management.

One limitation of our case report is the lack of adequate tumor sample for histologic diagnosis of a GCT. However, NGGCT or mixed GCTs can be diagnosed by the combination of elevated serum and/or CSF tumor markers, with characteristic radiographic tumor appearance without histologic confirmation². This option is especially helpful in cases where obtaining additional tissue is unsafe or unfeasible. The Third International CNS Germ Cell Tumor Symposium in 2013agreed upon this as an adequate diagnostic approach².

In conclusion, we describe choriocarcinoma syndrome in a pediatric patient with a metastatic intracranial primary GCT presenting with intratumoral hemorrhage and tumor-related stroke followed by intracranial and pulmonary hemorrhage during treatment. Despite this life-threatening presentation and complication during treatment, our patient was successfully treated with endovascular embolization, chemotherapy, and RT, highlighting the importance of multidisciplinary care in the management of this rare and potentially life-threatening manifestation of GCT.

Supplementary Material

FIG S1

Supplemental Figure S1. Axial noncontrast CT scan of the head, through the high parietal region (A) at presentation shows no hemorrhage, and (B) at 7 days after initiation of chemotherapy demonstrates a new hemorrhagic focus on the right (white arrow).

FIG S2

Supplemental Figure S2. Trend of serum tumor markers AFP (red) and β-hCG (black) throughout the patient’s treatment course.

TABLE S1

Supplemental Table S1. Dosing and schedule of chemotherapy agents used in treatment of the case patient, as per Children’s Oncology Group clinical trial ACNS1123. Six total 21-day cycles of chemotherapy were given, alternating between Cycle A and Cycle B.

Abbreviations:

AFP

α-fetoprotein

AV

Arteriovenous

β-hCG

β-human chorionic gonadotropin

CNS

Central nervous system

CSF

Cerebrospinal fluid

CT

Computed tomography

GCT

Germ cell tumors

MRI

Magnetic resonance imaging

NGGCT

Non–germinomatous germ cell tumor

RT

Radiation therapy