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Pitfalls in Diagnosis and Management of Testicular Choriocarcinoma Metastatic to the Brain: Report of 2 Cases and Review of Literature
Accepted Manuscript Pitfalls in diagnosis and management of testicular choriocarcinoma metastatic to the brain: Report of two cases and review of literature. Haydn Hoffman, M.D., Gentian Toshkezi, M.D., Joseph M. Fullmer, M.D., Walter Hall, M.D., Lawrence S. Chin, M.D. PII:
S1878-8750(17)31123-3
DOI:
10.1016/j.wneu.2017.07.023
Reference:
WNEU 6085
To appear in:
World Neurosurgery
Received Date: 15 April 2017 Revised Date:
5 July 2017
Accepted Date: 6 July 2017
Please cite this article as: Hoffman H, Toshkezi G, Fullmer JM, Hall W, Chin LS, Pitfalls in diagnosis and management of testicular choriocarcinoma metastatic to the brain: Report of two cases and review of literature., World Neurosurgery (2017), doi: 10.1016/j.wneu.2017.07.023. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Pitfalls in diagnosis and management of testicular choriocarcinoma metastatic to the brain: Report of two cases and review of literature.
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Haydn Hoffman M.D., Gentian Toshkezi M.D., Joseph M. Fullmer M.D., Walter Hall M.D., Lawrence S. Chin M.D.
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Department of Neurosurgery, SUNY Upstate Medical University
Conflicts of interest: none
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Key words: choriocarcinoma; metastasis; germ cell tumor
Abbreviations list: AVM – arteriovenous malformation; BEP - bleomycin, etoposide, and cisplatin; CNS – central nervous system; ED – emergency department; EVD – external ventricular drain; GCT – germ cell tumor; GTR – gross total resection; TIP - paclitaxel,
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ifosfamide, and cisplatin; VIP - etoposide, ifosfamide, and cisplatin
To whom correspondence should be addressed: Haydn Hoffman M.D. 750 E. Adams St. Syracuse, NY 13210 [email protected] 510-908-2124
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Abstract Introduction: Pure choriocarcinoma of the testes is a rare, aggressive germ cell tumor (GCT) that can metastasize to the brain. Although its prognosis has improved with the
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development of cisplatin-based chemotherapy regimens, cerebral metastases are prone to hemorrhage and are associated with high morbidity. Here, we present two cases of
testicular choriocarcinoma with cerebral metastasis and discuss potential pitfalls in their
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diagnosis and management. We also review cases in the literature that feature these rare lesions.
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Methods: Medline was searched for all publications including the terms "testicular choriocarcinoma" and "cerebral metastasis" or "brain metastasis." Articles that included patients with tumors classified as a mix of choriocarcinoma and other GCT subtypes were excluded.
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Results: A total of 15 cases from the literature and our own two cases were included in the analysis. The mean age at presentation was 25.5 years. Neurologic symptoms accounted for the initial presentation of nine patients (60%). Outcomes were
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predominantly poor, with ten patients (67%) expiring shortly after their initial diagnosis. Three of these deaths were related to mass effect from metastases-related hemorrhages.
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Two patients underwent emergent decompressive craniectomies and both died from cerebral herniation.
Conclusion: The potentially catastrophic nature of choriocarcinoma-related cerebral hemorrhages underscores the need for prompt, accurate diagnosis and aggressive surgical management of these lesions. Their highly vascular nature and lack of findings on cerebral angiography may cause them to be confused with occult vascular malformations.
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Introduction Choriocarcinoma is a highly aggressive, vascular germ cell tumor (GCT) that presents in young males as testicular cancer. It is prone to early hematogenous and
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lymphatic spread, frequently metastasizing to the central nervous system (CNS), lung,
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liver, lymph nodes, and bones1. As a result the disease is often not diagnosed until an
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advanced stage, and the initial symptoms are often related to metastases. Cerebral
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metastases have varied presentations, ranging from asymptomatic or non-specific, to
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focal deficits, to depressed mental status and impending herniation from hermorrhage.
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Approximately 10% of choriocarcinoma metastasizes to the brain2. When this
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occurs, tumor hemorrhage is a major cause of morbidity3. Numerous types of hemorrhage
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have been associated with choriocarcinoma including intratumoral and peritumoral
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hemorrhage, subarachnoid hemorrhage, intracerebral hematoma, subdural hematoma, and
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embolic vascular occlusion4. Hemorrhage can occur when tumor cells invade vessel walls
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and cause intratumoral hemorrhage or partially invade vessel walls and develop an
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aneurysm5,6.
Pure choriocarcinoma is rare, representing only 1% of testicular malignancies. As
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such, only a limited number of case reports documenting the clinical presentations and
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outcomes of its metastasis to the brain exist. Here, we present two cases of testicular
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choriocarcinoma and brain metastasis with divergent clinical courses. We include these
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cases with a systematic review of those described in the literature to provide an overview
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of the disease's presentation and treatment with an emphasis on potential pitfalls in
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diagnosis and management.
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Methods
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Medline was searched for all publications in the past 40 years including the terms "testicular choriocarcinoma" and "cerebral metastasis" or "brain metastasis." Articles
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were included for analysis only if they included cases with histologically-proven
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testicular choriocarcinoma. Articles that included patients with tumors classified as a mix
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of choriocarcinoma and other GCT subtypes were excluded because these are known to
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behave differently than pure choriocarcinoma. Articles without a version in English were
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also excluded.
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Case descriptions
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Case #1:
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A 22-year-old male with no significant past medical history presented to the emergency department (ED) with a sudden onset severe occipital headache. He was alert
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and fully oriented but had bilateral clonus and hyperreflexia. His head CT displayed a
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small acute parenchymal hemorrhage in the left cerebellum and subarachnoid
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hemorrhage in the ambient cistern. CT angiogram demonstrated hypervascularity to the
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area of hemorrhage and was interpreted as likely representing a small arteriovenous
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malformation (AVM) supplied by the left posterior cerebral artery, shown in Figure 1.
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Brain MRI with contrast did not show an enhancing lesion (Figure 1c), and a lack of flow
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voids was interpreted as being due to spontaneous thrombosis of the lesion. He was
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admitted for observation and scheduled to follow up for an outpatient cerebral
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arteriogram and repeat MRI.
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Ten days later, he presented to the ED again with pleuritic chest pain and
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hemoptysis. A CT angiogram of the thorax showed multiple soft tissue masses scattered
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throughout both lungs. On further questioning, the patient admitted noticing seven
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months ago that his right testicle felt hard. He was admitted to the hospital and underwent
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orchiectomy. Histology was consistent with choriocarcinoma, and he received
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chemotherapy with bleomycin, etoposide, and cisplatin (BEP). A cerebral arteriogram did
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not display an AVM, and a contrast-enhanced MRI only showed residual blood products
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at the site of his previous hemorrhage. He tolerated four cycles of BEP with improvement
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of his β-HCG from 46,442 to 385 U/L and decrease in the number of his lung nodules.
He was doing well from a neurologic standpoint until three months later, when he
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developed return of his headache and progressive visual loss. CT showed acute
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intraparenchymal hemorrhages in the right frontoparietal, left frontal, and left occipital
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regions (Figure 2). Given the patient's age, uncontrolled disease, multiple number of
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lesions, heterogeneously enhancing nature, and surrounding hyperintensities on FLAIR,
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these lesions were presumed to be metastatic choriocarcinoma. His β-HCG was 6,043
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U/L. Given the number of lesions present, surgical intervention was not pursued. He
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underwent daily fractionated whole brain radiation therapy for 14 days to receive 3750
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cGy. Salvage chemotherapy with paclitaxel, ifosfamide, and cisplatin (TIP) was begun.
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He responded to this with decrease in size and number of pulmonary and renal masses.
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However, approximately seven months later he was hospitalized again for renal
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hemorrhage and hemothorax. He expired approximately one year after his initial
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presentation.
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Case #2:
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A 24-year-old male presented with acute hemoptysis and thoracic back pain. A
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CT thorax demonstrated innumerable lobulated nodular densities throughout both lungs
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with hilar adenopathy. His β-HCG was 18,339 U/L. Biopsy of a lung nodule was
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consistent with choriocarcinoma. A MRI of the brain with contrast revealed a
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peripherally enhancing hemorrhagic right cerebellar mass 1.7 cm in size (Figure 3a). He
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was asymptomatic and had no neurologic deficits on exam. Outpatient radiosurgery and
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chemotherapy were planned.
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Three days later he returned to the ED with acute severe headache and vomiting.
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He remained neurologically intact. He was found to have acute hemorrhage at the site of
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his known cerebellar lesion with vasogenic edema, effacement of the fourth ventricle, and
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ventriculmoegaly (Figure 3b). An external ventricular drain (EVD) was placed with
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improvement in his symptoms. Three days later he underwent a right-sided suboccipital
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craniotomy for en bloc resection of his tumor. Intraoperatively, the tumor was noted to be
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well capsulated with intracapsular hemorrhage of dark red color and firm consistency.
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Histopathology showed cells with pleomorphic nuclei, increased mitotic activity, uniform
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positivity for CAM 5.2, and variable positivity for β-HCG (Figure 4), consistent with
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metastatic choriocarcinoma. His EVD was weaned and removed postoperative day five.
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He was subsequently started on BEP chemotherapy. His chemotherapy regimen was
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changed to etoposide, ifosfamide, and cisplatin (VIP) due to hypoxia and concerns for
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pulmonary toxicity of BEP. He has completed three cycles of VIP and remains
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neurologically intact four months after his craniotomy.
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Results
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The initial search yielded 38 papers that reported a total of 49 cases. Fifteen
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papers were excluded because they only reported on cases in which the histologic
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diagnosis was a mix of choriocarcinoma and other GCT subtypes. Two papers were
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excluded because they did not provide information on patient outcome. Eight papers were
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excluded because they were not available in English.
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A total of 15 cases from the literature and our own two previously described cases were included in the analysis (table 1). The mean age at presentation was 25.5 years.
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Neurologic symptoms accounted for the initial presentation of nine patients (60%). Initial
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neurologic symptoms were frequently nonspecific and included headache (47%),
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depressed level of consciousness (33%), and nausea or vomiting (20%). Other signs and
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symptoms included visual field defect (2), seizure (2), and paresthesia (1). Three patients
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did not develop any neurologic symptoms. Nine patients had hemorrhagic cerebral
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lesions (60%) and eleven had multiple lesions (73%). The location of lesions included
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parietal lobe (5), frontal lobe (5), occipital lobe (5), cerebellum (3), and intraventricular
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(1). All patients had lung metastases at the time of their CNS diagnosis. Other sites of
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metastasis included skin (3), kidney (3), GI tract (3), mediastinum (3), liver (2),
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retroperitoneum (2), gingiva (1), epicardium (1), pancreas (1), thyroid (1), and
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peritoneum (1). The mean β-HCG at the time of CNS involvement was 183,864 U/L,
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although this varied considerably (range: 1,478 – 620,000 U/L). Outcomes were
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predominantly poor, with ten patients (67%) expiring a mean of four months after their
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initial diagnosis. Among the five others, three were in remission at the time of most
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recent follow-up, one had a "guarded prognosis" due to his cerebral disease and was
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being considered for chemotherapy, and one paper did not report outcome. Three of these
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deaths were related to mass effect from metastases-related cerebral hemorrhages. Two
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patients underwent emergent decompressive craniectomies and both died from herniation.
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Three patients underwent craniotomy or craniectomy for tumor resection and one died
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from systemic disease progression.
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Discussion Choriocarcinoma is a malignant germ cell tumor that arises from trophoblastic
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tissue as well as germinal epithelium of placenta, ovaries, and testes. It is characterized
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by early hematogenous spread to the lungs, liver, kidney, and brain6,7. Similar to the two
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cases we have presented, the tumor has frequently already metastasized at the time of
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diagnosis. Choriocarcinoma metastases are frequently hemorrhagic and carry a poor
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prognosis8. Although the brain is not an uncommon site for choriocarcinoma metastasis,
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the literature regarding the clinical course, diagnosis, and management of pure
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choriocarcinoma's cerebral metastasis is sparse. This is especially true of testicular
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choriocarcinoma, which comprises only 1.5 - 4% of testicular tumors9. Our two cases
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illustrate how these tumors may mimic vascular lesions and are prone to sudden,
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spontaneous hemorrhage even in asymptomatic patients.
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The two cases we present along with the literature highlight the divergent clinical presentations and outcomes of metastatic choriocarcinoma. Based on our review of the
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literature, presentations of patients with cerebral metastases can broadly be categorized as
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1) neurologically asymptomatic with a testicular mass or symptom due to a lesion at
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another site (often attributable to hemorrhage), 2) subacute with a focal neurologic deficit
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related to the tumor site or generalized symptoms of intracranial hypertension, and 3)
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hyperacute with hemorrhage and signs of herniation. Outcomes were generally poor in
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the setting of hemorrhagic cerebral lesions, with eight of nine cases leading to death. In
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two cases, decompressive craniectomies were required10-11. As in our second case,
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cerebral lesions that are found and resected in the absence of a large hemorrhage (there
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was isolated intracapsular hemorrhage noted intraoperatively) and acute mass effect may
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tend towards a more favorable immediate clinical course. Short follow-up time and a lack
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of large case series prevent conclusive findings with respect to long-term prognosis after
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tumor resection. In the absence of severe complications from metastatic disease,
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remission can frequently be achieved owing to choriocarcinoma's sensitivity to cisplatin-
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based chemotherapy. Thus, we favor aggressive neurosurgical management of these
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lesions to afford the patient the best chance of a favorable systemic outcome.
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Presenting symptoms are often not neurologic even in the setting of cerebral metastases, as was seen in 40% of the cases in our series. When neurologic symptoms are
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present they are often non-specific, including headache and altered mental status. Thus, a
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high index of suspicion may be needed to diagnose cerebral metastases. Maintaining high
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clinical suspicion is especially important in reproductive age males as well as females
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with a history of recent abnormal pregnancy (50% occur after hydatidiform mole and
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25% after spontaneous abortion)12. As seen in our two cases and literature review, the β-
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HCG level is usually significantly elevated in patients with cerebral metastases13, which
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can help to clarify the diagnosis. In one autopsy study, the incidence of cerebral lesions in
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patients with choriocarcinoma was 66.7%14. The disparity between this value and the
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standard incidence reported in the literature (10%), suggests many metastases remain
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undiagnosed.
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Given the high mortality associated with tumor hemorrhage3,15, early surgical
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intervention is warranted when cerebral metastasis of choriocarcinoma is identified16-18.
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General principles of metastatic CNS tumor resection favor gross total resection (GTR)
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when possible19. If this can be achieved in the setting of low disease burden, outcomes
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are usually favorable. Sundarakumar et al reported a case of hemorrhagic
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choriocarcinoma metastasized to an arteriovenous malformation in which GTR was
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achieved with good outcome10. Similarly, after GTR was achieved in our second case, the
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patient was discharged home neurologically intact with no further need for CSF
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diversion. Despite adequate surgical treatment in the CNS, choriocarcinoma has a
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propensity to have already spread elsewhere. In our review, pulmonary metastases were
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present in every case at the time the CNS lesion was diagnosed. This supports the theory
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that tumor emboli from the lungs are the source of cerebral metastases in
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choriocarcinoma20. Furthermore, when CNS involvement is identified multiple cerebral
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lesions are already present, as was the case in 73% of cases we reviewed. We propose
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aggressive neurosurgical management should be undertaken, because choriocarcinoma is
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sensitive to modern chemotherapeutic regimens and remission can sometimes be
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achieved.
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The first case we presented demonstrates a potential pitfall of diagnosing metastatic cerebral choriocarcinoma when the primary lesion is unknown. Given the
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tumor’s highly vascular nature, it can be confused for an occult vascular malformation,
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especially on MRI21. Although the cerebral arteriogram was negative, the patient’s
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clinical picture was interpreted as being due to an AVM that had spontaneously
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thrombosed. Angiography is typically unrevealing with choriocarcinoma22. Contrast-
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enhanced MRI may be unrevealing in the presence of acute hemorrhage. Close follow-up
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with a repeat MRI once the hemorrhage has cleared should be considered. Further
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complicating the diagnosis is the fact that vascular malformations and choriocarcinoma
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metastases are not mutually exclusive entities. Multiple reports of their coexistence are
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available10,23. This may be due to vasodilation of brain parenchyma surrounding the
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AVM, which predisposes to tumor deposition in this area10. Due to choriocarcionma’s
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vascularity, delayed or missed diagnosis carries a high risk for poor outcome.
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Case #2 is instructive because it demonstrates the propensity for even small,
asymptomatic choriocarcinoma metastases to spontaneously hemorrhage in the absence
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of any external factors such as hypertension or coagulopathy. The suspected pathogenesis
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involves vessel occlusion from tumor emboli, proliferation of tumor cells within the
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vessel wall, rupture of the internal elastic lamina, and aneurysm formation from these
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processes5,20,24. Choriocarcinoma's ability to invade vessel walls is due to the
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syncytiotrophoblast component of the tumor, which has an innate ability to invade
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endothelium and extend into perivascular spaces10. The aggressive nature of the tumor
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supports a role for expedited surgical resection even when patients are neurologically
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asymptomatic.
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Conclusion
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The two cases we have presented along with our review of the literature illustrate
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the propensity for cerebral metastases of pure testicular choriocarcinoma to present with
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acute hemorrhage and lead to poor outcomes when not accurately diagnosed and
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surgically intervened upon early. The presentation of hemorrhagic choriocarcinoma may
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initially mimic that of an occult vascular malformation. Accurate diagnosis and prompt
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neurosurgical intervention greatly improves the short-term outcome.
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Funding
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This research did not receive any specific grant from funding agencies in the
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public, commercial, or not-for-profit sectors.
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Figure 1: a) Non-enhanced CT demonstrating acute subarachnoid hemorrhage anterior to
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the vermis; b) CT angiogram showing hypervascularity corresponding to the area of
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hemorrhage; c) T1 MRI with contrast did not show an enhancing lesion.
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Figure 2: Acute parenchymal hemorrhage with surrounding edema in the left occipital (a)
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and right frontal (b) regions.
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Figure 3: a) Contrast-enhanced T1 MRI demonstrating a well-circumscribed ring-
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enhancing lesion in the right cerebellum; b) Acute hemorrhage in the same patient at the
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site of the previously identified lesion with surrounding edema and mass effect on the
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fourth ventricle.
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Figure 4: a+b) H and E stained sections revealed cells with hyperchromatic, pleomorphic
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nuclei, prominent nucleoli, and increased mitotic activity. Numerous extravasated red
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blood cells were present. The neoplastic cells were uniformly positive for CAM 5.2 (c)
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and variably positive for β-HCG (d), consistent with choriocarcinoma.
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Table 1: Summary of the literature and the two cases we present here (uk = unknown, CR = complete remission, PR = partial
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remission, XRT = radiation therapy, BEP = bleomycin, etoposide, cisplatin, TIP = cisplatin, ifosfamide, paclitaxel, PEI = cisplatin, etoposide, ifosfamide, HA = headache, AMS = altered mental status, LOC = loss of consciousness, sx = symptoms)
Joret et al.27
18
Lowe et al.28
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Alkassar et al.31 Doyle, Einhorn32 Scolozzi et
355,000
HA, nausea, AMS HA, nausea, AMS
Frontal, parietal Frontal, parietal
32,219
None
533,081
N
Y
Y
Y
Additional sites Stomach, lung Lung, kidney, liver, skin, epicardium, peritoneum Lung, mediastinum
Parietal
N
Y
Stomach, lung
Y
N
Sternum
26
Neurologic sx
uk
25
Neurologic sx
uk
HA, homonymous hemianopia HA, nausea, LOC
Late 20s
Neurologic sx
uk
13
uk
Hemorrhagic? Y
Multiple? Y
Treatment Hemostasis
BEP, TIP Decompressive craniectomy, tumor resection (gross total), AVM resection
BEP Decompressive craniectomy, BEP
Outcome Death Death from pericardial tamponade Death Remission
N
N
Lung
LOC
Occipital Third ventricle Parietal, occipital
Y
Y
Lung, liver
620,000
Yes, uk
uk
N
Y
PEI
17
Neurologic sx, hemoptysis, chest pain
192,575
HA, paresthesia
Frontal, parietal
Y
Y
Lung Lung, mediastinum, skin, pancreas, thyroid
uk Death from brain herniation Death from disease progression
PEI
Remission
31 36
Neurologic sx Dyspnea,
115,834 100,000
Seizure None
Occipital Occipital
N Y
Y N
Lung Lung,
BEP, XRT. PEI
Remission Death from CNS
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Gobel et al.30
Neurologic sx Melena, anemia
Brain site uk
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Neurologic symptoms Eye deviation
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Nemeth et al.26
Testicular mass
β-HCG (U/L) uk
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Presentation Anemia
Sundarakumar et al.10 Syed, Westwood29 Vivekananda et al.11
Age
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Study Yazgan et al.25
uk Decompressive craniectomy
Hemianopsia
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al.33
melena
33
Stilp et al.35
31
Chhieng, et al.36
Hemoptysis, flank pain
141,450
AMS
Cerebellum
Y
N
Lung, abdomen
N
Lung, skin, liver, kidney Lung, retroperitoneum, kidney
BEP Craniotomy for tumor resection, BEP
Y
Lung
BEP, XRT
Y
Hemiparesis
Frontal, parietal
96,400
None
Cerebellum
Y
Y
This study
24
Neurologic sx
18,339
HA, vomiting
N
This study
22
Neurologic sx
1,478
HA, visual field deficit
Cerebellum Occipital, frontoparietal
Y
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uk
23
Neurologic sx Testicular mass, skin lesion
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hemorrhage None (death before initiated) Craniotomy and tumor resection, XRT, methotrexate, dactinomycin, cytarabine
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Strauchen et al.34
duodenum, gingiva Lung, retroperitoneum
N
Death from brain herniation
Death from disease progression Death from disease progression
Alive Death due to disease progression
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Highlights Prompt, accurate diagnosis of metastatic choriocarcinoma to the CNS is crucial
•
Choriocarcinoma is prone to hemorrhage, which can be rapidly fatal in the brain
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Surgical resection should be expedited, even when patients are asymptomatic
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Due to its vascularity, choriocarcinoma may mimic an occult vascular
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•
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malformation
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Abbreviations list: AVM – arteriovenous malformation; BEP - bleomycin, etoposide, and cisplatin; CNS – central nervous system; ED – emergency department; EVD – external ventricular drain; GCT – germ cell tumor; GTR – gross total resection; TIP - paclitaxel,
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ifosfamide, and cisplatin; VIP - etoposide, ifosfamide, and cisplatin
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The authors have no actual or potential conflicts of interest in relation to this manuscript.
S1878-8750(17)31123-3
DOI:
10.1016/j.wneu.2017.07.023
Reference:
WNEU 6085
To appear in:
World Neurosurgery
Received Date: 15 April 2017 Revised Date:
5 July 2017
Accepted Date: 6 July 2017
Please cite this article as: Hoffman H, Toshkezi G, Fullmer JM, Hall W, Chin LS, Pitfalls in diagnosis and management of testicular choriocarcinoma metastatic to the brain: Report of two cases and review of literature., World Neurosurgery (2017), doi: 10.1016/j.wneu.2017.07.023. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Pitfalls in diagnosis and management of testicular choriocarcinoma metastatic to the brain: Report of two cases and review of literature.
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Haydn Hoffman M.D., Gentian Toshkezi M.D., Joseph M. Fullmer M.D., Walter Hall M.D., Lawrence S. Chin M.D.
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Department of Neurosurgery, SUNY Upstate Medical University
Conflicts of interest: none
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Key words: choriocarcinoma; metastasis; germ cell tumor
Abbreviations list: AVM – arteriovenous malformation; BEP - bleomycin, etoposide, and cisplatin; CNS – central nervous system; ED – emergency department; EVD – external ventricular drain; GCT – germ cell tumor; GTR – gross total resection; TIP - paclitaxel,
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ifosfamide, and cisplatin; VIP - etoposide, ifosfamide, and cisplatin
To whom correspondence should be addressed: Haydn Hoffman M.D. 750 E. Adams St. Syracuse, NY 13210 [email protected] 510-908-2124
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Abstract Introduction: Pure choriocarcinoma of the testes is a rare, aggressive germ cell tumor (GCT) that can metastasize to the brain. Although its prognosis has improved with the
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development of cisplatin-based chemotherapy regimens, cerebral metastases are prone to hemorrhage and are associated with high morbidity. Here, we present two cases of
testicular choriocarcinoma with cerebral metastasis and discuss potential pitfalls in their
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diagnosis and management. We also review cases in the literature that feature these rare lesions.
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Methods: Medline was searched for all publications including the terms "testicular choriocarcinoma" and "cerebral metastasis" or "brain metastasis." Articles that included patients with tumors classified as a mix of choriocarcinoma and other GCT subtypes were excluded.
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Results: A total of 15 cases from the literature and our own two cases were included in the analysis. The mean age at presentation was 25.5 years. Neurologic symptoms accounted for the initial presentation of nine patients (60%). Outcomes were
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predominantly poor, with ten patients (67%) expiring shortly after their initial diagnosis. Three of these deaths were related to mass effect from metastases-related hemorrhages.
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Two patients underwent emergent decompressive craniectomies and both died from cerebral herniation.
Conclusion: The potentially catastrophic nature of choriocarcinoma-related cerebral hemorrhages underscores the need for prompt, accurate diagnosis and aggressive surgical management of these lesions. Their highly vascular nature and lack of findings on cerebral angiography may cause them to be confused with occult vascular malformations.
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Introduction Choriocarcinoma is a highly aggressive, vascular germ cell tumor (GCT) that presents in young males as testicular cancer. It is prone to early hematogenous and
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lymphatic spread, frequently metastasizing to the central nervous system (CNS), lung,
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liver, lymph nodes, and bones1. As a result the disease is often not diagnosed until an
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advanced stage, and the initial symptoms are often related to metastases. Cerebral
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metastases have varied presentations, ranging from asymptomatic or non-specific, to
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focal deficits, to depressed mental status and impending herniation from hermorrhage.
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Approximately 10% of choriocarcinoma metastasizes to the brain2. When this
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occurs, tumor hemorrhage is a major cause of morbidity3. Numerous types of hemorrhage
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have been associated with choriocarcinoma including intratumoral and peritumoral
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hemorrhage, subarachnoid hemorrhage, intracerebral hematoma, subdural hematoma, and
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embolic vascular occlusion4. Hemorrhage can occur when tumor cells invade vessel walls
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and cause intratumoral hemorrhage or partially invade vessel walls and develop an
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aneurysm5,6.
Pure choriocarcinoma is rare, representing only 1% of testicular malignancies. As
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such, only a limited number of case reports documenting the clinical presentations and
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outcomes of its metastasis to the brain exist. Here, we present two cases of testicular
19
choriocarcinoma and brain metastasis with divergent clinical courses. We include these
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cases with a systematic review of those described in the literature to provide an overview
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of the disease's presentation and treatment with an emphasis on potential pitfalls in
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diagnosis and management.
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Methods
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Medline was searched for all publications in the past 40 years including the terms "testicular choriocarcinoma" and "cerebral metastasis" or "brain metastasis." Articles
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were included for analysis only if they included cases with histologically-proven
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testicular choriocarcinoma. Articles that included patients with tumors classified as a mix
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of choriocarcinoma and other GCT subtypes were excluded because these are known to
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behave differently than pure choriocarcinoma. Articles without a version in English were
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also excluded.
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Case descriptions
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Case #1:
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A 22-year-old male with no significant past medical history presented to the emergency department (ED) with a sudden onset severe occipital headache. He was alert
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and fully oriented but had bilateral clonus and hyperreflexia. His head CT displayed a
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small acute parenchymal hemorrhage in the left cerebellum and subarachnoid
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hemorrhage in the ambient cistern. CT angiogram demonstrated hypervascularity to the
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area of hemorrhage and was interpreted as likely representing a small arteriovenous
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malformation (AVM) supplied by the left posterior cerebral artery, shown in Figure 1.
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Brain MRI with contrast did not show an enhancing lesion (Figure 1c), and a lack of flow
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voids was interpreted as being due to spontaneous thrombosis of the lesion. He was
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admitted for observation and scheduled to follow up for an outpatient cerebral
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arteriogram and repeat MRI.
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Ten days later, he presented to the ED again with pleuritic chest pain and
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hemoptysis. A CT angiogram of the thorax showed multiple soft tissue masses scattered
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throughout both lungs. On further questioning, the patient admitted noticing seven
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months ago that his right testicle felt hard. He was admitted to the hospital and underwent
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orchiectomy. Histology was consistent with choriocarcinoma, and he received
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chemotherapy with bleomycin, etoposide, and cisplatin (BEP). A cerebral arteriogram did
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not display an AVM, and a contrast-enhanced MRI only showed residual blood products
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at the site of his previous hemorrhage. He tolerated four cycles of BEP with improvement
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of his β-HCG from 46,442 to 385 U/L and decrease in the number of his lung nodules.
He was doing well from a neurologic standpoint until three months later, when he
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developed return of his headache and progressive visual loss. CT showed acute
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intraparenchymal hemorrhages in the right frontoparietal, left frontal, and left occipital
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regions (Figure 2). Given the patient's age, uncontrolled disease, multiple number of
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lesions, heterogeneously enhancing nature, and surrounding hyperintensities on FLAIR,
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these lesions were presumed to be metastatic choriocarcinoma. His β-HCG was 6,043
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U/L. Given the number of lesions present, surgical intervention was not pursued. He
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underwent daily fractionated whole brain radiation therapy for 14 days to receive 3750
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cGy. Salvage chemotherapy with paclitaxel, ifosfamide, and cisplatin (TIP) was begun.
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He responded to this with decrease in size and number of pulmonary and renal masses.
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However, approximately seven months later he was hospitalized again for renal
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hemorrhage and hemothorax. He expired approximately one year after his initial
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presentation.
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Case #2:
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A 24-year-old male presented with acute hemoptysis and thoracic back pain. A
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CT thorax demonstrated innumerable lobulated nodular densities throughout both lungs
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with hilar adenopathy. His β-HCG was 18,339 U/L. Biopsy of a lung nodule was
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consistent with choriocarcinoma. A MRI of the brain with contrast revealed a
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peripherally enhancing hemorrhagic right cerebellar mass 1.7 cm in size (Figure 3a). He
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was asymptomatic and had no neurologic deficits on exam. Outpatient radiosurgery and
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chemotherapy were planned.
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Three days later he returned to the ED with acute severe headache and vomiting.
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He remained neurologically intact. He was found to have acute hemorrhage at the site of
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his known cerebellar lesion with vasogenic edema, effacement of the fourth ventricle, and
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ventriculmoegaly (Figure 3b). An external ventricular drain (EVD) was placed with
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improvement in his symptoms. Three days later he underwent a right-sided suboccipital
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craniotomy for en bloc resection of his tumor. Intraoperatively, the tumor was noted to be
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well capsulated with intracapsular hemorrhage of dark red color and firm consistency.
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Histopathology showed cells with pleomorphic nuclei, increased mitotic activity, uniform
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positivity for CAM 5.2, and variable positivity for β-HCG (Figure 4), consistent with
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metastatic choriocarcinoma. His EVD was weaned and removed postoperative day five.
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He was subsequently started on BEP chemotherapy. His chemotherapy regimen was
85
changed to etoposide, ifosfamide, and cisplatin (VIP) due to hypoxia and concerns for
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pulmonary toxicity of BEP. He has completed three cycles of VIP and remains
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neurologically intact four months after his craniotomy.
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Results
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The initial search yielded 38 papers that reported a total of 49 cases. Fifteen
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papers were excluded because they only reported on cases in which the histologic
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diagnosis was a mix of choriocarcinoma and other GCT subtypes. Two papers were
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excluded because they did not provide information on patient outcome. Eight papers were
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excluded because they were not available in English.
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A total of 15 cases from the literature and our own two previously described cases were included in the analysis (table 1). The mean age at presentation was 25.5 years.
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Neurologic symptoms accounted for the initial presentation of nine patients (60%). Initial
97
neurologic symptoms were frequently nonspecific and included headache (47%),
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depressed level of consciousness (33%), and nausea or vomiting (20%). Other signs and
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symptoms included visual field defect (2), seizure (2), and paresthesia (1). Three patients
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did not develop any neurologic symptoms. Nine patients had hemorrhagic cerebral
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lesions (60%) and eleven had multiple lesions (73%). The location of lesions included
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parietal lobe (5), frontal lobe (5), occipital lobe (5), cerebellum (3), and intraventricular
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(1). All patients had lung metastases at the time of their CNS diagnosis. Other sites of
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metastasis included skin (3), kidney (3), GI tract (3), mediastinum (3), liver (2),
105
retroperitoneum (2), gingiva (1), epicardium (1), pancreas (1), thyroid (1), and
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peritoneum (1). The mean β-HCG at the time of CNS involvement was 183,864 U/L,
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although this varied considerably (range: 1,478 – 620,000 U/L). Outcomes were
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predominantly poor, with ten patients (67%) expiring a mean of four months after their
109
initial diagnosis. Among the five others, three were in remission at the time of most
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recent follow-up, one had a "guarded prognosis" due to his cerebral disease and was
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being considered for chemotherapy, and one paper did not report outcome. Three of these
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deaths were related to mass effect from metastases-related cerebral hemorrhages. Two
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patients underwent emergent decompressive craniectomies and both died from herniation.
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Three patients underwent craniotomy or craniectomy for tumor resection and one died
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from systemic disease progression.
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Discussion Choriocarcinoma is a malignant germ cell tumor that arises from trophoblastic
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tissue as well as germinal epithelium of placenta, ovaries, and testes. It is characterized
119
by early hematogenous spread to the lungs, liver, kidney, and brain6,7. Similar to the two
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cases we have presented, the tumor has frequently already metastasized at the time of
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diagnosis. Choriocarcinoma metastases are frequently hemorrhagic and carry a poor
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prognosis8. Although the brain is not an uncommon site for choriocarcinoma metastasis,
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the literature regarding the clinical course, diagnosis, and management of pure
124
choriocarcinoma's cerebral metastasis is sparse. This is especially true of testicular
125
choriocarcinoma, which comprises only 1.5 - 4% of testicular tumors9. Our two cases
126
illustrate how these tumors may mimic vascular lesions and are prone to sudden,
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spontaneous hemorrhage even in asymptomatic patients.
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The two cases we present along with the literature highlight the divergent clinical presentations and outcomes of metastatic choriocarcinoma. Based on our review of the
130
literature, presentations of patients with cerebral metastases can broadly be categorized as
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1) neurologically asymptomatic with a testicular mass or symptom due to a lesion at
132
another site (often attributable to hemorrhage), 2) subacute with a focal neurologic deficit
133
related to the tumor site or generalized symptoms of intracranial hypertension, and 3)
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hyperacute with hemorrhage and signs of herniation. Outcomes were generally poor in
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the setting of hemorrhagic cerebral lesions, with eight of nine cases leading to death. In
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two cases, decompressive craniectomies were required10-11. As in our second case,
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cerebral lesions that are found and resected in the absence of a large hemorrhage (there
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was isolated intracapsular hemorrhage noted intraoperatively) and acute mass effect may
139
tend towards a more favorable immediate clinical course. Short follow-up time and a lack
140
of large case series prevent conclusive findings with respect to long-term prognosis after
141
tumor resection. In the absence of severe complications from metastatic disease,
142
remission can frequently be achieved owing to choriocarcinoma's sensitivity to cisplatin-
143
based chemotherapy. Thus, we favor aggressive neurosurgical management of these
144
lesions to afford the patient the best chance of a favorable systemic outcome.
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Presenting symptoms are often not neurologic even in the setting of cerebral metastases, as was seen in 40% of the cases in our series. When neurologic symptoms are
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present they are often non-specific, including headache and altered mental status. Thus, a
148
high index of suspicion may be needed to diagnose cerebral metastases. Maintaining high
149
clinical suspicion is especially important in reproductive age males as well as females
150
with a history of recent abnormal pregnancy (50% occur after hydatidiform mole and
151
25% after spontaneous abortion)12. As seen in our two cases and literature review, the β-
152
HCG level is usually significantly elevated in patients with cerebral metastases13, which
153
can help to clarify the diagnosis. In one autopsy study, the incidence of cerebral lesions in
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patients with choriocarcinoma was 66.7%14. The disparity between this value and the
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standard incidence reported in the literature (10%), suggests many metastases remain
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undiagnosed.
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Given the high mortality associated with tumor hemorrhage3,15, early surgical
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intervention is warranted when cerebral metastasis of choriocarcinoma is identified16-18.
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General principles of metastatic CNS tumor resection favor gross total resection (GTR)
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when possible19. If this can be achieved in the setting of low disease burden, outcomes
161
are usually favorable. Sundarakumar et al reported a case of hemorrhagic
162
choriocarcinoma metastasized to an arteriovenous malformation in which GTR was
163
achieved with good outcome10. Similarly, after GTR was achieved in our second case, the
164
patient was discharged home neurologically intact with no further need for CSF
165
diversion. Despite adequate surgical treatment in the CNS, choriocarcinoma has a
166
propensity to have already spread elsewhere. In our review, pulmonary metastases were
167
present in every case at the time the CNS lesion was diagnosed. This supports the theory
168
that tumor emboli from the lungs are the source of cerebral metastases in
169
choriocarcinoma20. Furthermore, when CNS involvement is identified multiple cerebral
170
lesions are already present, as was the case in 73% of cases we reviewed. We propose
171
aggressive neurosurgical management should be undertaken, because choriocarcinoma is
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sensitive to modern chemotherapeutic regimens and remission can sometimes be
173
achieved.
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The first case we presented demonstrates a potential pitfall of diagnosing metastatic cerebral choriocarcinoma when the primary lesion is unknown. Given the
176
tumor’s highly vascular nature, it can be confused for an occult vascular malformation,
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especially on MRI21. Although the cerebral arteriogram was negative, the patient’s
178
clinical picture was interpreted as being due to an AVM that had spontaneously
179
thrombosed. Angiography is typically unrevealing with choriocarcinoma22. Contrast-
180
enhanced MRI may be unrevealing in the presence of acute hemorrhage. Close follow-up
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with a repeat MRI once the hemorrhage has cleared should be considered. Further
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complicating the diagnosis is the fact that vascular malformations and choriocarcinoma
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metastases are not mutually exclusive entities. Multiple reports of their coexistence are
184
available10,23. This may be due to vasodilation of brain parenchyma surrounding the
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AVM, which predisposes to tumor deposition in this area10. Due to choriocarcionma’s
186
vascularity, delayed or missed diagnosis carries a high risk for poor outcome.
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Case #2 is instructive because it demonstrates the propensity for even small,
asymptomatic choriocarcinoma metastases to spontaneously hemorrhage in the absence
189
of any external factors such as hypertension or coagulopathy. The suspected pathogenesis
190
involves vessel occlusion from tumor emboli, proliferation of tumor cells within the
191
vessel wall, rupture of the internal elastic lamina, and aneurysm formation from these
192
processes5,20,24. Choriocarcinoma's ability to invade vessel walls is due to the
193
syncytiotrophoblast component of the tumor, which has an innate ability to invade
194
endothelium and extend into perivascular spaces10. The aggressive nature of the tumor
195
supports a role for expedited surgical resection even when patients are neurologically
196
asymptomatic.
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Conclusion
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The two cases we have presented along with our review of the literature illustrate
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the propensity for cerebral metastases of pure testicular choriocarcinoma to present with
200
acute hemorrhage and lead to poor outcomes when not accurately diagnosed and
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surgically intervened upon early. The presentation of hemorrhagic choriocarcinoma may
202
initially mimic that of an occult vascular malformation. Accurate diagnosis and prompt
203
neurosurgical intervention greatly improves the short-term outcome.
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Funding
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This research did not receive any specific grant from funding agencies in the
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public, commercial, or not-for-profit sectors.
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References
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25. Yazgan Y, Oncu K, Kaplan M, et al. Upper gastrointestinal bleeding as an initial
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27. Joret MO, Starke RM, Scotter J, et al. Metastatic choriocarcinoma induced separate simultaneous intracerebral haemorrhages: a very rare occurrence and its
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28. Lowe K, Paterson J, Armstrong S, et al. Metastatic testicular choriocarcinoma: A
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31. Alkassar M, Gottschling S, Krenn T. Metastatic choriocarcinoma in a 17-year old boy. Klin Padiatr. 2009;221:179.
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34. Strauchen JA, Bergman SM, Hanson TA, et al. Abnormal seminiferous tubule cells associated with choriocarcinoma: immunoperoxidase study. Urology. 1979;14:613-616.
35. Stilp TJ, Bucy PC, Brewer JI. Cure of metastatic choriocarcinoma of the brain. JAMA. 1972;221:276-279.
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36. Chhieng DC, Jennings TA, Slominski A, et al. Choriocarcinoma presenting as a cutaneous metastasis. J Cutan Pathol. 1995;22:374-377. Figure legends
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Figure 1: a) Non-enhanced CT demonstrating acute subarachnoid hemorrhage anterior to
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the vermis; b) CT angiogram showing hypervascularity corresponding to the area of
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hemorrhage; c) T1 MRI with contrast did not show an enhancing lesion.
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Figure 2: Acute parenchymal hemorrhage with surrounding edema in the left occipital (a)
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and right frontal (b) regions.
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Figure 3: a) Contrast-enhanced T1 MRI demonstrating a well-circumscribed ring-
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enhancing lesion in the right cerebellum; b) Acute hemorrhage in the same patient at the
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site of the previously identified lesion with surrounding edema and mass effect on the
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fourth ventricle.
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Figure 4: a+b) H and E stained sections revealed cells with hyperchromatic, pleomorphic
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nuclei, prominent nucleoli, and increased mitotic activity. Numerous extravasated red
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blood cells were present. The neoplastic cells were uniformly positive for CAM 5.2 (c)
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and variably positive for β-HCG (d), consistent with choriocarcinoma.
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Table 1: Summary of the literature and the two cases we present here (uk = unknown, CR = complete remission, PR = partial
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remission, XRT = radiation therapy, BEP = bleomycin, etoposide, cisplatin, TIP = cisplatin, ifosfamide, paclitaxel, PEI = cisplatin, etoposide, ifosfamide, HA = headache, AMS = altered mental status, LOC = loss of consciousness, sx = symptoms)
Joret et al.27
18
Lowe et al.28
18
Alkassar et al.31 Doyle, Einhorn32 Scolozzi et
355,000
HA, nausea, AMS HA, nausea, AMS
Frontal, parietal Frontal, parietal
32,219
None
533,081
N
Y
Y
Y
Additional sites Stomach, lung Lung, kidney, liver, skin, epicardium, peritoneum Lung, mediastinum
Parietal
N
Y
Stomach, lung
Y
N
Sternum
26
Neurologic sx
uk
25
Neurologic sx
uk
HA, homonymous hemianopia HA, nausea, LOC
Late 20s
Neurologic sx
uk
13
uk
Hemorrhagic? Y
Multiple? Y
Treatment Hemostasis
BEP, TIP Decompressive craniectomy, tumor resection (gross total), AVM resection
BEP Decompressive craniectomy, BEP
Outcome Death Death from pericardial tamponade Death Remission
N
N
Lung
LOC
Occipital Third ventricle Parietal, occipital
Y
Y
Lung, liver
620,000
Yes, uk
uk
N
Y
PEI
17
Neurologic sx, hemoptysis, chest pain
192,575
HA, paresthesia
Frontal, parietal
Y
Y
Lung Lung, mediastinum, skin, pancreas, thyroid
uk Death from brain herniation Death from disease progression
PEI
Remission
31 36
Neurologic sx Dyspnea,
115,834 100,000
Seizure None
Occipital Occipital
N Y
Y N
Lung Lung,
BEP, XRT. PEI
Remission Death from CNS
EP
Gobel et al.30
Neurologic sx Melena, anemia
Brain site uk
SC
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Neurologic symptoms Eye deviation
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Nemeth et al.26
Testicular mass
β-HCG (U/L) uk
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20
Presentation Anemia
Sundarakumar et al.10 Syed, Westwood29 Vivekananda et al.11
Age
AC C
Study Yazgan et al.25
uk Decompressive craniectomy
Hemianopsia
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melena
33
Stilp et al.35
31
Chhieng, et al.36
Hemoptysis, flank pain
141,450
AMS
Cerebellum
Y
N
Lung, abdomen
N
Lung, skin, liver, kidney Lung, retroperitoneum, kidney
BEP Craniotomy for tumor resection, BEP
Y
Lung
BEP, XRT
Y
Hemiparesis
Frontal, parietal
96,400
None
Cerebellum
Y
Y
This study
24
Neurologic sx
18,339
HA, vomiting
N
This study
22
Neurologic sx
1,478
HA, visual field deficit
Cerebellum Occipital, frontoparietal
Y
M AN U
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SC
uk
23
Neurologic sx Testicular mass, skin lesion
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hemorrhage None (death before initiated) Craniotomy and tumor resection, XRT, methotrexate, dactinomycin, cytarabine
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Strauchen et al.34
duodenum, gingiva Lung, retroperitoneum
N
Death from brain herniation
Death from disease progression Death from disease progression
Alive Death due to disease progression
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Highlights Prompt, accurate diagnosis of metastatic choriocarcinoma to the CNS is crucial
•
Choriocarcinoma is prone to hemorrhage, which can be rapidly fatal in the brain
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Surgical resection should be expedited, even when patients are asymptomatic
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Due to its vascularity, choriocarcinoma may mimic an occult vascular
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malformation
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Abbreviations list: AVM – arteriovenous malformation; BEP - bleomycin, etoposide, and cisplatin; CNS – central nervous system; ED – emergency department; EVD – external ventricular drain; GCT – germ cell tumor; GTR – gross total resection; TIP - paclitaxel,
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ifosfamide, and cisplatin; VIP - etoposide, ifosfamide, and cisplatin
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The authors have no actual or potential conflicts of interest in relation to this manuscript.