The pathological spectrum of solid CNS metastases in the pediatric population

Clinical article

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Object

Collectively, metastatic tumors are the most common malignancy encountered in the adult central nervous system (CNS), arising most often from lung, breast, skin, and gastrointestinal tract carcinomas. Limited information is available in the literature regarding solid nonhematopoietic CNS metastases in children. The authors carried out a retrospective study of pediatric metastatic neoplasms to the CNS treated in a 30-year period to characterize their frequency, common histological subtypes, and sites of origin.

Methods

The archival pathology files were searched (1981–2011) for metastatic tumors to the CNS in patients 21 years of age and younger. Pathology material was reviewed, tumors were classified by site of origin and histological subtype, and survival was evaluated.

Results

The authors identified 26 patients with solid nonhematopoietic CNS metastases out of 1135 pediatric CNS tumors diagnosed from 1981 to 2011. Patients ranged in age from 1.5 to 20.3 years and were equally divided between sexes. Most CNS metastases were supratentorial (85%) and solitary (65%). The mean interval from primary malignant diagnosis to CNS metastasis was 27 months. Sites of origin included kidney/adrenal, bone/soft tissue, gonads, head and neck, lung, and liver. Mean survival after CNS involvement was 36.6 months. Overall 1-year and 5-year survival rates were 52% and 16%, respectively.

Conclusions

In neuropathology practice, nonhematopoietic pediatric CNS metastases are far less common than are nonhematopoietic adult CNS metastases, accounting for approximately 2% of all pediatric CNS tumors. The most common tumors to exhibit CNS metastasis are of kidney/adrenal origin, followed by those from bone/soft tissue. As expected, prognosis is dismal, despite aggressive therapy.

Abbreviation used in this paper:PNET = primitive neuroectodermal tumor.

Abstract

Object

Collectively, metastatic tumors are the most common malignancy encountered in the adult central nervous system (CNS), arising most often from lung, breast, skin, and gastrointestinal tract carcinomas. Limited information is available in the literature regarding solid nonhematopoietic CNS metastases in children. The authors carried out a retrospective study of pediatric metastatic neoplasms to the CNS treated in a 30-year period to characterize their frequency, common histological subtypes, and sites of origin.

Methods

The archival pathology files were searched (1981–2011) for metastatic tumors to the CNS in patients 21 years of age and younger. Pathology material was reviewed, tumors were classified by site of origin and histological subtype, and survival was evaluated.

Results

The authors identified 26 patients with solid nonhematopoietic CNS metastases out of 1135 pediatric CNS tumors diagnosed from 1981 to 2011. Patients ranged in age from 1.5 to 20.3 years and were equally divided between sexes. Most CNS metastases were supratentorial (85%) and solitary (65%). The mean interval from primary malignant diagnosis to CNS metastasis was 27 months. Sites of origin included kidney/adrenal, bone/soft tissue, gonads, head and neck, lung, and liver. Mean survival after CNS involvement was 36.6 months. Overall 1-year and 5-year survival rates were 52% and 16%, respectively.

Conclusions

In neuropathology practice, nonhematopoietic pediatric CNS metastases are far less common than are nonhematopoietic adult CNS metastases, accounting for approximately 2% of all pediatric CNS tumors. The most common tumors to exhibit CNS metastasis are of kidney/adrenal origin, followed by those from bone/soft tissue. As expected, prognosis is dismal, despite aggressive therapy.

Metastases are frequently seen in the adult brain, accounting for up to 50% of all brain tumors.2,12 Carcinomas originating from the lung, breast, and gastrointestinal tract and melanomas are the most common malignancies to metastasize to the central nervous system (CNS) in adults.3,12 In pediatric patients, however, metastatic neoplasms to the CNS are rare, accounting for an estimated 1%–10% of all brain tumors, and there are relatively few reports in the pathology literature concerning solid (that is, nonhematopoietic) CNS metastases in children.2 The overwhelming majority of tumors involving the CNS in the pediatric population are primary (www.cdc.gov/uscs). Hematopoietic malignancies commonly involve the CNS in children, and standard therapies for many pediatric hematopoietic malignancies include intensive CNS prophylaxis.10 Most reports regarding solid, nonhematopoietic CNS metastases in children have focused on incidence and outcome in particular tumor subsets, while only a few published reports have provided general analytical and statistical information on CNS metastases from a wide spectrum of solid malignancies.3–5,9,15,17 We retrospectively reviewed our institution's neuropathological experience over a 30-year time frame to better characterize the incidence and distribution of solid CNS metastases in the pediatric population at a large regional children's hospital.

Methods

This study was performed in accordance with the institutional review board guidelines at Indiana University School of Medicine. The archival pathology files of our health facilities were searched (1981–2011) for metastatic tumors to the CNS in patients 21 years of age and younger using a combination of text and SNOMED searches. Our health network is unique in having the only comprehensive care children's hospital in the state, providing service to a large pediatric population in the Midwest. A CNS metastasis was defined as hematogenous spread from a solid, nonhematopoietic malignancy from a distant primary site to involve the brain or spinal cord and/or its coverings (leptomeninges/dura mater). Data collected from the institutional electronic medical record system included patient demographics, clinical, radiographic, and follow-up information, if available. Pathology material obtained by neurosurgical intervention was reviewed, immunohistochemical studies were performed as needed, tumors were classified by site of origin and histological subtype, and survival rates were calculated.

Results

Patient Population

We identified 26 patients with solid nonhematopoietic CNS metastases out of 1135 cases of pediatric CNS tumors and nearly 4000 cases of primary pediatric solid non-CNS tumors diagnosed from 1981 to 2011. The incidence of CNS metastases varied widely by histological tumor type (Table 1). Our institution is a national referral center for pathological diagnosis and treatment of germ cell tumors, which is reflected in the exceptionally high number of primary germ cell tumors of non-CNS origin (> 3000) diagnosed during the aforementioned time frame. Excluding germ cell neoplasms due to this institutional bias, the overall incidence of CNS metastases in our identified patient cohort was 2.2%.

TABLE 1:

Incidence of CNS metastases in 26 pediatric patients with solid non-CNS primary malignancies

Solid Non-CNS Primary Malignancies (no. of cases)No. of PatientsIncidence of CNS Metastases
kidney/adrenal (377)102.7%
 malignant rhabdoid tumor (15)16.7%
 kidney clear cell sarcoma (5)120%
 neuroblastoma (236)41.7%
 nephroblastoma/Wilms tumor (121)43.3%
bone/soft tissue (526)91.7%
 soft-tissue sarcoma (61)11.6%
 osteosarcoma (146)21.4%
 PNET/Ewing sarcoma (151)32.0%
 alveolar soft part sarcoma (7)114.3%
 rhabdomyosarcoma (161)21.2%
gonads
 germ cell tumors (>3000)5<0.2%
lung
 primary lung sarcoma (4)125%
liver
 hepatoblastoma (46)12.2%

The 26 cases of CNS metastases were equally divided between sexes (13 male and 13 female) (Table 2). Patients ranged in age from 2 months to 19.8 years at the time of primary malignant diagnosis (mean 8 years; median 6.9 years) and 1.5 to 20.3 years (mean 10.7 years; median 10.6 years) at the time of CNS metastasis (Fig. 1).

TABLE 2:

Summary of 26 cases of solid CNS metastases in a pediatric population*

Case No.Diagnosis & Site of OriginCNS Location(s) of MetastasisSingle or Multiple CNS MetastasesLocation(s) of Other MetastasesSexAge at Primary Dx (yrs)Treatment of Primary TumorAge at CNS Metastasis (yrs)Treatment of CNS MetastasesAge at Death (yrs)Survival (mos)
After Primary DxAfter CNS Metastasis
kidney/adrenal
1malignant rhabdoid tumorFsngllymph nodes, lungsF0.5SR, CX, RX1.5op only2.018.66.5
2clear cell sarcomaBsngllymph nodesF1.3R, CX, RX3.1SR, CX**34.6**12.9**
3neuroblastomaO, C, Dsngllymph nodesM0.2SR, CX, RX1.5SR, CX**31.1**15.8**
4neuroblastomaDsngllymph nodes, bone (hip, pelvis, spine)F4.3SR, CX, RX8.7SR, CX, RX9.866.613.8
5neuroblastomaTsnglbone (pelvis, bone marrow)M6.9SR, CX8.0SR8.417.94.0
6neuroblastomaunkunkunkF1.8unk3.7biopsy, unk4.937.714.9
7nephroblastoma/Wilms tumorF, OmultlungsF4.9SR, CX, RX5.6SR, CX**224.9**217.6**
8nephroblastoma/Wilms tumorP, Dsngllungs, periaortic soft tissuesM4.8SR, CX, RX6.7biopsy, RX7.127.35.3
9nephroblastoma/Wilms tumorF, Dsngllungs, diaphragm, mediastinumM6.9SR, CX16.2op only16.5115.44.2
bone/soft tissue
10sarcoma, high gradeP, F, DmultlungsF8.9SR, CX9.2op only9.78.45.2
11osteosarcoma, high gradeDsnglbone (skull, spine, pelvis, knee), lung, breastF14.7SR, CX16.3op only**92.1**72**
12osteosarcoma, high gradeCunklungsF15.0unk19.7biopsy, unk19.958.83.8
13PNET/Ewing sarcomaF, Pmultlymph nodes, lungs, buttock soft tissuesM15.8SR, CX16.5SR, RX16.711.22.5
14PNET/Ewing sarcomaSSsngllungs, liver, bone (spine, pelvis)F12.1SR, CX, RX17.2SR, RX18.475.614.7
15PNET/Ewing sarcomaP, O, CmultlungsM12.3SR, CX14.4SR, RX14.829.94.0
16extrarenal nephroblastomaCsnglnoneF2.1SR, CX, RX4.3SR, RX**347.9**319.9**
17alveolar rhabdomyosarcomaLsngllymph nodesF1.1SR, CX, RX1.8biopsy, CXunkunkunk
gonads
18mixed germ cell tumor, testisOunklungsM19.2SR, CX19.7biopsy, unk20.934.326.9
19mixed germ cell tumor, testisFsngllungsM16.1SR, CX16.1biopsy, CX, RX18.730.930.9
20mixed germ cell tumor, testisFsngllungs, retroperitoneal soft tissuesM19.8SR, CX20.3SR, CX**95.9**91.4**
21embryonal carcinoma, testisOunkunkMunkunk19.0SR19.5unk5.0
22yolk sac tumor, ovaryFsngllungsF1.0unk2.0SR2.2121.3
head & neck
23alveolar rhabdomyosarcomaCsngllymph nodesM11.8SR, CX, RX12.3op only12.36.50.4
24alveolar soft part sarcomaPsngllungsF7.9SR, CX18.4op only**129.2**3.7**
lung
25pleomorphic sarcomaFsnglnoneM10.5SR, CX11.9SR, RX**44.7**26.8**
liver
26hepatoblastomaP, Omultlymph nodes, lungs, heart, spleenM1.7SR, CX, RX3.3op only4.332.812.5

B = basal ganglia; C = cerebellum; CX = chemotherapy; D = cerebral convexity dura mater; Dx = diagnosis; F = frontal lobe; L = leptomeninges; mult = multiple; O = occipital lobe; P = parietal lobe; RX = radiation therapy; sngl = single; SR = surgical resection; SS = sellar/suprasellar region; T = temporal lobe; unk = unknown.

Patient alive at writing.

Outside institution was consulted; follow-up treatment information not available other than knowledge of neurosurgical biopsy.

Fig. 1.
Fig. 1.

Comparison of age at primary diagnosis of malignancy to age at discovery of CNS metastasis. *Same age at diagnosis of primary disease and CNS metastasis. **Age at diagnosis of primary disease unknown.

Histological Subtypes and Sites of Origin of Metastatic Tumors

Sites of origin were kidney/adrenal (9 cases, 34%), bone/soft tissue (8 cases, 31%), gonads (5 cases, 19%), head and neck (2 cases, 8%), lung (1 case, 4%), and liver (1 case, 4%) (Table 2). Kidney/adrenal tumors consisted of 4 neuroblastomas, 3 nephroblastoma/Wilms tumors, 1 malignant rhabdoid tumor, and 1 clear cell sarcoma. An additional nephroblastoma/Wilms tumor was found to be of extrarenal origin from the lumbosacral region. Other tumors of bone/soft tissue origin were 3 primitive neuroectodermal tumor (PNET)/Ewing sarcomas arising from lower-extremity skeletal muscle or bone, 2 high-grade osteosarcomas arising from the femur, 1 high-grade undifferentiated sarcoma arising from the anterior region of the thigh, and 1 alveolar rhabdomyosarcoma arising from the soft tissue of the buttocks. The 1 metastasis of lung origin was that of a high-grade pleomorphic sarcoma for which extensive workup revealed no other primary site. Gonadal malignancies included 3 nonseminomatous mixed malignant germ cell tumors and 1 embryonal carcinoma of testicular origin as well as 1 yolk sac tumor of ovarian origin. The 2 head and neck primary malignancies were alveolar rhabdomyosarcoma arising from the nasal cavity and alveolar soft part sarcoma arising from the tongue. The metastatic liver malignancy was a hepatoblastoma.

Characteristics of CNS Metastases

The overwhelming majority of CNS metastases were supratentorial (22 [85%] of 26) (Table 2). In 1 patient there was metastasis to the sellar/suprasellar region (4%); in 5 patients there were infratentorial metastases, all in the posterior fossa (19%), of whom 2 had concomitant supratentorial lesions. Single CNS metastases were common (17 [65%] of 26), while 5 patients (19%) had 2 or more distinct lesions on neuroimaging studies. In the available medical records of 4 cases (15%), details on the number of CNS metastatic lesions were not recorded.

Supratentorial metastases most commonly involved the cerebral hemispheres: the frontal lobe in 9 cases (35%), parietal lobe in 6 (23%), occipital lobe in 6 (23%), and temporal lobe in 1 (4%). One metastasis (4%) involved the basal ganglia (Table 2). Metastatic lesions involving more than one area of the brain included 5 tumors with 2 or more discontinuous lesions on neuroimaging studies (Cases 7, 10, 13, 15, and 26) and 1 dumbbell-shaped lesion involving the cerebellum and occipital lobe (Case 3). In 3 cases (12%), the lesions were centered in the cerebellum.

In 7 cases (15%), the metastases involved the dura/leptomeninges: in 4 cases, they involved both the parenchyma and overlying brain coverings (Cases 3 and 8–10); in 2 cases, they were entirely extraaxial and only involved the dura and skull (Cases 4 and 11); and in 1 case, the lesion infiltrated the leptomeninges and subarachnoid space to present as leptomeningeal carcinomatosis (Case 17). None of the metastases in this patient cohort involved the brainstem or spinal cord.

No individual tumor type appeared to show a predilection toward involvement of any particular CNS site. Metastases to the cerebral hemispheres included tumors from all the sites of origin mentioned above. The sellar/suprasellar metastasis was from 1 of the PNET/Ewing sarcomas (Case 14). Cerebellar metastases consisted of neuroblastoma (Case 3), extrarenal nephroblastoma/Wilms tumor (Case 16), osteosarcoma (Case 12), and alveolar rhabdomyosarcoma arising from the nasal cavity (Case 22).

Therapeutic Interventions

Aggressive initial treatment, which included surgical resection and chemotherapy, for the primary malignant tumors was performed in 22 patients (85%), 11 of whom additionally underwent radiation therapy (Table 2). Nonsurgical treatment information for primary malignancies was unavailable for 4 patients.

Central nervous system metastases were treated with surgery and additional chemotherapy in 5 patients (20%), surgery and radiation in 6 patients (23%), and surgery plus a combination of chemotherapy and radiation therapy in 2 patients (8%). Ten patients (38%) had no additional treatment for their CNS metastasis other than resection or a biopsy for diagnostic purposes. Nonsurgical treatment information for CNS metastases was unavailable for 3 patients.

Clinical and Follow-Up Data

The interval between primary malignant diagnosis and CNS metastasis spanned up to 126 months (mean 27 months; median 18 months). One patient had CNS involvement at initial presentation of malignant disease (Case 19), and in 3 patients the CNS metastasis was seen within 6 months of initial presentation of primary malignancy (Cases 10, 21, and 23). Symptoms of CNS involvement in 17 patients included headache (11 cases, 42%), vomiting (9 cases, 35%), new-onset seizure (5 cases, 19%), peripheral weakness (4 cases, 15%), altered mental status, abnormal gait, hydrocephalus, photophobia, and changes in vision (Fig. 2). On routine imaging studies 3 patients were found to have a brain metastasis and were asymptomatic. Complete electronic medical records were unavailable for 6 patients, whose CNS symptoms were therefore unknown.

Fig. 2.
Fig. 2.

Summary of clinical presentations in pediatric patients with metastatic CNS disease.

In 22 patients (85%) synchronous and/or metachronous metastases developed in organs other than the brain, most commonly lungs (16 [62%] of 26) (Table 2). Other metastatic sites included regional and/or distant lymph nodes (8 cases, 31%), nonadjacent soft tissues (5 cases, 19%), and bone (4 cases, 15%). One of the PNET/Ewing sarcomas metastasized to the liver (Case 14), and the single hepatoblastoma metastasized to the heart and spleen (Case 26). Half of the patient cohort (13, 50%) had metastatic disease documented in organs/sites not involving the CNS at the time of initial presentation of primary malignancy. All 22 of the primary malignancies with documented metastases in organs other than the brain had manifestations of systemic disease at the time that CNS involvement developed.

Seventeen of the 26 patients died of their disease. The survival period after diagnosis of primary malignant disease ranged from 6.5 months to 29.0 years (mean 5.5 years; median 2.9 years). Four patients developed CNS involvement and died within 1 year of the diagnosis of their primary malignancy. Survival after the diagnosis of CNS involvement ranged from 0.4 months to 26.7 years (mean 3.1 years; median 12.5 months). Ten patients died within 6 months of CNS metastasis and 12 within the 1st year, yielding a 1-year survival rate of 52% (Table 2). The overall 5-year survival rate after CNS metastasis was 16% and the 10-year survival rate was 8%.

Discussion

Pediatric CNS metastases are far less common than adult CNS metastases, accounting for approximately 2% of all pediatric brain tumors in our series. Historically, the most common solid tumors outside the CNS in children have been neuroblastoma and subsets of sarcomas, including PNET/Ewing sarcoma and rhabdomyosarcoma.8 The results of our investigation suggest that the most common malignancies to exhibit CNS metastasis in children are likewise of kidney/adrenal or bone/soft tissue origin.

In the last 20 years only a handful of previous studies have examined CNS involvement by solid tumors in the pediatric population. Bouffet et al. have characterized 12 cases of CNS metastasis from 486 primary solid non-CNS tumors of all types seen over a 9-year period. In their study metastatic tumors included PNET/Ewing sarcoma, neuroblastoma, osteosarcoma, nephroblastoma/Wilms tumor, synovial sarcoma, and retinoblastoma, and they calculated a 2.4% incidence for CNS involvement.4 Two similar studies were published in 2005: Hauser et al. found CNS metastases in 14 of 406 primary solid non-CNS tumors of all types over a 14-year period for an incidence of 3.4%, and Kebudi et al. reported 16 CNS metastases from 1100 primary tumors over a 3-year period for an incidence of 1.5%.9,11 Metastatic tumors, in the study by Hauser et al., included rhabdomyosarcoma, neuroblastoma, PNET/Ewing sarcoma, non-Hodgkin lymphoma, and malignant chordoma. Metastatic malignancies, in the series by Kebudi et al., included osteosarcoma, PNET/Ewing sarcoma, rhabdomyosarcoma, soft-tissue clear cell sarcoma, alveolar soft part sarcoma, nephroblastoma/Wilms tumor, and germ cell tumors. All patients in their series had metastases to other sites at the time of CNS involvement. The pooled incidence of CNS metastases from these 3 studies is 2.1%, in approximate accordance with the incidence observed at our institution.

One of the metastatic tumors in our series was a nephroblastoma/Wilms tumor of extrarenal origin arising in the lumbosacral region. Extrarenal nephroblastoma is an exceptionally rare tumor.1 To our knowledge, this case is the first reported case of extrarenal nephroblastoma metastasizing to the CNS. The patient is living, at the time of writing, and has had long survival of 319.9 months (26.6 years) after brain metastasis and 347.9 months (29.0 years) after diagnosis of primary malignancy at age 2.1 years.

Of the nearly 4000 non-CNS solid malignancies identified in the pediatric population in our study, 4 primary malignancies were lung sarcomas: 2 high-grade sarcomas originating in the lung parenchyma or pleural surface and 2 pleuropulmonary blastomas. Pleuropulmonary blastomas are reportedly more likely to exhibit brain metastases than other pediatric sarcomas, with an incidence of CNS involvement of approximately 14% in a study of 271 pleuropulmonary blastomas.14 Interestingly, in our study neither of the pleuropulmonary blastomas exhibited CNS involvement, but 1 of the high-grade sarcomas did.

Pediatric CNS metastases in our series were most likely to present as solitary, supratentorial, symptomatic lesions. Adult CNS metastases are similarly most common in the cerebral hemispheres, corresponding to vascular distribution and tissue volumes, and they are often symptomatic.6,13,16 At the time that CNS involvement is diagnosed, the presence of metastases in other organs, particularly lungs, is common in the pediatric population, and, as expected, prognosis for pediatric CNS metastases is poor despite aggressive therapy for primary malignant disease and metastatic disease. It is, however, conspicuously better than that seen in the adult population, as overall median survival following CNS metastasis in adults can range up to 12–15 months with adequate surgical intervention, whole-brain radiotherapy, and adjuvant chemotherapy, but it is more typically in the range of 4–8 months, and can be as low as 1–2 months in the absence of treatment.7,13,16 Patients with a nephroblastoma/Wilms tumor had the longest overall survival and the longest survival after diagnosis of the CNS metastasis in our series. Overall, clinical outcome was poor but slightly better than reported in previous studies. Our study showed a 1-year survival rate of 52% but significantly reduced 5-year and 10-year survival rates of 16% and 8%, respectively. In comparison, Hauser et al. reported 1-year and 5-year survival rates of 48% and 0%, and 11 of 12 patients in the study by Bouffet died within the first 38 months (median survival 3 months).4,9

One potential bias in this study is the fact that our patient cohort reflects individuals who underwent neurosurgical intervention and, at least in theory, were either considered viable surgical candidates or their treatment depended on a pathological diagnosis and required biopsy. However, it is our institution's policy that patients undergoing therapy for metastatic disease undergo biopsy for tissue diagnosis. Furthermore, we queried the neuroradiology files for patients with metastatic CNS disease and could only identify 1 patient who was not accounted for in this study. Finally, the fact that the study spans a 30-year period in which cancer management has evolved potentially introduces another variable when considering survival data.

Conclusions

Our study shows that metastatic tumors to the CNS in a pediatric population are much less common than they are in an adult population but arise in a similar distribution, with cerebral metastases being more common than cerebellar or brainstem lesions. Central nervous system metastases in both children and adults are commonly symptomatic. When comparing children and adults, the sites of origin are vastly different, with kidney/adrenal and bone/soft-tissue tumors being the most common to exhibit CNS involvement in the pediatric population. Similar to adult patients, prognosis in general is dismal for children with CNS metastasis, but median survival after CNS involvement is slightly prolonged for pediatric patients.

Disclosure

The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

Author contributions to the study and manuscript preparation include the following. Conception and design: Hattab. Acquisition of data: both authors. Analysis and interpretation of data: both authors. Drafting the article: both authors. Critically revising the article: both authors. Reviewed submitted version of manuscript: both authors. Approved the final version of the manuscript on behalf of both authors: Hattab. Statistical analysis: both authors. Administrative/technical/material support: both authors. Study supervision: Hattab.

This article contains some figures that are displayed in color online but in black-and-white in the print edition.

References

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Article Information

Drs. Wiens and Hattab contributed equally to this work.

Address correspondence to: Eyas M. Hattab, M.D., Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, IU Health Pathology Laboratory, 350 W. 11th St., Rm. 4040, Indianapolis, IN 46202-4108. email: ehattab@iupui.edu.

Please include this information when citing this paper: published online June 13, 2014; DOI: 10.3171/2014.5.PEDS13526.

© AANS, except where prohibited by US copyright law.

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Figures

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    Comparison of age at primary diagnosis of malignancy to age at discovery of CNS metastasis. *Same age at diagnosis of primary disease and CNS metastasis. **Age at diagnosis of primary disease unknown.

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    Summary of clinical presentations in pediatric patients with metastatic CNS disease.

References

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