Brain metastases in patients diagnosed with a solid primary cancer during childhood: experience from a single referral cancer center

Clinical article

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Object

Metastasis to the brain is frequent in adult cancer patients but rare among children. Advances in primary tumor treatment and the associated prolonged survival are said to have increased the frequency of brain metastasis in children. The authors present a series of cases of brain metastases in children diagnosed with a solid primary cancer, evaluate brain metastasis trends, and describe tumor type, patterns of occurrence, and prognosis.

Methods

Patients with brain metastases whose primary cancer was diagnosed during childhood were identified in the 1990–2012 Tumor Registry at The University of Texas M.D. Anderson Cancer Center. A review of their hospital records provided demographic data, history, and clinical data, including primary cancer sites, number and location of brain metastases, sites of extracranial metastases, treatments, and outcomes.

Results

Fifty-four pediatric patients (1.4%) had a brain metastasis from a solid primary tumor. Sarcomas were the most common (54%), followed by melanoma (15%). The patients' median ages at diagnosis of the primary cancer and the brain metastasis were 11.37 years and 15.03 years, respectively. The primary cancer was localized at diagnosis in 48% of patients and disseminated regionally in only 14%. The primary tumor and brain metastasis presented synchronously in 15% of patients, and other extracranial metastases were present when the primary cancer was diagnosed. The remaining patients were diagnosed with brain metastasis after initiation of primary cancer treatment, with a median presentation interval of 17 months after primary cancer diagnosis (range 2–77 months). At the time of diagnosis, the brain metastasis was the first site of systemic metastasis in only 4 (8%) of the 51 patients for whom data were available. Up to 70% of patients had lung metastases when brain metastases were found. Symptoms led to the brain metastasis diagnosis in 65% of cases. Brain metastases were single in 60% of cases and multiple in 35%; 6% had only leptomeningeal disease. The median Kaplan-Meier estimates of survival after diagnoses of primary cancer and brain metastasis were 29 months (95% CI 24–34 months) and 9 months (95% CI 6–11 months), respectively. Untreated patients survived for a median of 0.9 months after brain metastasis diagnosis (95% CI 0.3–1.5 months). Those receiving treatment survived for a median of 8 months after initiation of therapy (95% CI 6–11 months).

Conclusions

The results of this study challenge the current notion of an increased incidence of brain metastases among children with a solid primary cancer. The earlier diagnosis of the primary cancer, prior to its dissemination to distant sites (especially the brain), and initiation of presumably more effective treatments may support such an observation. However, although the actual number of cases may not be increasing, the prognosis after the diagnosis of a brain metastasis remains poor regardless of the management strategy.

Abbreviations used in this paper:CNS = central nervous system; LMD = leptomeningeal disease; M.D. Anderson = The University of Texas M.D. Anderson Cancer Center; SRS = stereotactic radiosurgery; WBRT = whole-brain radiotherapy.

Abstract

Object

Metastasis to the brain is frequent in adult cancer patients but rare among children. Advances in primary tumor treatment and the associated prolonged survival are said to have increased the frequency of brain metastasis in children. The authors present a series of cases of brain metastases in children diagnosed with a solid primary cancer, evaluate brain metastasis trends, and describe tumor type, patterns of occurrence, and prognosis.

Methods

Patients with brain metastases whose primary cancer was diagnosed during childhood were identified in the 1990–2012 Tumor Registry at The University of Texas M.D. Anderson Cancer Center. A review of their hospital records provided demographic data, history, and clinical data, including primary cancer sites, number and location of brain metastases, sites of extracranial metastases, treatments, and outcomes.

Results

Fifty-four pediatric patients (1.4%) had a brain metastasis from a solid primary tumor. Sarcomas were the most common (54%), followed by melanoma (15%). The patients' median ages at diagnosis of the primary cancer and the brain metastasis were 11.37 years and 15.03 years, respectively. The primary cancer was localized at diagnosis in 48% of patients and disseminated regionally in only 14%. The primary tumor and brain metastasis presented synchronously in 15% of patients, and other extracranial metastases were present when the primary cancer was diagnosed. The remaining patients were diagnosed with brain metastasis after initiation of primary cancer treatment, with a median presentation interval of 17 months after primary cancer diagnosis (range 2–77 months). At the time of diagnosis, the brain metastasis was the first site of systemic metastasis in only 4 (8%) of the 51 patients for whom data were available. Up to 70% of patients had lung metastases when brain metastases were found. Symptoms led to the brain metastasis diagnosis in 65% of cases. Brain metastases were single in 60% of cases and multiple in 35%; 6% had only leptomeningeal disease. The median Kaplan-Meier estimates of survival after diagnoses of primary cancer and brain metastasis were 29 months (95% CI 24–34 months) and 9 months (95% CI 6–11 months), respectively. Untreated patients survived for a median of 0.9 months after brain metastasis diagnosis (95% CI 0.3–1.5 months). Those receiving treatment survived for a median of 8 months after initiation of therapy (95% CI 6–11 months).

Conclusions

The results of this study challenge the current notion of an increased incidence of brain metastases among children with a solid primary cancer. The earlier diagnosis of the primary cancer, prior to its dissemination to distant sites (especially the brain), and initiation of presumably more effective treatments may support such an observation. However, although the actual number of cases may not be increasing, the prognosis after the diagnosis of a brain metastasis remains poor regardless of the management strategy.

There are well-established differences in cancer epidemiology between the adult and pediatric populations. Of particular interest relative to this paper is the differential incidence of brain metastasis between the two groups. Whereas solid brain metastases are known to occur frequently in adult patients with a solid cancer primary tumor and are the most common intracranial tumors in this group, they are uncommon in the pediatric population. Estimates from published clinical reports put the frequency of brain metastases in adults at 20%–40% of all patients with a solid primary cancer versus 1%–10% in the corresponding pediatric population.

The type of primary cancer and the presence of pulmonary metastases have been most frequently noted as determinants of brain metastases in children with solid primary cancers in published case reports and small series. More effective treatment for the primary cancer and prolonged survival over the recent years12 may have resulted in an increased frequency of brain metastases in the pediatric population. Improvement in neuroimaging techniques may also have led to improved detection and earlier diagnosis of brain metastasis, with greater certainty in both groups. We present a relatively large series of cases of brain metastasis in patients from a single center who were diagnosed with a solid primary cancer and brain metastasis during childhood, evaluate the brain metastasis trends, and describe multiple variables, including tumor type, patterns of occurrence, and prognosis.

Methods

The study was conducted under the auspices of a protocol approved by institutional review board of The University of Texas M.D. Anderson Cancer Center (M.D. Anderson). Patients with a solid brain metastasis or leptomeningeal disease (LMD) (referred to collectively as brain metastases) whose primary cancer was diagnosed during childhood were identified from a review of the 1990–2012 Tumor Registry records at M.D. Anderson. A retrospective review of the patients' hospital records was conducted. Included in our study were patients with parenchymal, epidural, and subdural metastases. Also included were patients with calvarial and supragaleal metastases invading the epidural space or beyond and patients with leptomeningeal involvement. Excluded were patients with metastases to the calvaria only and patients with the direct extension of an extracranial primary tumor into the brain. Autopsy reports were not reviewed as part of this study.

Data obtained included patient sex and date of birth; details on the primary cancer, including site, histology, date of diagnosis and treatment; site and timing of extracranial metastasis, if any; presence of symptoms leading to the diagnosis of the brain metastasis; details on the brain metastases, including number, size, location, date of diagnosis, and treatment; and survival information. The date of death (when available) was also confirmed with the Social Security Death Index.

Frequencies and descriptive statistics of the demographic and clinical variables were obtained. The data were analyzed using IBM SPSS v.19. The Kaplan-Meier method was used to estimate overall survival proportions, measured from the dates of diagnosis of the primary cancer and brain metastasis and from the date of brain metastasis treatment. All tests were 2-tailed. A p value ≤ 0.05 was considered statistically significant.

Results

A review of the Tumor Registry records identified 7625 pediatric patients with cancer registering at the institution between January 1, 1990 and September 30, 2012. Of those, 3950 had a solid primary cancer outside the central nervous system (CNS). During that same period, 54 patients (1.4%) were found to have a solid brain metastasis and/or leptomeningeal disease. These patients constitute our study population.

Of the 54 patients with brain metastases, 44% were female and 56% were male. The median ages at diagnosis of the primary cancer and the brain metastasis were 11.37 years (range birth–17.96 years) and 15.03 years (range 3 months–20.74 years), respectively. The family history was positive for cancer in 63% of patients. Thirty of the brain metastasis histologies (56%) were confirmed by pathology. The most frequent primary cancer was sarcoma, seen in 29 patients (54%) (Table 1). We did not identify any case of Wilms tumor with brain metastasis (0 of 159 patients). Table 2 shows the incidence of brain metastasis among different types of primary cancer based on the records of the Tumor Registry at M.D. Anderson.

TABLE 1:

Characteristics of 54 pediatric patients with brain metastases*

CharacteristicNo. of Pts w/ Data AvailableValue
age at primary cancer Dx53
 median (yrs)11.37
 range (yrs)0–17.96
age at brain metastasis Dx53
 median (yrs)15.03
 range (yrs)0.24–20.74
sex54
 female24 (44)
 male30 (56)
family history of cancer41
 yes26 (63)
 no15 (37)
family history of CNS malignancy41
 yes3 (7)
 no38 (93)
Sx leading to brain metastasis Dx4831 (65)
 headache16 (33)
 nausea/vomiting13 (27)
 seizure11 (23)
 hemiparesis6 (12)
 motor disturbance3 (6)
 drowsiness3 (6)
 speech difficulty3 (6)
 sensory disturbance2 (4)
 confusion2 (4)
 cranial nerve deficit2 (4)
 visual problem1 (2)
 irritability1 (2)
 dizziness1 (2)
time from Sx to brain metastasis Dx§16
 median (days)3
 range (days)0–23
brain metastasis diagnosed by imaging5252 (100)
type of scan47
 MRI25 (53)
 CT20 (43)
 octreotide nuclear scan1 (2)
 PET-CT1 (2)
no. of brain metastases at Dx52
 single31 (60)
 multiple18 (35)
 LMD only throughout3 (6)
brain metastasis type50
 parenchymal36 (72)
 dura-based10 (20)
 LMD only3 (6)
 calvarial & epidural1 (2)
location of solid brain metastasis45
 infratentorial4 (9)
 supratentorial40 (89)
 both1 (2)
largest diameter of largest solid brain metastasis33
 median (cm)3.0
 range (cm)0.3–6.0
solid brain metastasis—hemorrhagic on imaging30
 yes18 (60)
 no12 (40)
solid brain metastasis—calcified on imaging22
 yes5 (23)
 no17 (77)
solid brain metastasis—cystic on imaging26
 yes9 (35)
 no17 (65)
path confirmation of brain metastasis5430 (56)
 resection26
 CSF analysis2
 biopsy2
LMD status at presentation of brain metastasis—excl cases w/ LMD only51
 LMD at presentation before Tx3 (6)
 LMD after initiation of Tx of brain metastasis5 (10)
 no LMD43 (84)
LMD Dx11
 imaging only8 (73)
 CSF only0 (0)
 both3 (27)
site of LMD10
 spinal cord2 (20)
 brain4 (40)
 both4 (40)
primary cancer types—excl hematol cancers54
 sarcoma29 (54)
  osteosarcoma11
  sarcoma, unclassified6
  Ewing sarcoma3
  clear cell sarcoma of kidney3
  rhabdomyosarcoma, alveolar3
  rhabdomyosarcoma, embryonal1
  angiosarcoma1
  pleuropulmonary blastoma1
 malignant melanoma8 (15)
 testicular3 (6)
  choriocarcinoma2
  endodermal sinus tumor1
 thyroid3 (6)
  papillary carcinoma3
 adrenal3 (6)
  neuroblastoma3
 lung1 (2)
  carcinoid1
 unknown primary2 (4)
  choriocarcinoma1
  neuroendocrine carcinoma, high grade1
 gastric1 (2)
  signet ring cell carcinoma1
 paraspinal1 (2)
  pPNET1
 eye1 (2)
  retinoblastoma1
 mediastinum1 (2)
  malignant epithelioid neoplasia consistent w/ YST1
 thigh (soft tissue)1 (2)
  round cell malignancy w/ melanocytic differentiation1
stage of primary cancer at the time of its Dx50
 localized24 (48)
 regional7 (14)
 distant19 (38)
primary cancer diagnosed before brain metastasis54
 yes46 (85)
 no8 (15)
time from primary cancer Dx to brain metastasis52
 median (mos)15
 range (mos)0–77
time from primary cancer Dx to brain metastasis among pts whose brain metastasis was diagnosed after primary45
 median (mos)17
 range (mos)2–77
status of primary cancer at time of brain metastasis Dx32
 stable/responding5 (16)
 progressing4 (12)
 no evidence of disease23 (72)
extracranial metastasis at time of brain metastasis Dx5144 (86)
 lung5032 (64)
 lymph nodes5314 (26)
 bone, extraspinal548 (15)
 spine546 (11)
 liver534 (8)
 soft tissue542 (4)
 other**545 (9)
extracranial metastasis by time of brain metastasis Dx5147 (92)
 lung5035 (70)
 lymph nodes5314 (26)
 bone, extraspinal548 (15)
 spine546 (11)
 liver534 (8)
 soft tissue542 (4)
 other**545 (9)

Values represent numbers of patients (%) unless otherwise specified. Percentage totals may not equal 100% due to rounding. Dx = diagnosis; excl = excluding; hematol = hematological; LMD = leptomeningeal disease; path = pathological; pPNET = peripheral primitive neuroectodermal tumor; pt = patient; Sx = symptom(s); Tx = treatment; YST = yolk sac tumor.

A value of 0 indicates diagnosis at birth.

One additional patient whose brain metastasis was initially diagnosed through screening did subsequently develop headache, hemiparesis, and sensory disturbance prior to treatment of the brain metastasis.

Among patients with symptoms and available data.

Some of the non-CNS metastases (3 lung metastases) had been treated and were no longer present at the time of diagnosis of the brain metastasis, hence the difference in the data between “by” the time of brain metastasis and “at” the time of brain metastasis.

Paraspinal, ovarian, peritoneal, renal, and pancreatic (one each).

TABLE 2:

Frequency of brain metastasis relative to tumor histology in pediatric patients at The University of Texas M.D. Anderson Cancer Center, 1990–2012*

HistologyPts w/ Brain MetastasisDenominator From Tumor Registry Over Same IntervalFrequency of Brain Metastasis (%)
choriocarcinoma3743
clear cell sarcoma of the kidney31030
signet ring cell carcinoma1911
angiosarcoma1911
neuroendocrine tumors1128
endodermal sinus tumor & YST2316
unclassified sarcoma61404
malignant melanoma82793
carcinoid1383
pPNET1323
osteosarcoma116022
pleuropulmonary blastoma1422
rhabdomyosarcoma43261
Ewing sarcoma33111
neuroblastoma32281
papillary carcinoma33041
retinoblastoma1159<1
round cell malignancy w/ melanocytic differentiation1
Wilms tumor01590

Data from The University of Texas M.D. Anderson Cancer Center Tumor Registry records. Brain and other CNS primary tumors were excluded from the total. Values represent numbers of patients unless otherwise specified.

Total represents all thyroid tumors.

The imaging modality used for initial brain metastasis diagnosis was MRI in 53% of the 47 patients for whom data were available, CT scans in 43%, and PET-CT and octreotide scan in 1 patient each (4%).

The primary cancer was localized at the time of its diagnosis in 48% of the cases. In an additional 14%, the patients had only regional dissemination (to lymph nodes linked to the primary site of involvement). The presentation of the primary tumor and brain metastasis was synchronous in 8 patients (15%). This synchronicity was observed in 7% of the sarcoma cases and in 24% of those with other primary cancers (p = 0.12). In all of these cases, the patient had other extracranial metastatic sites at the time of diagnosis of the primary malignancy. The profile of extracranial metastatic sites included lung metastases in 4 patients, 3 each with bone and lymph node involvement, and 2 with spinal metastasis. In 3 of the 8 patients in whom the primary tumor and brain metastasis were synchronous (1 patient with testicular choriocarcinoma, 1 with unclassified sarcoma, and 1 with high-grade neuroendocrine carcinoma from an unknown primary, all presenting at 16–17 years of age), CNS symptoms were the initial manifestation of brain metastasis rather than any direct symptoms from the primary malignancy. In 4 of the 8 cases, brain metastasis was identified on routine surveillance scans while the patients remained asymptomatic. One patient's medical records were insufficient for analysis. The rest of the patients were diagnosed with brain metastases after initiation of treatment for the primary cancer, with a median presentation interval of 17 months after diagnosis of the primary cancer (range 2–77 months).

The primary cancer was progressing in only 12% of patients at the time of diagnosis of the brain metastasis, but 86% had an extracranial metastasis outside the primary site. Three additional patients had a history of eradication of an extracranial metastasis (bringing the total to 92% with an extracranial metastasis at the time of brain metastasis diagnosis or conversely 8% in whom brain metastasis was the first site of systemic metastasis). As many as 70% of the patients had lung metastasis by the time they presented with brain metastasis, with no statistically significant difference according to tumor histology. None of the 3 patients with neuroblastoma had a lung metastasis or lung invasion at the time of diagnosis of the brain metastasis. Two of these patients had calvarial tumors with intracranial extensions, and the third had a dura-based metastasis.

In regard to clinical presentation of brain metastases, 65% of the patients were symptomatic at presentation. Headache (33%), nausea/vomiting (27%), and seizures (23%) were the most common symptoms, with no difference in patients with sarcoma versus those with other primary cancers. Thirty-five percent of brain metastases were discovered during staging or screening.

Of the 52 patients for whom data were available on the number of brain metastases at initial brain metastasis presentation, 31 (60%) had a single tumor, 18 (35%) had multiple tumors (6 had 2 brain metastases, 9 had 3 or more brain metastases, and 3 had an unknown number), and 3 (6%) had only LMD. The tumors were parenchymal in 36 cases (72%) and dura-based in 10 (20%; Table 1). One patient had a calvarial/epidural tumor. Regarding location of the solid brain metastases, 89% of patients for whom data were available had supratentorial tumors, 9% had infratentorial tumors, and 2% had tumors in both locations. The numbers of patients were too small to show statistically significant differences in number of tumors or tumor location among sarcoma, melanoma, and other primaries. Seven melanoma patients had supratentorial tumors; one had both supratentorial and infratentorial tumors. The median largest tumor diameter was 3.0 cm (range 0.3–6.0 cm); 60% of tumors for which data were available appeared hemorrhagic on imaging scans, and 35% were cystic.

All 3 patients with LMD as the sole manifestation of brain metastasis developed the LMD after treatment for the primary cancer. Two patients had LMD in conjunction with the solid brain metastases at initial discovery of the brain metastasis (one with retinoblastoma in the spinal cord and one with unclassified sarcoma in both brain and spinal cord); one developed brain metastasis 3 months later, prior to any brain treatment (melanoma in the brain). Five patients (one with neuroblastoma in the brain, one with alveolar rhabdomyosarcoma in both the brain and the spinal cord, one with papillary thyroid carcinoma in the spinal cord, one with malignant melanoma from an unknown site, and one with round cell malignancy with melanocytic differentiation in the brain) developed LMD later in the course of the disease.

Most patients (91%) received treatment for brain metastases as shown in Table 3 (treatment data were not available for 1 patient). Of the 3 patients with LMD as the sole manifestation of brain metastasis mentioned above, one received no treatment (peripheral primitive neuroectodermal tumor); one received WBRT (alveolar rhabdomyosarcoma); and one received chemotherapy followed by WBRT (signet ring cell gastric carcinoma). All died within 2 months of LMD diagnosis. The other 3 patients with a solid brain metastasis and an LMD diagnosis prior to initiation of brain treatment received stereotactic radiosurgery (SRS, administered to the metastasis, an unclassified sarcoma), whole-brain radiotherapy (WBRT, for melanoma), or chemotherapy followed by WBRT + intensitymodulated radiation therapy (for retinoblastoma). Of the remaining 48 patients, 45% received combination therapy as initial brain metastasis treatment (28% of those had resection with WBRT and/or chemotherapy, and 17% received chemotherapy followed by WBRT); 28% underwent resection alone; 9% received WBRT alone; 9% received chemotherapy alone; and 9% received no treatment. The numbers were too small to permit detection of statistically significant differences in type of therapy administered to patients or tumor characteristics such as status of the primary or systemic noncerebral cancers at the time of initial brain metastasis treatment, number or location of brain metastases, or tumor histology.

TABLE 3:

Treatments and outcomes in pediatric patients with brain metastases*

VariableNo. of Pts w/ Data AvailableValue
brain metastasis treated during lifetime5348 (91)
if treated, initial Tx was the only Tx45
 yes29 (64)
 no16 (36)
reason initial Tx was the only Tx26
 no brain metastasis recurrence22 (85)
 no Tx despite recurrence2 (8)
 death soon after brain metastasis Dx1 (4)
 went to hospice1 (4)
initial Tx type52
 none5 (10)
 resection13 (25)
 WBRT5 (10)
 SRS2 (4)
 chemo4 (8)
 resection & WBRT4 (8)
 resection & chemo3 (6)
 chemo & WBRT6 (12)
 chemo & SRS3 (6)
 chemo & proton therapy1 (2)
 resection, chemo, & WBRT3 (6)
 resection, chemo, & SRS2 (4)
 resection, chemo, & radiation (unspecified)1 (2)
vital status at last follow-up54
 alive12 (22)
 dead42 (78)
overall survival after primary cancer Dx (mos)
 median29
 95% CI24–34
overall survival after brain metastasis Dx (mos)
 median9
 95% CI6–11
overall survival after brain metastasis Tx (mos)
 median8
 95% CI6–11

Values represent numbers of patients (%) unless otherwise specified. Percentage totals may not equal 100% due to rounding. chemo = chemotherapy; SRS = stereotactic radiosurgery.

The median duration of follow-up after diagnosis of brain metastasis among the patients remaining alive at the end of the study was 24 months (range 0.5–160.5 months). All but 2 patients had durations of follow-up or survival of 3.5 years or less. The patient with the longest follow-up (160.5 months) was a 17-year-old male initially diagnosed with a Clark's Level 2 melanoma on his midback. The patient had a wide local resection without residual tumor. Five years later, he developed right facial palsy that led to the diagnosis of a hemorrhagic lesion in the left frontal lobe. The tumor was resected and WBRT was administered. Further evaluation during the same interval showed evidence of systemic metastatic disease in the liver, lungs, and soft tissue, as well as lymphadenopathy, for which the patient received biochemotherapy. Two years later, at last study follow-up, there was continued response and no evidence of brain metastasis recurrence. The patient with the second longest follow-up (141.7 months) was a male child diagnosed with a localized lung carcinoid at age 11 and with a liver metastasis and a supratentorial brain metastasis at around age 16. The brain metastasis was asymptomatic and was diagnosed through staging. It was completely resected, and there has been no recurrence as of the last follow-up visit.

The median Kaplan-Meier estimate of survival after primary tumor diagnosis was 29 months (95% CI 24–34 months) (Fig. 1). The median Kaplan-Meier estimate of survival after brain metastasis diagnosis was 9 months (95% CI 6–11 months; Fig. 2). The 6-month and 1-year survival rates were 66% and 38%, respectively. After excluding the 6 patients with an LMD diagnosis prior to initial treatment, the median survival time after brain metastasis diagnosis was 9 months (95% CI 6–13 months).

Fig. 1.
Fig. 1.

Kaplan-Meier plot of overall survival after primary cancer diagnosis in a series of 54 pediatric patients with brain metastasis from a solid primary cancer.

Fig. 2.
Fig. 2.

Kaplan-Meier plot of overall survival after diagnosis of brain metastasis in a series of 54 pediatric patients with brain metastasis from a solid primary cancer.

Patients not receiving treatment survived for a median of 0.9 months after brain metastasis diagnosis (95% CI 0.3–1.5 months); those receiving treatment survived for a median of 8 months after initiation of therapy (95% CI 6–11 months). Corresponding figures, after excluding patients with LMD at presentation, are 0.9 months (95% CI 0.0–11.2 months) and 8 months (95% CI 6–11 months), respectively.

Discussion

Metastasis to the CNS is the most common type of brain tumor in the adult population, contributing almost one-third of all cases with such a diagnosis. It is estimated that 20%–40% of all adults with cancer will develop brain metastasis. Brain metastases originate mainly from lung, breast, melanoma, kidney, and gastrointestinal primary cancers. Tumors from unknown primary cancers are not uncommon (15% of brain metastasis cases). In the pediatric population, brain seeding is common in patients with leukemia. On the other hand, brain metastasis from a solid extracranial primary tumor is uncommon, with reported frequencies of 1.5%–10%1,8,14,22,27 from various clinical sources and 6%–13% from autopsy series.7,24 Differences in frequency and patterns of occurrence between adults and children have been loosely linked to a number of factors, including but not limited to the different spectrum of primary cancer histologies seen between the 2 populations; physiological/biological differences between children and adults, such as a less mature blood-brain barrier in the former (enabling penetration of the drugs into the cerebral parenchyma); and the different treatment methodologies used.20 The 3 factors of histology, physiology, and treatment are not independent of each other, as the type of tumor and its sensitivity to various treatments also dictate the treatment methodology chosen, which in turn may impact physiology (particularly the integrity of the blood-brain barrier and its capacity to prevent neoplastic cells from invading the brain).21 These differences limit attempts to extrapolate data from the adult literature to treat the pediatric population having brain metastases.

Many recent publications on pediatric brain metastasis suggest 1) that more effective treatment of the primary cancer and an increase in survival in recent years may have resulted in an increased incidence of brain metastases in the pediatric population and 2) that improved neuroimaging techniques may have in turn led to improved detection, with brain metastases being diagnosed at an earlier stage and with greater certainty. Owing to the rarity of the condition in children, the earlier published reports were only anecdotal. In more recent decades, there has been a surge in published small series, bolstering support for the notion that the incidence of the condition and/ or its rate of detection could be on the increase (Tables 4 and 5). These series do not include more than 30 patients, hindering the extraction of solid conclusions as to epidemiology, natural history, uniformity, and efficacy of various treatment approaches and detailed patient outcomes. Our series' estimate of a 1.4% frequency of brain metastases in pediatric cancer patients registered at M.D. Anderson and the trend over time (Fig. 3) may or may not be construed as evidence against an increase in the incidence of brain metastasis. These data were obtained from the hospital's Tumor Registry. At the Tumor Registry, abstracting of patient records takes place either 6 months after initial registration, upon determining that a patient has developed a second primary, or at death. Ascertainment of metastases is based on information in the patient's record at the time of each abstracting. Consequently, metastases in patients not known to be dead, who have not developed a second primary, or who have not returned to M.D. Anderson may not be reflected in the Tumor Registry data, making our 1.4% figure an underestimate of the true frequency of brain metastases. On the other hand, the 1.4% figure could be a true estimate of the incidence of brain metastases in our patient population, reflecting an earlier diagnosis of the primary cancer prior to its dissemination to a distant site, and particularly, prior to seeding of the brain or the use of more effective treatments. The latter hypothesis is supported by the finding that the primary cancer was localized at the time of its diagnosis in 48% of our cases and that there was only regional dissemination in another 14%. The current notion that there is an increased incidence of brain metastasis among children with a primary solid cancer is therefore challenged in our series.

TABLE 4:

Summary of the published literature on pediatric cases of brain metastasis from a solid primary cancer: Part 1

Authors & YearStudy YearsNo. of Pts w/ Brain MetastasesPrimary Cancer HistologyDistribution of Primary Cancer HistologyCases w/ Only LMD Included?Cases w/ Intracranial Extension From Skull: Dura Included?Autopsy Results Included?Pt Age at Dx*Time From Primary Dx to Brain Metastasis Dx
Kramer et al., 20011980–199911neuroblastoma (Stage IV)neuroblastoma, 11 (100)yesnonoprimary: median 37 mos (range 27–96 mos)median 12.2 mos (range 5–32 mos)
Kebudi et al., 20051989–200216all extracranial solid tumors including lymphomasarcoma, 12 (75); Wilms tumor, 2 (12.5); germ cell tumors, 2 (12.5)nononounspecified: 10.5 yrs (range 1–16 yrs)median 16 mos (range 1–70 mos)
Bouffet et al., 19971987–199512all solid primaries excl lymphoma & primary brain tumorsEwing sarcoma, 3 (25); neuroblastoma, 3 (25); Wilms tumor, 1 (8.3); soft-tissue sarcoma, 1 (8.3); osteosarcoma, 3 (25); retinoblastoma, 1 (8.3)nononounspecified: median 9 yrs (range 3–17 yrs)median 15 mos (range 9–24 mos)
Rodriguez-Galindo et al., 19971962–19958melanomamelanoma, 8 (100)NRNRnoprimary: median 15 yrs (range 11–21 yrs)median 20 mos (range 0–50 mos)
Graus et al., 19831973–198231all solid extracranial tumors excl lymphomafor the 18 cases diagnosed postmortem: osteosarcoma, 5 (27.8); rhabdomyo-sarcoma, 3 (16.7); Ewing sarcoma, 2 (11.1); germ cell tumor, 4 (22.2); melanoma, 1 (5.6); angiosarcoma, 1 (5.6); malignant schwannoma, 2 (11.1)NRnoyesNRosteosarcoma, median 22 mos (range 10–56 mos); germ cell tumor, median 13 mos (range 0–39 mos); rhabdomyosarcoma, median 8.5 mos (range 3–144 mos); other tumors, median 20 mos (range 10–60 mos)
Stefanowicz et al., 20111992–201010all solid extracranial malignanciessoft-tissue sarcoma, 3 (30); germ cell tumors, 3 (30); neuroblastoma, 1 (10); clear cell sarcoma of the kidney, 1 (10); osteosarcoma, 1 (10); pleuropulmonary blastoma, 1 (10)NRnonometastasis: median 13.8 yrs (range 2.6–17.7 yrs)median 8 mos (range 1–32 mos)
Tasdemiroglu & Patchell, 19971982–199412 (total w/ parenchymal, calvarial, & duralmets; the 7 cases of parenchymal were described further)all non-CNS primaries excl lymphoma & leukemiaWilms tumor, 2 (28.6); neuroblastoma, 2 (28.6); melanoma, 1 (14.3); hepatocellular carcinoma, 1 (14.3); angiosarcoma, 1 (14.3)NRnonounspecified: median 6 yrs (range 1–18 yrs)mean 327 days (range 0–755 days)
Parasuraman et al., 19991962–199821rhabdomyosarcoma & Ewing sarcomaEwing sarcoma, 11 (52.4); rhabdomyo-sarcomas, 10 (47.6)noyesyesprimary: median 10.4 yrs (range 0.4–18 yrs)NR
Weyl-Ben Arush et al., 19951986–19906all solid primaries excl brain tumors & lymphoproliferative disordersneuroblastoma, 3 (50); osteosarcoma, 1 (16.7); rhabdomyosarcoma, 1 (16.7); hepatocarcinoma, 1 (16.7)NRNRnoNRmedian 13 mos (range 1–36 mos)
Vannuci & Baten, 19741951–197213all extracranial solid malignanciesneuroblastoma, 2 (15.4); embryonal rhabdomyosarcoma, 3 (23); Wilms tumor, 4 (30.7); osteogenic sarcoma, 1 (7.7); hepatocellular carcinoma, 1 (7.7); melanoma, 1 (7.7); ovarian carcinoma, 1 (7.7)NRnoyesprimary: median 58.5 mos (range 1 mo–13 yrs)median 23 mos (range 5–48 mos)
Marina et al., 19931962–198913osteosarcoma except head & neck primariesosteosarcoma, 13 (100)NRNRyesprimary: range 4–25 yrsmedian 3 mos (range 15 days–33 mos)
Spunt et al., 20041962–200216germ cell tumorsgerm cell tumors, 16 (100)NRNRyesprimary: median 6.5 yrs (range 0.7–17.7 yrs)median 7 mos (range 0–37 mos)
Postovsky et al., 20031990–200118sarcomasarcoma, 18 (100)nononoprimary: mean 15.4 yrs (range 4–24 yrs); metastasis: mean 17.4 yrs (range 5.5–27 yrs)for the 10 pts w/ localized disease at Dx, mean 34.3 mos (range 12–126 mos); for the 8 pts w/ metastatic disease at time of Dx, mean 11.1 mos (range, 0–24 mos)
Paulino et al., 20031965–200030sarcoma, neuroblastoma, & Wilms tumorsarcoma, 20 (66.7); neuroblastoma, 9 (30); Wilms tumor, 1 (3.4)nonoyesmetastasis: median 14 yrs (range 8 mos–20 yrs)5 mos (range 1–43 mos)
present case1993–201144solid tumors outside the CNSsarcoma, 24 (54.5); melanoma, 5 (11.4); choriocarcinoma, 3 (6.8); endodermal sinus tumor, 2 (4.5); neuroblastoma, 3 (6.8); thyroid, 2 (4.5); signet cell gastric carcinoma, 1 (2.3); carcinoid, 1 (2.3); pPNET, 1 (2.3); neuroendocrine tumor, 1 (2.3); retinoblastoma, 1 (2.3)yesyesnoprimary: median 11 yrs (range 0–8 yrs); metastasis: 13 yrs (range 4 mos–20 yrs)16 mos (range 2–77 mos)

Values are given for age at diagnosis of primary tumor or brain metastasis as indicated. For values marked as “unspecified,” the reference point was unclear. mets = metastases; NR = not reported.

TABLE 5:

Summary of the published literature on pediatric cases of brain metastasis from a solid primary cancer: Part 2*

Authors & YearBrain Metastasis IncidenceBrain Metastasis Dx (screening vs Sx vs postmortem)Brain Metastasis LocationNo. of Brain MetsCNS Mets at Time of Primary DxCases w/ Other Organ Involvement at Dx of PrimaryNon-CNS Mets at Dx of Brain MetastasisDuration of Survival After Primary DxSurvival After Brain Metastasis Dx
Kramer et al., 200111/251 (4.3)NRNRNR0 (0)11 (100)3 (27)NRmedian 6.7 mos (no range given)
Kebudi et al., 200516/1100 (1.4)NRsupratentorial in 11 pts; infratentorial in 3; both in 2single in 8 pts; multiple in 84 (25)12 (75)16 (100)NRfor the pts who died (n = 15), median 2 mos (range 2 days–6 mos); 1 patient was still alive at 20 mos
Bouffet et al., 199712/486 (2.4)Sx in 10 cases, screening in 2supratentorial in 8 pts; infratentorial in 1; both in 3single in 5 pts; multiple in 70 (0)9 (75)10 (83.3)NRfor the pts who died (n = 11) median 3 mos (range 1 day–38 mos); 1 pt was still alive at 6 yrs
Rodriguez-Galindo et al., 19978/44 (18), only 6 described in studySx in 4 cases, screening in 2supratentorial in 4 pts; infratentorial in 1; both in 1single in 3 pts; multiple in 31 (16.7%)4 (67.7)5 (83.4)NRfor the pts who died (n = 5), median 5 mos (range 2–10 mos); 1 pt was still alive at 34 mos
Graus et al., 198331/139 (22.3)Sx in 25 cases; postmortem in 6NRsingle in 7 pts; multiple in 24NRNR30 (96.7)NRnot enough data for a summary
Stefanowicz et al., 201110/511 (2)Sx in 8 cases, screening in 2supratentorial in 10 ptssingle in 5 pts; multiple in 52 (20)7 (70)NRNRnot enough data for a summary
Tasdemiroglu & Patchell, 199712/154 (8); 7 (4.5) parenchymalNRNRsingle in 4 pts; multiple in 3NRNRNRNRmedian 30 days (range 0–363 days)
Parasuraman et al., 199911/335 (3.3) for Ewing sarcoma; 10/419 (2.4) for rhabdomyosarcomaNRNR as a summary, but as case by case w/ incomplete informationsingle in 15 pts; multiple in 161 (4.7)12 (57)NR76.2% ± 9% at 1 yr; 28.6% ± 9.1% at 3 yrsmedian 2.7 mos; 1-yr survival 23.8% ± 8.5%
Weyl-Ben Arush et al., 19956/61 (10)NRNRNRNRNRNRNR9.8 mos (range 2–54 mos)
Vannuci & Baten, 197413/217 (6)Sx in 10 cases, postmortem in 3supratentorial in 13 ptssingle in 4 pts; multiple in 9NRNRNRNRinformation available in 9 cases; median 31.5 days (range 1–600 days)
Marina et al., 199313/254 (5%)Sx in all 13 casesNRNR0 (0)6 (46.1)NRNRmedian 16 mos (range 8–103 mos)
Spunt et al., 200416/206 (8)Sx in 12 cases, screening in 2, postmortem in 2supratentorial in 9 pts; infratentorial in 3; both in 4NR2 (12.5)NR15 (87.5)NRinformation available in 11 cases; for those who died (n = 9), median survival 4 mos (range 0–19); 2 pts still alive (at 4 yrs & 18 yrs)
Postovsky et al., 200318/411 (4)Sx in 18 casessupratentorial in 15 pts; infratentorial in 2; both in 1single in 7 pts; multiple in 110 (0)8 (44.4)13 (72.2)NRmean 5.03 ± 5.8 mos
Paulino et al., 200330/611 (5)Sx in 25 cases, screening in 1 (remainder unavailable)not enough to classifysingle in 18 pts; multiple in 125 (16.7)NR29 (96.7)NRmedian 4 mos (range 1 wk–16 mos); 6-mo survival rate 27%; 1-yr survival rate 11.5%
current series44/3613 (1.2)Sx in 26 cases, screening in 10, findings on other images in 4, no data in 4supratentorial in 30 pts; infratentorial in 4; both in 1for solid brain mets: single in 23 pts; multiple in 16 (where data were available)8 (18)22 (55)39 (95)28 mos (95% CI 20–36 mos)median 8 mos (95% CI 5–10 mos)

Values represent numbers of patients (%) unless otherwise specified. Means are presented with SDs.

Fig. 3.
Fig. 3.

Yearly trends of brain metastasis diagnosis. Data are from The University of Texas M.D. Anderson Cancer Center Tumor Registry, 1990–2012.

The solid primary cancer histologies most commonly reported in the pediatric population are sarcomas, neuroblastomas, nephroblastomas, and germ cell tumors.6 The tendency of these non-CNS primary cancers to metastasize varies among different reports. An earlier study described Wilms tumor as a common precursor to brain tumors.24 No case of brain metastasis in a patient with Wilms tumor was found in our series, which is consistent with the findings of others,1,7 a probable reflection of the effectiveness of chemotherapy against this particular histological type. Graus et al.7 reported a high incidence of brain metastasis for germ cell tumors. We found a brain metastasis incidence of 43% among the patients with choriocarcinoma. Within the sarcoma category, different subhistologies are said to have different predilections for metastasis to the brain. The incidence of brain metastases among various sarcoma subtypes in our series was equally low. In the adult population, melanoma has the highest propensity to metastasize to the brain. In children, melanoma is cited among the primary tumors associated with a relatively higher incidence of metastasis (8% to 18%).3,16,17 In our series, melanoma accounted for 15% of the cases of metastasis, but the overall prevalence of melanoma in our pediatric patient population was only 3%.

Brain metastasis was diagnosed at the same time as the primary cancer in 8 patients (15%), another unusual finding in this study. This frequency is higher than is usually reported in children (5%–10%1) and more similar to that reported in adults. To our knowledge, brain metastasis has rarely been reported as the site of initial presentation of a solid primary cancer in children. In 3 of the 8 cases, the brain symptom was the initial manifestation of the cancer and led to the diagnosis of the brain metastasis and the subsequent prompt establishment of the primary cancer diagnosis. The rest of the patients in our series developed brain metastasis after initiation of treatment for the primary tumor, within a median of 17 months after the primary cancer diagnosis (range 2–77 months). This figure falls within the range of medians from other series (13–22 months).1,4,5,8,27

In 10% of adult patients with a solid primary cancer, the brain is the primary site of systemic metastasis after the diagnosis of the primary cancer.20 In the other 90%, a brain metastasis is preceded by a systemic noncerebral metastasis. Similarly, in the pediatric population, brain metastasis generally follows extensive systemic metastasis and disease progression.1,6–8,14,20 Our results are consistent with these previous findings, but we did find 4 cases (8%) in which the brain was the first site of metastasis after the diagnosis of the primary tumor. Bouffet et al.1 reported 2 patients (17%) in their series of 12 pediatric patients with metastatic brain tumors, in whom the brain was the first and only site of metastasis. It is possible that although systemic chemotherapy effectively suppresses systemic metastases, it is kept out of the CNS by the blood-brain barrier and hence is ineffective in preventing brain metastasis.

Lung cancer, both primary and secondary, is associated with a high incidence of brain metastasis in the adult population, supporting the hypothesis that brain metastasis results from hematogenous spread. Primary lung tumors are rare in pediatric patients, a likely explanation for the lower incidence of brain metastases observed in pediatric patients. However, secondary lung tumors do occur, and these have been reported to be often associated with a brain metastasis.1,4,7,24,25 In our series, as many as 70% of patients had a lung metastasis at the time brain metastasis was found, suggesting a route of transmission similar to that in adults. There was no statistically significant difference relative to tumor histology, possibly owing to the small number of cases in the various histological groups. Although a majority of patients had lung metastasis, one-third or so did not. In their 1983 series on brain metastases in children, Graus et al.7 reported an absence of neuroblastoma cases and attributed this finding to the rarity of pulmonary metastasis from that disease; so did Shaw and Eden18 in their 1992 paper and Westphal et al. in their 2003 paper.26 In our series, among the patients with no pulmonary metastasis, we found 3 instances of brain metastasis from a neuroblastoma primary. Owing to the absence of pulmonary metastasis in that disease, brain metastases from neuroblastoma are rarely parenchymal.8,22 These lesions generally arise from the adjacent bone. Likewise, none of the 3 tumors from a neuroblastoma primary tumor in our series was parenchymal.

Regarding brain metastasis characteristics, the tumors were symptomatic in 65% of patients, and headache, nausea/vomiting, and seizures were the most common symptoms. These symptoms occurred among patients with various tumor histological types and ages at the time of diagnosis of brain metastasis. Our findings with regard to symptoms are similar to those previously published.1,7,8,13,14

About one-third of the instances of brain metastasis were discovered during staging or screening. A few years ago, the rarity of the condition in pediatric patients did not warrant routine surveillance imaging in cases of a solid primary tumor.6 However, the alleged change in the epidemiology toward an increasing trend may have somewhat altered clinical practice. In our series, only 1 of 17 cases of metastasis (in a patient with testicular choriocarcinoma) discovered during screening or staging was from the 1990s. The absence of denominator data, however, does not allow a firm conclusion of a true change in practice in favor of screening for brain metastases.

Overall, 3 patients had LMD as the initial presentation of the brain metastasis. In their series from the University of Iowa Hospitals and Clinics, Paulino et al.14 used lumbar puncture at initial diagnosis to report an LMD incidence of 28.5% in 7 patients with brain metastasis. There was a high prevalence of LMD at autopsy (found in 6 of 7 children). The authors recommended performing a lumbar puncture as well as imaging of the spine in pediatric patients with a diagnosis of a brain metastasis.

The overall prognosis of pediatric patients with brain metastasis is poor because the disease is already very advanced when diagnosed. Treatment only improved survival marginally, with only 2 children in this series surviving beyond 10 years after diagnosis of brain metastasis. The heterogeneity of the patient population and the small number of patients prevent the formulation of definitive recommendations regarding the optimal treatment of brain metastasis in children.

Like all other published series, this series is based on a retrospective review of available patient records and suffers from many of the biases inherent in such reviews, including information and selection biases. It is nevertheless one of the largest, if not the largest, published series on pediatric patients with brain metastases. Another caveat in our series concerns the fact that the most common solid tumor was osteosarcoma. We see a larger number of patients at our institution with pediatric osteosarcoma because of the referral pattern and the institutional expertise with this tumor, thus contributing to its higher incidence. However, in other major published series,1,7,14,24 Ewing sarcoma and soft tissue sarcoma, followed closely by osteosarcoma, are the main primary tumors that metastasize to the brain.

The poor prognosis and possible change in natural history of the condition should be a concern to pediatric oncologists. Some authors have argued in favor of CNS prophylaxis in pediatric patients with solid cancers, especially Ewing sarcoma.11 Their argument is predominantly based on the premise that systemic chemotherapy prevents systemic metastases but is prevented by the bloodbrain barrier from reaching the CNS and protecting it against brain metastasis. Trigg et al.23 reviewed data from National Cancer Institute protocols through July 1980 and compared the incidence of CNS involvement in Ewing sarcoma between 92 patients receiving CNS prophylaxis (WBRT of 2000 rads) and a single dose of intrathecal methotrexate (12 mg/m2) and 62 patients not receiving any CNS prophylaxis. They found no difference between the 2 groups in the incidence of CNS metastasis. More studies to identify new agents that are likely to cross the blood-brain barrier are warranted. Some authors have also argued in favor of routine surveillance in all pediatric patients with a solid primary cancer10 or visceral metastasis.17 Those same authors are skeptical as to whether early detection is likely to impact outcome with the currently available therapies.10 According to Buzaid et al.,2 routine surveillance for brain metastasis may not be warranted in all patients. The authors referred to the rate of false positives obtained with the use of CT as the main reason for not following this practice. Other reasons include the advanced disease status of most patients at brain metastasis diagnosis and the facts that many brain metastases are usually symptomatic and associated with poor outcome regardless of the therapy used.13 In the absence of routine surveillance, changes in neurological status should alert these oncologists to the possible presence of a brain metastasis. Phase II studies of promising new agents in the pediatric population, particularly certain subsets of it, may be warranted.

Conclusions

From the findings of this study of brain metastases in children, we conclude that heightened awareness and prompt diagnosis of the primary cancer increase the chance of its identification before it can disseminate and may result in improved chances of survival by preventing complications such as brain metastasis.3

Acknowledgments

We thank David M. Wildrick, Ph.D., for editorial assistance and Stephanie Jenkins for assistance with manuscript preparation.

Disclosure

This work was supported by financial assistance from the Apache Corporation Brain Tumor Data Management Fund, a donor who had no direct involvement in this study.

Author contributions to the study and manuscript preparation include the following. Conception and design: Suki, Khatua, Sawaya. Acquisition of data: Suki, Khoury Abdulla, Ding. Analysis and interpretation of data: all authors. Drafting the article: Suki. Critically revising the article: all authors. Reviewed submitted version of manuscript: all authors. Approved the final version of the manuscript on behalf of all authors: Suki. Statistical analysis: Suki. Administrative/technical/material support: Sawaya.

Please include this information when citing this paper: published online August 15, 2014; DOI: 10.3171/2014.7.PEDS13318.

References

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Article Information

Address correspondence to: Dima Suki, Ph.D., Department of Neurosurgery, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Unit 442, Houston, TX 77030-4009. email: dsuki@mdanderson.org.

© AANS, except where prohibited by US copyright law.

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    Kaplan-Meier plot of overall survival after primary cancer diagnosis in a series of 54 pediatric patients with brain metastasis from a solid primary cancer.

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    Kaplan-Meier plot of overall survival after diagnosis of brain metastasis in a series of 54 pediatric patients with brain metastasis from a solid primary cancer.

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    Yearly trends of brain metastasis diagnosis. Data are from The University of Texas M.D. Anderson Cancer Center Tumor Registry, 1990–2012.

References

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