Brain tumors of infancy--an institutional experience and review of the literature.

Original Paper Pediatr Neurosurg 2013;49:145–154 DOI: 10.1159/000358308

Received: January 28, 2013 Accepted after revision: December 31, 2013 Published online: March 22, 2014

Brain Tumors of Infancy – An Institutional Experience and Review of the Literature Chandan B. Mohanty Dhaval P. Shukla B. Indira Devi Department of Neurosurgery, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India

Abstract Introduction: Brain tumors in infants are rare and form a distinct subgroup of pediatric brain tumors. These tumors differ from tumors in older children with respect to histology and management and tend to have a poorer outcome. Methods: We analyzed 31 consecutive cases of brain tumors in infancy managed in our institute in the last 15 years and reviewed the published literature since 1990. Results: Only 2 of these patients had congenital tumors. Choroid plexus tumors were the most common histological subtype, followed by medulloblastoma; 62% of patients underwent a gross total or neartotal excision of the tumor with 1 perioperative mortality; 68% of patients had a good outcome. Conclusion: Choroid plexus tumors were the most common histological type. Safe resection should be the goal of surgery. Surgeries for tumors in this age group were associated with lower rates of total excision and higher morbidity. Low-grade lesions as expected are associated with longer survival; however, long-term outcomes are far from satisfactory. © 2014 S. Karger AG, Basel

© 2014 S. Karger AG, Basel 1016–2291/14/0493–0145$39.50/0 E-Mail [email protected] www.karger.com/pne

Introduction

Childhood brain tumors present a unique challenge to a neurosurgeon. Amongst these, brain tumors of infancy, i.e. tumors in children less than 1 year of age, form a distinct group. The incidence of infantile tumors constitutes 1.4–18% of all brain tumors occurring in children [1]. Intracranial tumors are the most common malignancy second to neuroblastoma in infancy and hematological malignancy in children [2]. Incidence of brain tumors in infancy is about 1.1 per 100,000 live births [2]. In stark contrast to other systemic malignancies, brain tumors have shown an increasing incidence in infants in the last 2 decades. These tumors differ in their location, histological type, treatment, and amenability to adjuvant therapy and have a worse overall outcome with respect to tumors occurring in other age groups. Brain tumors in infancy are also unique since there is a minimal time of exposure to exogenous factors and thus there may be a possible role of genetic predisposition in the causation of these tumors. We report our experience in dealing with these rare tumors and review all literature published since 1990.

Dr. B. Indira Devi Professor, Department of Neurosurgery National Institute of Mental Health and Neurosciences (NIMHANS) Bangalore 560029 (India) E-Mail bidevidr @ gmail.com

Downloaded by: University of Aberdeen139.133.11.3 - 10/4/2014 7:10:24 AM

Key Words Intracranial tumors · Brain tumors · Infants · Congenital tumors · Neoplasms · Choroid plexus papilloma · Medulloblastoma

Case records of all patients less than 1 year of age diagnosed with brain tumors and treated in our institute in the last 15 years (1997–2011) were retrospectively reviewed. Demographic patterns presenting complaints, management modality, radiological and histological features, and outcome at the time of follow-up were analyzed. Congenital tumors were defined as tumors diagnosed antenatally or at less than 4 weeks of age [3, 4].

Results

Demographic Pattern A review of the records revealed that a total of 31 patients were operated on during this period. This included 18 males and 13 females with a mean age of 6.9 months. None of the mothers had been exposed to possible predisposing factors like viral infections, prolonged unexplained bouts of fever, exposure to radiation or any other teratogenic agents. No family history of any malignancy was found. None of the patients had any congenital anomalies. See table 1 for a summary of all cases. Clinical Features Raised ICP features like increasing head size and persistent vomiting constituted the most common clinical features affecting 24 infants. Seizures were uncommon, occurring in only 3 patients; 2 patients had congenital tumors: 1 had an embryonal rhabdomyosarcoma of the right supraorbital rim with cerebellar metastasis and the other had a posterior third ventricular teratoma (patient 9). The patient with embryonal rhabdomyosarcoma was diagnosed with the tumor at birth, underwent excision of the supraorbital growth elsewhere and then referred to us for the management of the cerebellar metastasis with hydrocephalus (patient 22). The patient was already on chemotherapy, hence underwent a VP shunt for the accompanying hydrocephalus and was planned for serial imaging but was lost to follow-up. The patient with posterior third ventricular teratoma was diagnosed in the third trimester and underwent excision at 1 month of age. The child is doing well at followup without any evidence of tumor recurrence. Location Supratentorial tumors were seen in 18 patients while infratentorial tumors were seen in the remaining 13 patients. Intraventricular (mainly the lateral ventricle) was the most common site of tumor followed by the vermis. The location and radiological appearance varied in view of the different histology of the tumors. 146

Pediatr Neurosurg 2013;49:145–154 DOI: 10.1159/000358308

Management Overall, 31 patients underwent a total of 46 surgical procedures. As a policy, the goal of surgical management was to achieve a safe resection. Most of the tumors could be resected completely. Gross total resection was achieved in 11/29, while near-total resection was done in 7 patients; 11 patients underwent a subtotal resection while 4 patients underwent an endoscopic third ventriculostomy and biopsy. Only 1 patient (patient 6) needed a staged surgery. The patient had a choroid plexus papilloma (CPP) and surgery had to be abandoned in view of severe intraoperative blood loss. The patient was re-explored after being stabilized and a near-total excision could be achieved. Thus 62% patients had a total or near-total excision. Preoperative shunt was performed in 8 patients, while 2 patients had shunt by the time of first follow-up. Shunt revision was performed in 2 patients. Duration of surgery ranged from 45–400 min which included shunt surgery. The mean duration for tumor excision surgery was about 218 min (excluding patients undergoing only shunt surgery). Blood loss ranged from 150–800 ml, mean blood loss being 326 ml (excluding endoscopic procedures and shunt surgery where the blood loss was minimal). Histopathology Choroid plexus tumors were the most common tumors. Out of the 12 choroid plexus tumors, 8 were CPP with 2 cases each of atypical choroid plexus tumor and choroid plexus carcinoma (CPC). Medulloblastoma with extensive nodularity (MBEN) was the next most common subtype. Complications There was 1 perioperative mortality where a patient developed cardiorespiratory arrest 16 h after surgery (case of primitive neuroectodermal tumor, PNET); 1 patient developed intraoperative hypotension (choroid plexus tumor) because of which the procedure was abandoned and the patient was operated on at a later date. Near total excision was achieved at the time of second surgery. Adjuvant Therapy In cases of residual in high-grade tumor, chemotherapy is usually added. Low-grade tumors are usually monitored with serial imaging and in the presence of new symptoms or radiological evidence of growth can be resected. The treatment was individualized. Chemotherapy was instituted after discussion with our medical oncology colleagues. Typically, chemotherapy was started Mohanty/Shukla/Devi


Materials and Methods

Serial Age/sex/ No. weight

Symptoms

Location/diagnosis

Management/duration of surgery/blood loss

Follow-up duration/outcome

1

5/F/4.2

diencephalic syndrome

thalamus/pilocytic astrocytoma

ETV + biopsy/120/–

3/delayed milestones

2

5/M/4.9

raised ICP

vermian/MBEN

pre-op VPS (poor sensorium, underweight, anemic) + NTR/200/200

6/shunt infection, shunt removed

3

10/M/6.3

raised ICP

vermian/MBEN

pre-op VPS (poor sensorium, hyponatremia, underweight, anemic ) + STR/400/700

–

4

9/F/6.1

seizures

temporal/DIG

STR/220/150

6/doing well

5

12/F/7.6

neurological deficit

thalamus, basal ganglia/ pilomyxoid astrocytoma

STR/240/600

13/worsening of hemiparesis

6

8/F/7

raised ICP

lateral ventricle/choroid plexus carcinoma

initially STR due to excessive blood loss/300/800 3/doing well postop pneumocephalus treated with tapping; underwent re-exploration after 10 days and NTR/200/250

7

7/M/5.9

raised ICP

trigonal/CPP

pre-op VPS (anemic, underweight) + GTR/330/300 after 3 months patient developed bilateral subdural hygroma for which VPS removed

87/II

8

11/M/7.8

raised ICP

frontal/PNET

GTR/80/200

died on 1st postoperative day

9

1/F/2.1

raised ICP

3rd ventricular/teratoma

GTR/20/150

74/I

10

9/M/6.8

raised ICP

lateral ventricle/CPP

GTR/00/200

–

regression of motor milestones

vermian/MBEN

pre-op VPS (comatose, hydrocephalic attacks, underweight, anemic) + NTR/270/200

6/received CT, doing well

11

12/F/6.9

12

5/M/5.3

raised ICP

CP angle/CPP

pre-op VPS (anemic, underweight) + STR/200/180

8/delayed milestones

13

5/M/5.8

seizures

temporal/glioblastoma

NTR/180/150

10/recurrent seizures, received CT, died after 10 months

14

2/M/5.2

raised ICP

trigonal/CPP

endoscopic septostomy, placement of VPS and GTR/330/700 intra-op hypotension due to bleeding

8/doing well

15

6/M/4.4

raised ICP

vermian/MBEN

pre-op VPS (poor sensorium, underweight, anemic) + NTR/270/300

10/doing well

16

3/M/4.4

raised ICP

tectum/pilocytic astrocytoma

ETV + biopsy/90/–

82/I

17

10/M/7.5

raised ICP

thalamus/anaplastic astrocytoma

endoscopic placement of shunt + biopsy/60/– shunt malfunction after 5 years, underwent shunt revision

120/defaulted adjuvant therapy after first surgery, completed RT at the age of 5 years; IV

18

10/F/7.1

raised ICP

tectal/anaplastic astrocytoma

ETV + biopsy/60/– wound dehiscence treated with resuturing

6/doing well

19

6/F/5.7

raised ICP

3rd ventricle/CPP

pre-op VPS (poor sensorium, anemic, hyponatremia) + GTR/300/300 subdural collection treated by subduroperitoneal shunt

105/I

20

3/M/4.8

raised ICP


GTR/300/250 hydrocephalus treated with VPS

127/IV

21

6/F/7.4

raised ICP

lateral ventricle/atypical CPP

STR/150/200

4/developed ventriculitis, treated with antibiotics

22

1/M/3.1

raised ICP

cerebellar hemisphere/orbital rhabdomyosarcoma with cerebellar metastasis

VPS/45/–

2/undergoing CT, doing well

Brain Tumors of Infancy


147


Table 1. Summary of the cases

Table 1. (continued) Serial Age/sex/ No. weight

Symptoms

Location/diagnosis

Management/duration of surgery/blood loss

Follow-up duration/outcome

23

8/F/8.3

raised ICP


GTR/270/200

12/doing well

24

6/M/6.8

raised ICP

trigonal/CPP

GTR/240/600

6/doing well

25

9/F/8.8

raised ICP

vermian/CPC

STR/150/300

5/CT refused by parents, doing well

26

3/M/6.9

seizures

frontoparietal/anaplastic ependymoma

NTR/180/150

–

27

12/M/8.1

raised ICP

lateral ventricle/atypical CPP

GTR/180/200

3/doing well

28

3/M/5.7

raised ICP

vermian/Mb

NTR/180/200

–

29

6/M/7.5

raised ICP

vermian/no histology

VPS (parents wish)/45/–

–

30

11/F/8.9

raised ICP

fourth ventricular/ATRT

STR/300/600 persistent postop hydrocephalus treated with VPS

3/doing well, undergoing CT

31

11/M/9.1

neurological deficit

frontoparietal/PNET

GTR/210/200

4/doing well, undergoing CT

Age is expressed in months, weight in kilograms, duration of surgery in minutes, blood loss in milliliters, and follow-up duration in months. ATRT = Atypical teratoid rhabdoid tumor; CT = chemotherapy; DIG = desmoplastic infantile ganglioglioma; ETV = endoscopic 3rd ventriculostomy; GTR = gross total resection; NTR = near-total resection; STR = subtotal resection; VPS = ventriculoperitoneal shunt – the reason for shunt surgery is mentioned in brackets.

Outcome Out of the 25 patients for whom follow-up was available, 1 patient had expired 10 months after surgery (histopathology – glioblastoma). Outcome at follow-up was divided into short-term (5 years, n = 6). The range of follow-up was 2–127 months with a median follow-up of 6 months. Of the patients with short-term follow-up, 13 patients were asymptomatic without deficits, 2 had delayed milestones, 2 had infection and 1 patient had residual hemiparesis. Long-term outcome (follow-up >5 years) was assessed as per the following score: I – Going to school, performance comparable to peers (n = 3) II – Going to school, but performance inferior (n = 1) 148


III – Special school (for disabled, mentally, physically challenged) IV – Not going to school, independent for ADL (n = 2) V – Dependent on ADL VI – Dead Thus, out of 25 available patients, 17 (68%) had a good outcome while 8 (32%) had a poor outcome (table 1).

Discussion

Incidence The incidence of brain tumors in infants is about 1.3– 11% [5]. Brain tumors of infancy constitute up to 1/6 of all brain tumors in the pediatric age group, ranging from 3.6– 18% of all pediatric brain tumors [6, 7]. Tumors in this age group have been reported to have an equal incidence in males and females in contrast to male predominance seen in older children [6]. True incidence of these tumors can be ascertained only in a detailed study where they are diagnosed in a well-defined population with histological confirmation or even confirmation at the time of postmortem. Such detailed studies are lacking and most of our data are based on studies carried out in small population groups. See table 2 for a review of the published literature since 1990. Mohanty/Shukla/Devi


2–4 weeks after surgery and was dependent on the physical status of the patient and evaluation by the medical oncologist. Out of the 15 patients with high-grade tumors, only 5 patients received chemotherapy while 1 patient, who defaulted on adjuvant therapy initially, received radiotherapy (RT) at the age of 5 years. The remaining 9 patients either defaulted or refused adjuvant therapy.

Table 2. Review of published literature since 1990 Author, year

Number of Commonest Commonest patients clinical features histology subtype

Gross total and near-total resection

Oi et al. [1], 1990

307

raised ICP

astrocytomas = 23.3% MB = 17.2%

Di Rocco et al. [6], 1991

886

raised ICP

astrocytomas = 28.7% MB, ependymomas = 11.5% each

7

raised ICP

PNET = 42.9% astrocytomas = 28.6%

Tewari et al. [11], 1994 (only supratentorial tumors)

14

raised ICP

Rickert et al. [3], 1997

22

Chung et al. [5], 1998

–

Adjuvant therapy

55/307 (21.7%)

RT = 110 (32.6%) CT = 41 (15.6%) RT + CT = 9.9%

–

CT = 119 (17%) RT = 129 (18%)

0 (0%)

2/7 (28.6%)

CT = 1 (14.3%)

astrocytomas = 50%

7 (50%)

8/14 (57%)

CT = 5 (36%) CT + RT = 1 (7%)

–

PNET = 27% astrocytomas = 23%

–

–

–

21

raised ICP

astrocytomas, PNET, MB = 14.3% each

8 (38%)

2/21 (9.5%)

CT = 5 (24%) RT + CT = 2 (9%) RT = 3 (14%)

Kane et al. [22], 1999

75

raised ICP

astrocytomas = 27% MB, choroid plexus tumor = 10.7% each

22 (33%)

5/66 (7.6%)

CT = 26 (34%) RT = 13 (17%)

Rivera-Luna et al. [8], 2003

61

irritability

astrocytomas = 36% ependymomas = 19%

20 (33%)

16/61 (26.2%)

CT = 7 (11%) RT = 8 (13%)

Young et al. [12], 2004

16

raised ICP

low-grade astrocytomas = 50% high-grade astrocytomas = 12.5%

1 (6%)

1/14 (7%)

Mehrotra et al. [2], 2009

18

–

astrocytomas = 22% PNET = 22%

8 (44%)

3/18 (16.7%)

CT = 8 (44%) RT = 3 (17%)

El-Gaidi et al. [14], 2010

21

raised ICP

choroid plexus tumor = 28.5% teratomas = 19%

13 (65%)

3/21 (14%)

CT = 3 (15%)

Jaing et al. [40], 2011

22

raised ICP and seizures

astrocytomas, MB = 18% each

11 (50%)

3/22 (13.6%)

CT = 3 (14%) CT + RT = 1 (4%)

Current study

31

raised ICP

choroid plexus tumor = 40% MB = 16.7%

18 (62%)

1/31 (3.2%)

CT = 5 (16.1%) delayed RT = 1 (3.2%)

Mapstone et al. [13], 1991

389 (44%)

Operative/ perioperative mortality

CT = Chemotherapy; MB = medulloblastoma.

Location Supratentorial tumors are more common in infants than infratentorial tumors, in stark contrast to older children where infratentorial tumors are more common. A cooperative study by the International Society of Pediatric Neurosurgery reported the incidence of supratentorial tumors to be 65.4% [6]. A recent review of infantile brain tumors revealed that 66.1% of tumors in infants are supratentorial [7]. In the present series, 58% of patients had supratentorial tumors, and the lateral ventricle was the most common location. This is due to the high incidence of choroid plexus tumors in the pres-

ent series. Supratentorial tumors are more commonly benign in contrast to infratentorial tumors which are malignant more than 50% of the time [8].



149


Clinical Features Increasing head size due to raised ICP was the most common presenting feature in more than 50% of infants [7], which was also corroborated in the present series (83%). Seizures were the next most common symptom, affecting 5–25% of patients in the literature [7] and 9.7% of cases in the current series.

Histology Choroid plexus tumors were the most common tumors in the current study, followed by MBEN. A large number of cases in the present series were benign in nature. However, most of the literature shows that astrocytic tumors are the most common histological subtype, followed by medulloblastoma and ependymomas [6, 7]. Notable exceptions are the series of Rickert et al. [3] and 150


Mapstone and Warf [13], where PNET was the most common tumor followed by astrocytomas. This difference is important to note since these affect the overall patient outcome and survival in the present study. There is also a difference in tumor histology with respect to geography. Interested readers are directed to an excellent review by Rickert et al. [3] dealing with this topic published in 1997. It was shown by these authors that the most common tumor in Europe, USA, Canada, Mexico, Argentina, Japan and the Far East was astrocytoma. Reports published after 1997 showed a similar incidence (table 2). Interestingly, the most common subtype in Rickert et al. [3] itself is PNET. It can also be seen that medulloblastoma and teratomas were common in the Far East compared to other places [1]. The only reported series from Egypt [14] and Saudi Arabia [15] showed choroid plexus tumors and medulloblastoma as the most common subtypes, respectively. The commonest subtypes in a paper from Korea were PNET, medulloblastoma and astrocytoma (equal incidence) [5]. A previously published report from India, which included supratentorial tumors only, showed astrocytoma as the commonest subtype [11], while choroid plexus tumors were the commonest subtype in the present paper. These differences are not surprising because since the effect of exogenous factors in the causation of brain tumors is minimal in this age-group, racial factors may play an important role. The difference in tumor histology may also be due to a possible referral bias, where benign tumors are more commonly referred. Many a time, when radiological study clearly depicts the malignant nature of the disease, the decision of not going ahead with surgery is taken by parents. The current study is also noteworthy in view of the high incidence of MBEN. MBEN is a subtype afflicting very young children and is known to be associated with a better prognosis than other subtypes of medulloblastomas [16]. Adjuvant Therapy The deleterious effects of radiation on the growing brain of an infant are well known and hence RT is avoided in children less than 3 years. In spite of this about 5–39% of patients in this age group have received RT as stated in the literature, while 4–44% of patients have received chemotherapy [2, 7]. However, a definite pattern is evident from table 2, where the use of RT has decreased in the recently published papers. Multiple treatment strategies have been employed as per chemosensitivity or radiosensitivity of the tumor. Not surprisingly, Mohanty/Shukla/Devi


Surgery and Complications In the study by the International Society of Pediatric Neurosurgery, about 40% of the cases (250/574) for whom data was available underwent CSF diversion [6]. About 51.6% of patients in the current study underwent CSF diversion, either as a part of treatment or as the only treatment. Shunt was carried out more often in the present study since these patients were in poor general health (underweight, anemic, deranged biochemical parameters) or presented to the emergency department in altered sensorium or due to parents’ wishes (when shunt was the only procedure done). A total of 29 out of 31 patients underwent tumor excision/biopsy, and 62% underwent a gross total or near-total excision of the tumor. Complete resection has been achieved in 6–65% of cases reported in the literature (table 2) and in 43.9% of cases in the ISPN survey [6]. The high incidence of total resection in the present series is due to the high proportion of choroid plexus tumors, where the tumors have a good plane and resection is possible after the vascular pedicle is visualized. Operative and perioperative mortality varied, ranging from no mortality as reported by Haddad et al. [9] to 33% as reported by Jooma et al. [10]. Tewari et al. [11] reported a mortality of 57%, though this series included only supratentorial tumors. Surgical mortality is lower in the current series, which may be due to the high incidence of benign tumors in the present series. Such low mortality was also a feature of the series reported by Young and Johnston [12], which also had a high incidence of low-grade tumors. Unfortunately, surgical complications have not been reported in detail in the literature. One of the recent series reported infection in 2/18 cases, persistent or new onset seizures in 8/18 cases and worsened neurological status in 1 patient, while 1 patient developed bilateral radiation-induced cataract [2]. It is surprising that parameters like blood loss and duration of surgery, which are especially important in this age group and may have a role in the perioperative period and in the overall outcome, have not been studied in detail in the literature.

Outcome The extent of surgical resection has an important effect on survival. Complete resection provides the best possible outcome in terms of survival [8, 13]. Diseasefree survival rate of 62 and 26% was reported with complete resection and subtotal resection, respectively [8]. Tumor histology and the degree of tumor resection have a significant effect on survival and long-term outcome [2, 8, 18]. Some authors have reported a better outcome with supratentorial location of tumors compared to infratentorial tumors [2, 13]. Patients receiving adjuvant therapy have a better long-term survival [2, 19], though secondary malignancies are also known in long-term survival [20, 21]. The 1- and 5-year survival rates ranges were 45–85% and 21–81%, respectively [7]. The overall 5-year survival reported by Young and Johnston [12] was 81%, while the 5-year survival for benign tumors was 100%. Supratentorial tumors are known to have a poorer long-term outcome in terms of cognitive development and postoperative seizures. Unfortunately, the quality of life parameters are difficult to evaluate in pediatric patients. The Karnofsky performance scale has been used widely to report the functional outcome at follow-up [2, 5], though other scales were used to measure the ability to cope in school [22]; 50% of the children in the reported series were able to attend mainstream school, while 25% required special help and the remaining 25% required special school. We too find this system for assessing long-term outcome more suitable in school-going children, and have used this scale with some modification. Young and Johnston [12] noted surgical morbidity of 54% in their series. They observed new postoperative seizures in 6 patients and 6 patients developed new neurological deficits following surgery; 14 patients underwent surgery in this series. Of the 473 survivors in the ISPN study, only 12.6% were described as ‘normal’, while psychomotor retardation was seen in 26.8%, neurological deficits in 37.8% and persistent seizures in 14.4% [6]. Brain Tumors of Infancy

Table 3. Compilation of tumor-specific management of all studies published since 1990 Total cases

Astrocytoma Malignant gliomas 559 MB 225 Choroid plexus tumor 204 CPP 2 ACPP 19 CPC

GTR NTR STR CSF RT CT diversion only

1 6

– 0

1 2

1 0

5 2 1

0 0 1

3 0 2

0 0 0

41 23 26 39 4 0 4

4 0 4

ACPP = Atypical CPP; CPC = choroid plexus carcinoma; MB = medulloblastoma; CT = chemotherapy; GTR = gross total resection; NTR = near-total resection; STR = subtotal resection; RT = radiotherapy; VPS = ventriculoperitoneal shunt.

Management of Specific Tumor Subtypes Surprisingly, there were no studies dedicated to evaluating the management of specific tumor subtypes in infants. Hence, we have reviewed the management of specific tumor subtypes. It should be kept in mind that in many studies, children less than 2 or 3 years of age were included instead of less than 1 year, thus making direct extrapolation of results difficult [17, 23–26]. We have combined the results of all the studies listed in table 2 and listed the treatment strategies employed for the 3 most common tumor subtypes (table 3). The low numbers are striking and also testify to the point made earlier that literature supporting management strategies is scarce. The low numbers are due to the fact that most studies have not discussed the treatment individually based on histology [1, 3, 5, 8, 11, 22]. Choroid Plexus Tumors Choroid plexus tumors are of 3 subtypes, namely CPP, atypical CPP and CPC. These tumors are more commonly seen in the neonatal age group and in the first 6 months of infancy. Astrocytomas are more commonly seen in the latter 6 months of infancy. CPP can also be seen in association with Li-Fraumeni and Aicardi syndromes. Other implicated factors in the pathogenesis of these tumors are upregulation of the TWIST-1 factor, Notch3 gene and the role of JC, SV 40 and BK virus [27, 28]. Choroid plexus tumors are typically located in the lateral ventricles. Hence macrocephaly and raised ICP features are the most common clinical presentation. The malignant subtype, namely the CPC, is more heterogePediatr Neurosurg 2013;49:145–154 DOI: 10.1159/000358308

151


the results are extremely variable in the absence of a standard protocol and superiority of one treatment modality over another. Strategies like ‘HTT-SKK’ (use of high-dose systemic methotrexate with intraventricular methotrexate), high-dose myeloablative chemotherapy with autologous stem cell rescue, low-dose radiation with a tumor bed boost, or use of conformal RT have been employed to avoid the adverse effects of conventional RT [17].

Medulloblastomas Medulloblastomas are the most common posterior fossa tumors. They can occur in association with syndromes like Gorlin syndrome, Li-Fraumeni syndrome and Cowden syndrome. WHO classifies these tumors as classical, large cell, anaplastic, nodular desmoplastic and MBEN. Newer molecular classification, which is prognostically more important, divides them into wingless, sonic hedgehog, group 3 and group 4 [33]. CSF dissemination is seen in about 30% of patients. Hence a preoperative contrast-enhanced MRI of the entire neuraxis is 152


essential. Surgical resection is the primary treatment modality. In the current series 5 patients had MBEN. Many multicenter trials have looked at the results of adjuvant therapy in the treatment of medulloblastomas in infants. Some of the notable trials were Baby POG (Pediatric Oncology Group), CCG (Children’s Cancer Group), BB SPOF (Baby Brain Society of Pediatric Oncology), GPOH (German Society of Pediatric Oncology and Hematology), Head Start I and II and P9934 [17]. The underlying idea of all these trials was to use RT as a salvage treatment or delayed adjuvant for residual disease and to use chemotherapy as a mainstay adjuvant treatment. The P9934 trial was different from the other trials since it instituted early adjuvant focal RT. The Head Start trial studied the role of high-dose chemotherapy with autologous stem cell transplantation. The main drawback of all these studies was the small sample size (21–92 patients) and the varying treatment modalities which were employed. No single treatment protocol has shown a clearly superior survival or cognitive outcome [17]. Histology, residual disease and metastatic disease are other important factors determining outcome. It is being increasingly realized that molecular characteristics of medulloblastomas are important in formulating treatment. Group 3 has the worst prognosis and wingless group has the best prognosis. Thus, it is our opinion that the results of the older trials may no longer be valid for infants with medulloblastomas in view of the results of their molecular characteristics. Newer trials needs to be initiated to determine the best adjuvant therapy for medulloblastomas based on molecular classification. Astrocytomas Malignant gliomas include anaplastic astrocytomas, glioblastomas or mixed tumors with a high-grade astrocytic component. Interestingly, infants with high-grade gliomas or diffuse brainstem tumors have a better prognosis compared to older patients [23, 34]. None of the factors such as symptom duration, patient age, degree of resection, radiation dose and degree of anaplasia, which are important prognostic factors in adults or older children, are important in infants [23]. Some of the peculiar features in infantile astrocytomas are lower incidence of p53 mutations [35], lower incidence of isocitrate dehydrogenase mutation (young pediatric age group in general) [35, 36], higher incidence of allelic loss on 17p (young pediatric age group in general) [36], and NF-1 Ras activation in causing optic pathway gliomas (young pediatric age group in general) [37]. However, it may not be correct to extrapolate these data to infants. Peculiarities Mohanty/Shukla/Devi


neous in nature, with signs of brain infiltration. Typically they have less hydrocephalus than CPP but have associated vasogenic edema. CPP has the best prognosis amongst all brain tumors in infancy [29]. No study has specifically studied the prognosis of various management modalities in infants. The recommendations are from studies in adults and young children. Total surgical excision of CPP is usually curative. Malignant transformation of incompletely resected CPP has also been reported [30]. However, a ‘wait and watch’ policy for a residual CPP is reasonable. Adjuvant therapy is not recommended in CPP [29]. In our experience, this policy is applicable to infants as well. All the infants with CPP in the current series were treated with surgery only. On the other hand, following complete CPC resection, RT is usually recommended in young children. Residual CPC should be reoperated on if it does not involve the eloquent area, since complete surgical excision has the maximum survival benefit. In our opinion this is a potential grey area, since RT is not recommended in infants. Repeat surgery and CT are reasonable options for management of residual CPC in infants until they attain 3 years of age, after which RT can be employed. The impact of chemotherapy on long-term survival is still missing. Atypical CPP is a histological diagnosis characterized by two or more mitoses per 10 HPF [31]. About 15% of previously diagnosed CPP cases have now been diagnosed as atypical CPP. In the present series we had 2 patients with atypical CPP, both of which were managed with periodic surveillance after surgical resection, since the efficacy of chemotherapy is unknown with these types of tumors. However, the follow-up duration is short for both these patients. As stated earlier, there is no paper investigating treatment options for atypical CPP in infants. Authors in one of the case reports have in fact suggested that atypical CPP should be considered as CPC and treated the patient with chemotherapy [32].

of infantile astrocytomas can be further understood by case reports of cure with chemotherapy alone in patients with high-grade glioma [19], the spontaneous regression of diffuse pontine glioma [38] and the differentiation of high-grade glioma into pilocytic astrocytoma [39]. In the National Cancer Institute’s Surveillance, Epidemiology, and End Results study comprising 242 patients with gliomas in children less than 1 year of age, 188 patients had astrocytomas, with cerebrum and brainstem being the most common sites [34]. Only 12% (n = 30) in this report underwent a gross total resection and 10-year survival was 59 ± 3.6%. Survival in patients less than 1 year was significantly lower compared to patients in the age groups of 1–3 and 3–5 years. Surgery other than gross total resection and high-grade tumor were the most important adverse prognostic factors. Interestingly, brainstem gliomas had the best prognosis in patients less than 1 year of age compared to other age groups; 12% of patients underwent RT but no information was available regarding the use of chemotherapy [34].

Future Directions and Conclusion

There is surprisingly sparse literature on the management of brain tumors in infancy. Future prospective studies will need to be more thorough in reporting these cases. This is important since the biological behavior of tumors will be better understood in the future and future trials will have to take this into consideration, especially in regard to medulloblastoma. In the present study, choroid plexus tumors were the most common histological type. Surgeries for tumors in this age group were associated with lower rates of total excision and higher morbidity. Low-grade lesions as expected are associated with longer survival; however, longterm outcomes are far from satisfactory. Safe and complete resection should be the goal of surgery. These tumors need to be dealt with in a center where the necessary expertise exists and the treatment needs to be individualized since definite guidelines for the management of these tumors is lacking.

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