Introduction
Medulloblastomas are the most common malignant brain tumors in children, comprising
10% of all pediatric brain tumors.[1]
[2] They are highly malignant and often recur even after appropriate treatment.
Among areas of recurrence, the subfrontal area is relatively rare. Certain factors
have been postulated to increase the risk for this type of tumor spread: prone position,
inadequate irradiation of the cribriform plate area, management of hydrocephalus,
adverse histopathologic, immunohistochemical, and/or molecular profile. We herein
present a case of pediatric subfrontal recurrence and analyze similar cases identified
in the literature, focusing on the commonly described risk factors for subfrontal
recurrence.[3]
Case History
An 8-year-old boy presented with a space-occupying lesion in the subfrontal area.
The mass was identified on scheduled follow-up screening and the patient had no symptoms
or change in clinical status.
At the age of 4 years, the patient was diagnosed with a medulloblastoma of the fourth
ventricle, for which he underwent surgery followed by chemotherapy, radiation therapy,
and proton beam therapy. At the time of surgery, a right-sided ventriculoperitoneal
shunt was placed and the pressure was set at 7 cm of H2O. The patient is on levetiracetam following an episode of status epilepticus 5 months
before the current presentation.
On physical exam, there is postural and gait instability, a 4/5 left-sided hemiparesis,
dysarthria, and psychomotor retardation. More specifically, the patient is able to
stand, but walks with support, and he is able to feed himself, but has difficulty
drawing and writing. The onset of all neurological deficits can be traced back to
the postoperative period.
A right frontal craniotomy was performed and the tumor was resected to macroscopic
clear margins ([Figs. 1]–[2]). The intraoperative blood loss was as little as 70 mL. The course of the operation
was uneventful. The patient was then admitted to the pediatric intensive care unit
(ICU), where he stayed for 6 days and no adverse events were reported other than delayed
awakening. At the time of discharge from the ICU, the patient was alert and able to
move all four limbs against gravity. No new neurological deficits or clinical deterioration
were noted.
Fig. 1 Preoperative magnetic resonance imaging scans—axial view.
Fig. 2 Preoperative magnetic resonance imaging scans—coronal view.
The pathology report confirmed that the tumor was a medulloblastoma and its molecular
profile is currently under investigation.
Upon the first postoperative imaging, a small residual lesion was noted on the temporal
neocortex and there were no other lesions across the neuraxis ([Fig. 3]). The patient then received adjuvant radiation therapy in the form of simultaneous
boost-volumetric modulated arc therapy. A dose of 39.6 Gy was administered for the
tumor bed and 50.6 Gy in the area of the residual tumor. The patient underwent a total
of 22 sessions. Post radiation magnetic resonance imaging) showed near-total tumor
recess ([Figs. 4], [5]).
Fig. 3 First postoperative magnetic resonance imaging scans.
Fig. 4 Postradiation magnetic resonance imaging scans—axial view.
Fig. 5 Postradiation magnetic resonance imaging scans—coronal view.
For the purpose of long-term follow-up, the patient was referred to the Pediatric
Oncologic Department of our institution.
Discussion
Literature Review Strategy
A literature search was performed on PubMed, Web-Of-Science, and Ovid, using the search
terms “Subfrontal recurrence,” “Medulloblastoma,” and “Child.” The search was last
performed on August 10, 2021, and the Preferred Reporting Items for Systematic Reviews
and Meta-Analyses (PRISMA) 2009 flow diagram was used to graphically present the study
selection process.[4] The included studies were critically appraised using the Joanna Briggs Institute
critical appraisal tools: Checklist for Case Series[5] and Checklist for Case Reports.[6] The Risk-of-bias VISualization tool[7] was then used to generate traffic light plots. The extracted data for individual
patients is presented in tabular form. Patient data was additionally analyzed with
respect to the most prominent risk factors for medulloblastoma recurrence described
in the literature: degree of resection; local relapse; prone position during surgery,
and/or radiation therapy; type of radiation therapy received; adequacy of irradiation
of the subfrontal area; management of perioperative hydrocephalus; histopathologic
characteristics; immunohistochemical profile. The results of our analysis are presented
in the form of pie charts.
Summary of Literature Review Results
The initial search returned a total of 10 results, out of which 8 articles referring
to data on patients with subfrontal medulloblastoma recurrence were chosen for further
analysis. Four additional articles were later identified by handsearching. A detailed
flowchart of the study selection process can be seen in [Fig. 6]. [Fig. 7] graphically presents the results of quality assessment.
Fig. 6 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flowchart.
Fig. 7 Quality assessment using the Joanna Briggs Institute critical appraisal tools.
Patient data, including demographics, treatment of the primary tumor, recurrence interval,
location of recurrence(s), treatment of recurrent lesion(s), and patient outcomes
after management of one or more recurrences are presented in [Table 1].[8]
[9]
[10]
[11]
[12]
[13]
[14]
[15]
[16]
[17]
[18]
[19]
[Table 2]
[8]
[9]
[10]
[11]
[12]
[13]
[14]
[15]
[16]
[17]
[18]
[19] summarizes the predisposing factors per patient, namely the presence of a local
relapse, prone position during surgery and/or radiation therapy, inadequate irradiation
of the cribriform plate area (as reported by the authors of each included article),
shunt placement for the management of perioperative hydrocephalus, as well as histopathologic
and immunohistochemical characteristics of the tumor.
Table 1
Summary of similar cases described in the literature
|
Name of study
|
Number of cases
|
Patient demographics
|
Treatment of primary tumor
|
Recurrence interval
|
Location of recurrence
|
Treatment of recurrence
|
Outcomes
|
|
Hardy et al 1978[8]
|
3
|
M, 11 yo
|
PR, CSI
|
13 mo, 9 mo
|
Subfrontal region
Atypical cells in the CSF and bulbar involvement
|
GTR, CT (IT methotrexate, IV vincristine)
|
Uneventful recovery, no new neurological deficits
Death 2 months after second recurrence
|
|
M, 12 yo
|
GTR, CSI
|
17 mo
|
Subfrontal region
|
CT (PO CCNU, IV vincristine), RT (frontal lobes)
Followed 5 months later by: GTR, CT (IT methotrexate), RT (cribriform plate)
|
Clinical improvement and decrease in tumor size
After resection: Asymptomatic and in good clinical status
|
|
M, 2 yo
|
PR, CSI
|
7 mo
|
Subfrontal region
|
RT (subfrontal region)
|
No residual tumor noted following RT, good clinical status and active
|
|
Jereb et al 1981[9]
|
6
|
F, 6 yo
|
PR, CSI, CT (vincristine)
|
19 mo
|
Cribriform plate/subfrontal region
|
RT (cribriform plate)
|
Clinical improvement
|
|
3 mo
|
Lumbar spine, ilium, femur
|
RT (lumbar spine)
|
Death within 1 y
|
|
M, 6 yo
|
STR, CSI
|
49 mo
|
Cribriform plate/subfrontal region
|
STR, RT (frontal lobes), CT (BCNU)
|
Temporary improvement
|
|
15 mo
|
Frontal lesion and meningeal seeding
|
RT (spina l cord), CT (methotrexate, vincristine, BCNU)
|
|
|
6 mo
|
Cribriform plate region
|
TR
|
Death within 4 mo
|
|
F, 5 yo
|
GTR, CSI
|
23 mo, 2 mo
|
Cribriform plate/subfrontal region
Lumbar spine
|
R(DNC), (cribriform plate)
RT (lumbosacral region), CT (vincristine, Me-CCNU, methotrexate)
|
Death 10 months after the bony metastases were identified
|
|
F, 5 yo
|
Biopsy, CSI
|
16 mo
|
Cribriform plate/subfrontal region
|
R(DNC)
|
Good clinical status and no signs of CNS relapse up to 6 months follow-up
|
|
N/A
|
N/A
|
N/A
|
Cribriform plate/ subfrontal region (identified on autopsy)
|
N/A
|
N/A
|
|
N/A
|
N/A
|
N/A
|
Cribriform plate/subfrontal region (identified on autopsy)
|
N/A
|
N/A
|
|
Donnal et al, 1992[10]
|
5
|
N/A
|
GTR, CSI
|
N/A
|
Subfrontal region
|
N/A
|
Death (uncontrolled tumor growth)
|
|
N/A
|
GTR, CSI
|
N/A
|
Subfrontal region
|
N/A
|
Death (uncontrolled tumor growth)
|
|
N/A
|
GTR, CSI
|
N/A
|
Subfrontal region
|
N/A
|
Death (uncontrolled tumor growth)
|
|
N/A
|
GTR, CSI
|
N/A
|
Subfrontal region
|
N/A
|
Death (uncontrolled tumor growth)
|
|
N/A
|
GTR, CSI
|
N/A
|
Subfrontal region and spine (synchronous lesion)
|
N/A
|
Death (uncontrolled tumor growth)
|
|
Benk et al, 1995[11]
|
5
|
N/A
|
R(DNC), RT
|
10–35 mo
|
Frontal lobe/olfactory plate
|
N/A
|
N/A
|
|
N/A
|
R(DNC), RT
|
10–35 mo
|
Frontal lobe/olfactory plate
|
N/A
|
N/A
|
|
N/A
|
R(DNC), RT
|
10–35 mo
|
Frontal lobe/olfactory plate
|
N/A
|
N/A
|
|
N/A
|
R(DNC), RT
|
10–35 mo
|
Frontal lobe/olfactory plate
|
N/A
|
N/A
|
|
N/A
|
R(DNC), RT
|
10–35 mo
|
Frontal lobe/olfactory plate
|
N/A
|
N/A
|
|
Sure et al, 1995[12]
|
6
|
N/A
|
GTR, CSI, RT (posterior fossa), CT
|
At first admission
|
Subfrontal region
|
N/A
|
N/A
|
|
N/A
|
GTR, CSI, RT (posterior fossa), CT
|
At first admission
|
Subfrontal region
|
N/A
|
N/A
|
|
N/A
|
GTR, CSI, RT (posterior fossa), CT
|
At first admission
|
Subfrontal region
|
N/A
|
N/A
|
|
N/A
|
GTR, CSI, RT (posterior fossa), CT
|
At first admission
|
Subfrontal region
|
N/A
|
N/A
|
|
N/A
|
GTR, CSI, RT (posterior fossa), CT
|
16 mo
|
Subfrontal region
|
N/A
|
N/A
|
|
N/A
|
GTR, CSI, RT (posterior fossa), CT
|
29 mo
|
Subfrontal region
|
N/A
|
N/A
|
|
La Marca and Tomita, 1997[13]
|
1
|
M, 11 yo
|
GTR, CSI
|
36 mo
|
Subfrontal region
|
R(DNC), GKR (tumor bed), CT
|
Good health and able to support himself, below average height (GH discontinued)
|
|
Kumar et al, 2001[14]
|
1
|
M, 9 yo
|
GTR, CSI
|
20 mo
|
Subfrontal region
|
GTR, CT (vincristine, etoposide, cisplatin)
|
No improvement, refused further treatment
|
|
Sun et al, 2002[15]
|
7
|
N/A
|
R(DNC), RT
|
N/A
|
Subfrontal region
|
N/A
|
N/A
|
|
N/A
|
R(DNC), RT
|
N/A
|
Subfrontal region
|
N/A
|
N/A
|
|
N/A
|
R(DNC), RT
|
N/A
|
Subfrontal region
|
N/A
|
N/A
|
|
N/A
|
R(DNC), RT
|
N/A
|
Subfrontal region
|
N/A
|
N/A
|
|
N/A
|
R(DNC), RT
|
N/A
|
Subfrontal region
|
N/A
|
N/A
|
|
N/A
|
R(DNC), RT
|
N/A
|
Subfrontal region
|
N/A
|
N/A
|
|
N/A
|
R(DNC), RT
|
N/A
|
Subfrontal region
|
N/A
|
N/A
|
|
Jouanneau et al, 2006[16]
|
1
|
M, 45 yo
|
R(DNC), CSI, CT
|
21 y
|
Subfrontal region
|
GTR, (subfrontal region), CT (etoposide, carboplatin)
|
Good clinical status, able to work
|
|
13 mo
|
Distant supratentorial metastasis
|
N/A
|
|
Roka et al, 2009[17]
|
1
|
F, 13 yo
|
GTR, CSI
|
60 mo
|
Subfrontal region
|
GTR
|
N/A
|
|
Lee et al, 2015[18]
|
5
|
M, 7 yo
|
R(DNC), CSI
|
18.2 mo
|
Subfrontal region
|
R(DNC), RT, CT
|
Death 16 months after recurrence
|
|
F, 5 yo
|
R(DNC), CSI
|
17.1 mo
|
Subfrontal region
|
RT
|
Death 1 month after recurrence
|
|
M, 6 yo
|
R(DNC), CSI
|
5.7 mo
|
Subfrontal region
|
RT, CT
|
Death 9 months after recurrence
|
|
N/A
|
R(DNC), CSI
|
N/A
|
Subfrontal region
|
N/A
|
N/A
|
|
N/A
|
R(DNC), CSI
|
N/A
|
Subfrontal region
|
N/A
|
N/A
|
|
Martinez-Moreno et al, 2018[19]
|
2
|
M, 34 yo
|
GTR, CSI, CT
|
48 mo
|
Simultaneous bilateral recurrence on both temporal poles
|
GTR (One procedure per tumor)
|
N/A
|
|
M, 38 yo
|
R(DNC), CSI, CT
|
72 mo
|
Simultaneous bilateral recurrence on both temporal poles
|
GTR (One procedure per tumor)
|
N/A
|
|
48 mo
|
N/A
|
N/A
|
|
Yue et al, 2018[3]
|
4
|
M, 14 yo
|
NTR, CSI, CT (temozolomide)
|
45 mo
|
Subfrontal region
|
PR, Local RT, CT (temozolomide)
|
Death 21 months after resection of recurrent tumor
|
|
M, 4 yo
|
GTR, CSI
|
48 mo
|
Subfrontal region
|
PR, Local RT, CT (temozolomide, bevacizumab, Vp16, CTX, VDS)
|
Death 15 months after recurrent tumor resection
|
|
N/A
|
Spine
|
N/A
|
|
F, 7 yo
|
GTR, CSI
|
12 mo
|
Subfrontal region
|
PR, Local RT, CT (temozolomide)
|
Death 20 months after resection of recurrent tumor
|
|
M, 13 yo
|
GTR, CSI
|
21 mo
|
Subfrontal region
|
PR, Local RT, CT (temozolomide)
|
Death 18 months after resection of recurrent tumor
|
|
Present case, 2021
|
1
|
M, 8 yo
|
GTR, CT, proton beam therapy
|
48 mo
|
Subfrontal region
|
GTR, SIB-VMAT
|
Near-total tumor recess, no symptoms/new neurological deficits
|
Abbreviation: BCNU, 1,3-bis(2-chloroethyl)-1-nitrosourea; CCNU, 1-(2-chloroethyl)-3-cycloethyl-1-nitrosurea;
CSI, craniospinal irradiation; CT, chemotherapy; F, female; GKR, Gamma knife radiosurgery;
GTR, gross total resection; IT, intrathecal; IV, intravenous; M, male; Me-CCNU, 1-(2-chloroethyl)-3(4-methylcyclohexyl)-1-nitrosourea;
mo, month(s); NTR, near-total resection; PO, per os; PR, partial resection; R(DNC),
resection (degree not clarified); RT, radiation therapy; SIB-VMAT, simultaneous boost
volumetric-modulated arc therapy; STR, subtotal resection; y, years(s); yo, years
old.
Table 2
Predisposing factors for subfrontal recurrence of medulloblastoma in cases reported
in the literature
|
Name of study
|
Local relapse
|
Prone position during surgery
|
Prone position during radiation therapy
|
Inadequate irradiation of the cribriform plate areaa
|
Perioperative hydrocephalus management
|
Histopathologic characteristics
|
Immunohistochemical markers
|
Comments
|
|
Hardy et al, 1978[8]
|
N/A
|
✓
|
✓
|
N/A
|
N/A
|
Typical medulloblastoma and foci of oligodendroglial cells
|
N/A
|
Extracerebral recurrent lesion without oligodendroglial elements
|
|
N/A
|
✓
|
✓
|
N/A
|
N/A
|
Typical medulloblastoma, foci of oligodendroglial cells, Microscopic calcifications
|
N/A
|
Extracerebral recurrent lesion with oligodendroglial elements
|
|
N/A
|
✓
|
✓
|
N/A
|
N/A
|
Typical medulloblastoma
|
N/A
|
N/A
|
|
Jereb et al, 1981[9]
|
N/A
|
–
|
✓
|
✓
|
N/A
|
Medulloblastoma
|
N/A
|
Surgery in the sitting position, prone position during RT
Calculated dose of RT to the cribriform plate area: 350 rads
|
|
N/A
|
–
|
✓
|
✓
|
N/A
|
Medulloblastoma
|
N/A
|
Surgery in the sitting position, prone position during RT
Calculated dose to the cribriform plate area: 400 rads
|
|
N/A
|
–
|
✓
|
✓
|
N/A
|
Medulloblastoma
|
N/A
|
Surgery in the sitting position, prone position during RT
Calculated dose to the cribriform plate area: 350 rads
|
|
N/A
|
–
|
✓
|
✓
|
N/A
|
Medulloblastoma
|
N/A
|
Surgery in the sitting position, prone position during RT
Calculated dose to the cribriform plate area: 900 rads
|
|
N/A
|
N/A
|
N/A
|
✓
|
N/A
|
Neuronal differentiation
|
N/A
|
Recurrent tumor: primitive undifferentiated medulloblastoma
|
|
N/A
|
N/A
|
N/A
|
✓
|
N/A
|
Glial differentiation
|
N/A
|
Recurrent tumor: primitive undifferentiated medulloblastoma
|
|
Donnal et al, 1992[10]
|
N/A
|
✓
|
✓
|
✓
|
N/A
|
Medulloblastoma
|
N/A
|
N/A
|
|
N/A
|
✓
|
✓
|
✓
|
N/A
|
Medulloblastoma
|
N/A
|
|
N/A
|
✓
|
✓
|
✓
|
N/A
|
Medulloblastoma
|
N/A
|
|
N/A
|
✓
|
✓
|
✓
|
N/A
|
Medulloblastoma
|
N/A
|
|
N/A
|
✓
|
✓
|
–
|
N/A
|
Medulloblastoma
|
N/A
|
|
Benk et al, 1995[11]
|
N/A
|
N/A
|
N/A
|
✓
|
N/A
|
Medulloblastoma
|
N/A
|
1/5 recurrence in the subfrontal area, 4/5 recurrences in the frontal/cribriform plate
area, 3/5 solitary recurrent lesion, 2/5 additional recurrent lesions
|
|
N/A
|
N/A
|
N/A
|
✓
|
N/A
|
Medulloblastoma
|
N/A
|
|
N/A
|
N/A
|
N/A
|
✓
|
N/A
|
Medulloblastoma
|
N/A
|
|
N/A
|
N/A
|
N/A
|
✓
|
N/A
|
Medulloblastoma
|
N/A
|
|
N/A
|
N/A
|
N/A
|
✓
|
N/A
|
Medulloblastoma
|
N/A
|
|
Sure et al, 1995[12]
|
N/A
|
–
|
N/A
|
N/A
|
✓
(VA, VP, or EVD)
|
Medulloblastoma
|
MIB-1 (+), NSE (+)
|
Surgery in the sitting position
|
|
N/A
|
–
|
N/A
|
N/A
|
✓
(VA, VP, or EVD)
|
Medulloblastoma
|
MIB-1 (+), NSE (+)
|
|
N/A
|
–
|
N/A
|
N/A
|
✓
(VA, VP, or EVD)
|
Medulloblastoma
|
MIB-1 (+), NSE (+)
|
|
N/A
|
–
|
N/A
|
N/A
|
✓
(VA, VP, or EVD)
|
Medulloblastoma
|
MIB-1 (+), NSE (+)
|
|
N/A
|
–
|
N/A
|
N/A
|
✓
(VA, VP, or EVD)
|
Medulloblastoma
|
MIB-1 (+), NSE (+)
|
|
N/A
|
–
|
N/A
|
N/A
|
✓
(VA, VP, or EVD)
|
Medulloblastoma
|
MIB-1 (+), NSE (+)
|
|
La Marca and Tomita, 1997[13]
|
–
|
✓
|
✓
|
✓
|
N/A
|
Medulloblastoma—DNA aneuploid tumor
|
N/A
|
GH supplementation therapy
|
|
Kumar et al, 2001[14]
|
N/A
|
✓
|
✓
|
N/A
|
N/A
|
Medulloblastoma
|
N/A
|
Primary tumor in the CPA
|
|
Sun et al, 2002[15]
|
N/A
|
✓
|
✓
|
N/A
|
N/A
|
Medulloblastoma
|
N/A
|
N/A
|
|
N/A
|
✓
|
✓
|
N/A
|
N/A
|
Medulloblastoma
|
N/A
|
|
N/A
|
✓
|
✓
|
N/A
|
N/A
|
Medulloblastoma
|
N/A
|
|
N/A
|
✓
|
✓
|
N/A
|
N/A
|
Medulloblastoma
|
N/A
|
|
N/A
|
✓
|
✓
|
N/A
|
N/A
|
Medulloblastoma
|
N/A
|
|
N/A
|
✓
|
✓
|
N/A
|
N/A
|
Medulloblastoma
|
N/A
|
|
N/A
|
✓
|
✓
|
N/A
|
N/A
|
Medulloblastoma
|
N/A
|
|
Jouanneau et al, 2006[16]
|
N/A
|
✓
|
✓
|
N/A
|
✓
(VAS)
|
Medulloblastoma
|
N/A
|
N/A
|
|
Roka et al, 2009[17]
|
N/A
|
✓
|
✓
|
N/A
|
✓
(VPS)
|
Medulloblastoma
|
N/A
|
N/A
|
|
Lee et al, 2015[18]
|
N/A
|
✓
|
✓
|
✓
|
N/A
|
Medulloblastoma
|
N/A
|
Surgery in prone position, 3/5 patients RT in supine position and 2/5 in prone position
|
|
N/A
|
✓
|
✓
|
✓
|
N/A
|
Medulloblastoma
|
N/A
|
|
N/A
|
✓
|
–
|
✓
|
N/A
|
Medulloblastoma
|
N/A
|
|
N/A
|
✓
|
–
|
✓
|
N/A
|
Medulloblastoma
|
N/A
|
|
N/A
|
✓
|
–
|
✓
|
N/A
|
Medulloblastoma
|
N/A
|
|
Martinez-Moreno et al, 2018[19]
|
–
|
✓
|
✓
|
✓
|
–
|
Classic medulloblastoma
|
N/A
|
N/A
|
|
–
|
✓
|
✓
|
✓
|
✓
(Intra-op VPS placement 6 years ago)
|
Classic medulloblastoma
|
N/A
|
|
Yue et al, 2018[3]
|
–
|
✓
|
✓
|
✓
|
✓
(Pre-op VD)
|
Medulloblastoma
|
Syn (+), VIM (−), GFAP (−), EMA (−), S-100 (−)
|
N/A
|
|
–
|
✓
|
✓
|
✓
|
✓
(Pre-op VD)
|
Medulloblastoma
|
NeuN (+), Syn (+), CD56 (+), CD99 (+), VIM (+), GFAP (+), PCK (−), EMA (−), CgA (−),
NSE (−), S-100 (−), Nestin (−), Ki-67 > 90%
|
|
–
|
✓
|
✓
|
✓
|
✓
(Pre-op VD)
|
Medulloblastoma
|
NeuN (+), Syn (+), VIM (+), GFAP (−), EMA (−), CgA (−), NSE (−), S-100 (−), Nestin
(−)
|
|
–
|
✓
|
✓
|
✓
|
✓
(Pre-op VD)
|
Medulloblastoma
|
NeuN (+), Syn (+), CD56 (+), CgA (+), Myogenin (+), CD99 (−), GFAP (−), PCK (−), EMA
(−), Desmin (−), MyoD1 (−), Ck8/18 (−), Ki-67 = 40%,
|
|
Present case, 2021
|
–
|
✓
|
✓
|
N/A
|
✓
(VPS placed at the time of the initial surgery)
|
Medulloblastoma
|
N/A
|
N/A
|
Abbreviations: EVD, external ventricular drainage; GH, growth hormone; intra-op, intraoperative;
NSE, neuron-specific enolase; pre-op, preoperative; RT, radiation therapy; VAS, ventriculoatrial
shunting; VD, ventricle drainage; VPS, ventriculoperitoneal shunting.
a As reported by the authors.
A total of 48 cases (including the case reported by the authors) were studied. The
mean age of the patients is 12.3 years of age and the male:female ratio is 5:2. The
resection of the primary tumor was characterized as “gross total resection or GTR”
in 21 patients (44%), “near-total resection or NTR” in one patient (2%), “subtotal
resection or STR” in one patient (2%), “partial resection or PR” in three patients
(6%), “resection - degree not specified or R(DNC)” in 19 patients (40%), and as just
“biopsy” in one patient (2%). For two patients (4%), no information on degree of resection
was found. Most of the patients then received adjuvant radiation therapy, in the form
of craniospinal irradiation or CSI (27 patients or 56%), CSI and irradiation of the
posterior fossa (six patients or 13%), radiation therapy for which no specific characteristics
were reported (13 patients or 27%), and no relevant information was identified for
another two cases or 4%. At least 12 patients (25%) additionally received chemotherapy.
The details on the chemotherapeutic agents used in each patient can be seen in [Table 1]. The mean recurrence interval was found to be approximately 2.6 years (30.8 months).
Forty-one patients (85.4%) had only one recurrence, six patients (12.5%) had two recurrences,
and one patient (2.1%) had three recurrences. The mean number of recurrences per patient
is 1.2. Most patients had their first recurrence in the cribriform plate/subfrontal
area. Additional recurrences were found in the frontal lobe/ olfactory plate (six
cases), the spine (four cases), both temporal poles (two cases), as well as one of
each of the following: bulbar metastases, distant supratentorial metastases, meningeal
seeding, the presence of atypical cells in the cerebrospinal fluid. The treatment
of the first recurrent lesion consisted of surgery alone in five patients (10.42%),
radiation therapy alone in three patients 6.25%), surgery followed by chemotherapy
in three patients (6.25%), surgery followed by radiation therapy in one patient (2.08%),
chemotherapy and radiation therapy in one patient (2.08%), surgery followed by adjuvant
chemotherapy and radiation therapy in seven patients (14.58%), and neoadjuvant chemotherapy
and radiation therapy and then surgery followed by adjuvant chemotherapy and radiation
therapy in one patient (2.08%). In 27 patients (56.25%), no information regarding
treatment of the (first) recurrent lesion was identified. For the management of the
second recurrence, one out of the six patients who presented with a second recurrent
lesion (16.7%) underwent radiation therapy alone, two patients (33.3%) were treated
with a combination of chemotherapy and radiation therapy, and for the remaining three
patients (50%) no relevant data was found. The only patient in our analysis who had
a third recurrence was managed with surgical resection of the lesion. Nine patients
(18.75%) had an uneventful recovery and/or clinical improvement after treatment of
the first recurrence. The mean survival period after diagnosis of the primary tumor
for the patients whose death was documented in the included articles was calculated
to be 39.5 months (3.3 years). For an additional five patients, death was reported
in the absence of specific data on the time interval since the initial presentation.
Moreover, one patient was noted to have no improvement after receiving surgery and
chemotherapy for the recurrent lesion and he refused further treatment. However, it
is unclear when (and if) he succumbed to the disease. No data on clinical outcomes
was found for 25 patients (52.08%).
Risk Factors for Subfrontal Medulloblastoma Recurrence
According to Jereb et al, medulloblastomas most commonly recur within the posterior
fossa, and supratentorial metastases are quite uncommon.[20] Among them, subfrontal recurrences seem to be even rarer, given that no more than
50 such cases have been described in the literature.
Our case describes a patient in whom remote tumor spread occurred in the absence of
local relapse. Moreover, some of the many factors postulated to increase the risk
of subfrontal recurrence, such as the “face-down” position during posterior fossa
surgery, and the presence of a ventriculoperitoneal shunt, seem to apply to our case.
Other factors such as adequacy of irradiation of the cribriform plate area cannot
be appraised since the primary tumor was treated at another institution in a different
country. Following is a brief discussion of our findings with regard to all identified
cases.
Degree of Resection
Although meticulous resection of the primary tumor is considered critical in preventing
local and remote spread of the tumor, it seems that it is not on itself enough to
protect against it. Among the 48 cases of subfrontal recurrence studied in this review,
21 patients (44%) had undergone gross total resection of the primary tumor, and for
the rest of the patients varying degrees of resection have been reported ([Fig. 8]). These findings highlight the well-known fact that medulloblastomas are very aggressive
tumors and additionally indicate the presence of other factors that may affect the
potential of this tumor for spread, other than just excision of as much of the tumor
bulk as possible.
Fig. 8 Degree of resection of the primary tumor.
Presence of Local Relapse
The presence of local tumor relapse is commonly described as one of the predisposing
factors for additionally developing remote metastases from medulloblastoma. Remarkably,
this factor is absent in our patient. Unfortunately, the data gathered from the included
articles does not suffice for even the rough analysis performed for other risk factors.
“Face-Down” Position
The “face-down” or prone position is typically used both in surgery and during radiation
therapy sessions for posterior fossa tumors like medulloblastomas. This is also the
case in the studies analyzed herein, given that 31 patients (64%) were positioned
“face-down” during surgery for the primary tumor, 32 patients (67%) underwent adjuvant
radiation therapy in the prone position, and a total of 35 cases (73%) were placed
in the same position in at least one of the above treatment modalities ([Fig. 9]). It is worth noting, however, that some centers have attempted either surgery[9] or radiation therapy[18] in the sitting position, in an attempt to tackle the assumed higher risk of supratentorial
spread with the use of the prone position.
Fig. 9 Prone position during surgery and/or radiation therapy.
Management of Perioperative Hydrocephalus
Shunt placement and external ventricular drainage are another commonly described risk
factor for medulloblastoma spread. In this study, 14 patients (29%) had a ventriculoperitoneal
shunting (VPS) or ventriculoatrial shunting (VAS) placed or underwent external drainage
for the management of perioperative hydrocephalus, and one patient (2%) did not undergo
any procedure related to hydrocephalus ([Fig. 10]). However, for the vast majority of cases, we have not been able to spot relevant
patient-specific information.
Fig. 10 Management of perioperative hydrocephalus.
Adequacy of Irradiation to the Subfrontal Area
Adjuvant radiation therapy is an essential component of medulloblastoma treatment
and attention needs to be paid to the proper design and administration of treatment.
Inadequate irradiation of the subfrontal area, among others due to shielding of the
eyes during radiation therapy, is commonly held responsible for the development of
metastases in the cribriform plate area. As defining inadequate irradiation is not
easy, we additionally attempted to collect authors' views on the adequacy of subfrontal
area irradiation received by their patients. It appears that in more than half (56%)
of the included studies, authors thought that the amount of radiation reaching the
cribriform plate could be insufficient. However, in a large number of studies (42%)
no clear view was expressed ([Fig. 11]).
Fig. 11 Radiation therapy received after resection of the primary tumor and adequacy of irradiation
of the subfrontal area.
Histopathologic Characteristics and Immunohistochemical Profile
Histopathologic characteristics, the presence of certain immunohistochemical markers,
as well as the molecular profile of the tumor are considered of paramount importance
in classifying tumors and predicting long-term prognosis. Classification according
to tumor histology is done based on the WHO classification, which is subject to regular
modifications. For the purpose of determining the molecular identity of the tumor,
certain biochemical pathways are monitored, such as the Wingless or Wnt/β-catenin
pathway or the Sonic hedgehog pathway. Last but not least, several immunohistochemical
markers have been found to be positive in the different subtypes of medulloblastoma.[2]
In this review of 48 patients, five primary tumors were characterized as typical or
classic medulloblastoma,[8]
[19] one tumor as medulloblastoma with neuronal differentiation, one tumor as medulloblastoma
with glial differentiation,[9] and one tumor was referred to as a DNA-aneuploid type medulloblastoma.[13] For the remaining 40 primary medulloblastomas, we have not been able to retrieve
any specific histopathologic information. Regarding immunohistochemical markers, Sure
et al[12] and Yue et al[3] have reported relevant findings for a total of 10 patients. Among their findings,
certain well-known markers, such as neuron-specific enolase, S-100, glial fibrillary
acidic protein, and CD56, have been identified. Again, no information has been found
for the rest of the patients included in our analysis.
Although the importance of the above characteristics has been emphasized in the literature,
both in terms of recognizing possible recurrence patterns[21] and in designing targeted treatment,[22] it appears that pathology results are usually only briefly discussed, and molecular
and immunohistochemical test results may not be reported at all. Dedicating part of
the diagnostic and therapeutic efforts into interpreting these findings may lead to
improvement in the care of medulloblastoma patients.
