doi:10.1111/j.1750-3639.2010.00381.
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CASE OF MONTH JANUARY 2010
12-YEAR-OLD BOY WITH MULTIPLE BRAIN MASSES
Luca Massimi MD, Massimo Caldarelli MD, Quintino Giorgio D’Alessandris MD, Massimo Rollo MD1,
Libero Lauriola MD2, Felice Giangaspero MD3, Concezio Di Rocco MD
Institute of Neurosurgery, Division of Pediatric Neurosurgery, Catholic University of Rome, Italy
1
Department of Bio-images and Radiological Sciences, Catholic University Medical School, Rome, Italy
2
Institute of Pathology, Catholic University of Rome, Italy
3
Department of Experimental Medicine and Pathology, University “La Sapienza”, Rome, Italy and IRCCS NEUROMED, Pozzilli, Italy
PART 1
Clinical history-1
This 12-year-old boy presented with a one-month history of intra-
cranial raised pressure syndrome, characterized by headache and
vomiting, followed by nuchal pain and torticollis. Physical and
neurological examinations were normal except for papilledema.
No hereditary syndromes were disclosed.
Neuroradiological findings-1
Brain MRI showed a 35 ¥ 30 ¥ 26 mm a grossly round, irregularly
shaped tumor mass of the posterior cranial fossa, hypo/isointense
on T1, iso/hyperintense on T2 and FLAIR, and heterogeneously
enhanced by contrast medium (Figure 1). The tumor originated
from the cerebellar vermis, extended into the paramedian region of
the left cerebellar hemisphere, and compressed the fourth ventricle,
causing triventricular hydrocephalus. Both spinal, infratentorial
and supratentorial leptomeningeal tumor seeding were evident
(Figures 2, 3). Moreover, within the left frontal lobe was present a
strongly contrast-enhanced lesion considered as a possible
metastasis (Figure 2).
Surgical treatment and postoperative course-1
Surgical treatment and postoperative course-1: The patient
underwent the excision of the vermian tumor and the treatment of
the hydrocephalus (March 2007) with resolution of the preopera-
tive clinical picture. The tumor macroscopically appeared as a
reddish, soft, friable and richly vascularized mass.
Microscopic pathology-1
Tumor cells showed marked nuclear pleomorphism, with hyper-
chromatic nuclei and high mitotic activity; apoptosis was promi-
nent (Figure 4). Immunohistochemical labeling for synaptophysin
(Figure 5), chromogranin and neurofilaments was present, while no
GFAP-staining was observed. Proliferation index assessed by Ki67
antibody exceeded 60%. Immunohistochemical staining expres-
sion of INI1 protein, performed with BAF47 antibody, showed
nuclear expression of the protein. The total body radiological
workup did not reveal evidence of primary extracranial neoplasms.
What is the diagnosis of #1?
PART 2
Clinical history-2
The young boy underwent fractionated radiotherapy on the cran-
iospinal axis plus a boost on the posterior cranial fossa followed,
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after a 6 weeks rest period, by 4 cycles of high-dose chemotherapy,
each cycle being integrated by stem-cells rescue. Radiotherapy was
carried out from April to May 2007 and consisted on craniospinal
irradiation (total dose: 36 Gys) plus a conformal boost on the tumor
bed (total dose: 54 Gys). Chemotherapy started on July 2007 and
was completed on December 2007. Cisplatin, vincristine and
cyclophosphamide were administered. All the scheduled treatment
was concluded and well tolerated except for the appearance of
iatrogenic Cushing disease.
Neuroradiological findings-2
The first post-treatment MRI (January 2008) showed the reduction
of the leptomeningeal enhancement and the absence of local recur-
rences, but no changes of the left frontal mass. Such a lesion even
appeared slightly increased in size at the following MRI (March
2008) (Figure 6).
Surgical treatment and postoperative course-2
The surgical removal of this mass was realized (March 2008). The
tumor nodule appeared as a fatty, bloodless mass, with a little
infiltration of the surrounding brain tissue. The postoperative
course was uneventful.
Microscopic pathology-2
The tumor consisted of a population of pleomorphic astrocytic
cells, some of them containing small hyaline eosinophilic bodies.
Among them, vacuolated cells with adipocyte-like appearance
were present (Figure 7). Mitoses and vascular proliferation were
absent. By immunohistochemistry, the cells showed strong GFAP
positivity (Figure 8). Synaptophysin and neurofilaments were
negative. Ki67 proliferative index did not exceed 2% and p53 was
not expressed. What is the diagnosis of #2?
PART 3
Clinical history-3
The patient underwent maintenance chemotherapy
(temozolomide).
Neuroradiological findings-3
At follow-up MRIs, two progressively enlarging nodules were
appreciable, the first located within the upper cerebellar vermis,
close to the tentorial notch, and the second lying in the left lateral
aspect of the surgical field (Figure 9).
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Figure 1 Figure 2
Figure 3

Figure 4
Figure 5

Figure 6 Figure 7 Figure 8

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Figure 9 Figure 11

Surgical treatment and postoperative course-3 Rosenthal fibers were present. No mitotic activity was observed.
The patient was re-admitted on September 2008 because of recur- Infiltration of the subarachnoid space was observed in the regions
rent vomiting and treated by surgical excision of these two cerebel- were residual cerebellar tissue was present (Figure 12). By immu-
lar masses, both infiltrating and quite vascularized. The patient is nohistochemistry, neoplastic cells were positive for GFAP and
currently going on with adjuvant chemotherapy. negative for neuronal markers such as synaptophysin and neuro-
filaments. The Ki-67 labeling index did not exceed 3%. What is
diagnosis #3?
Microscopic pathology-3
The tumor was composed of compact elongated piloid cells with
occasional Rosenthal fibers (Figure 10). In some areas, the cells
had bizarre appearance with large hyperchromatic nuclei. Numer-
ous monstrous multinucleated cells were present (Figure 11). In
these areas, numerous eosinophilic granular bodies and abundant

Figure 10 Figure 12

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DIAGNOSES AND DISCUSSION
Diagnosis #1—Anaplastic medulloblastoma.
Diagnosis #2—Low-grade lipoastrocytoma.
Diagnosis #3—Pilocytic astrocytoma with radiation induced
modification.
Discussion
The present case illustrates the exceptional occurrence of three
different brain tumors in a single patient. The clinical history and
the clinico-radiological findings ruled out a possible syndrome so
that the occurrence of additional neoplasms was considered. In
2006, Hope et al (3) reported on 17 astrocytomas secondary to
medulloblastoma treatment. Since then, three new cases have been
added, all of them occurring in irradiated children. The authors’
hypothesis was that adjuvant treatments are able to provoke genetic
aberrations in the irradiated tissues, leading to induced neoplasms.
In the present case, the cerebellar pilocytic astrocytoma could
represent a secondary tumor. Nevertheless, the time from the adju-
vant treatment to the appearance of this tumor (about 1 year) is too
short compared with the criteria used to define a secondary malig-
nancy, the shortest interval reported in the literature being 26
months (average: 13.1 years) (5).
Koksal et al (4) proposed an alternative etio-pathogenetic
hypothesis based on foci of glial or neuronal differentiation possi-
bly found in medulloblastomas. Accordingly, radiotherapy (RT) or
chemotherapy (CT) administration would result more effective
against the undifferentiated cells than against the differentiated
areas; subsequently, the second malignancy would represent a
“remnant” of the more differentiated medulloblastoma surviving
cells. On these grounds, the second malignancy could also origi-
nate from the medulloblastoma cancer stem cells (CSCs). Astrocy-
tomas occurring after RT or CT for medulloblastoma, indeed,
would represent the differentiation along glial lineage of the multi-
potent and multiresistant CSCs. Actually, CSCs have been demon-
strated to be more radio/chemo-resistant than the other, mitotically
more active tumor cells (1). Moreover, RT and CT can induce just
the differentiation of the CSCs.
Alternatively, it has to be accepted that, at the time of the removal
of the medulloblastoma, our patient harbored also a small pilocytic
astrocytoma, possibly infiltrating the tentorium and/or the surround-
ing cerebellar tissue, which was not excised during the first opera-
tion so that it was not appreciable at the first pathological examina-
tion. The comparison between the first preoperative MRI (Figure 1)
and the MRI at the moment of the recurrence (Figure 9) seems to
suggest that the small subtentorial nodule in Figure 1 (black arrow) –
considered as the expression of the tumor spreading—is separated
from the main tumor mass and it reappears grossly unchanged more
than one year later (Figure 9) (white arrow). Moreover, this neo-
plasm showed areas largely composed of monstrous cells, with
irregular and hyperchromatic nuclei and without proliferative activ-
ity. Such features can be related on the effects of radiation therapy on
a pre-existing tumor, thus supporting the hypothesis that the pilo-
cytic astrocytoma was coexistent with the medulloblastoma.
Differently, the frontal lipoastrocytoma was clearly detectable at
the first MRI, and did not disappear after RT and CT, even showing
a mild increase in size over the time. Lipoastrocytoma is a very
rare, quite recently described variant of pediatric low-grade
glioma, consisting of astrocytic cells with a diffuse lipoma-like
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degeneration (2). In the present case, the contiguity of this tumor
with the meninges and the presence of several other subarachnoid
contrast enhancing nodules in the whole neuraxis initially sug-
gested the diagnosis of supratentorial metastasis of medulloblas-
toma. However, the pathological investigation provided the
diagnosis of an “incidental”, synchronous astrocytic neoplasm.
Accordingly, one could postulate that there were two foci of low-
grade glioma which followed two distinct pattern of differentiation.
The adipocyte-like appearance due to the coalescence of small fat
droplets into large lipid droplets actually characterizes the lipoas-
trocytoma, while the presence of monstrous, multinucleated cells
describes the post-radiation changes of the pilocytic astrocytoma.
A further hypothesis can be formulated considering the “chang-
ing histology” after adjuvant therapy. In our case, RT and CT could
have killed all the medulloblastoma typical cells, leaving behind
only a lipomatous degeneration and glial cells that are more radio/
chemoresistant than the undifferentiated medulloblastoma cells.
Such a theory is supported by the description of possible adipose
transformation in PNETs (6).
The explanation of the association of three different neoplasms
in our patient remains speculative. Consequently, it should be con-
sidered as the result of the occurrence of three synchronous brain
tumors.
REFERENCES
1. Fan X, Eberhart CG (2008) Medulloblastoma stem cells. J Clin Oncol
26:2821–2827.
2. Giangaspero F, Kaulich K, Cenacchi G, Cerasoli S, Lerch KD, Breu H,
Reuter T, Reifenberger G (2002) Lipoastrocitoma: a rare low grade
astrocitoma variant of pediatric age. Acta Neuropathol 103:152–156.
3. Hope AJ, Mansur DB, Tu P, Simpson JR (2006) Metachronous
secondary atypical meningioma and anaplastic astrocytoma after
postoperative craniospinal irradiation for medulloblastoma. Childs
Nerv Syst 22:1201–1207.
4. Koksal Y, Toy H, Unal E, Baysal T, Esen H, Paksoy Y, Ustun ME
(2008) Pilocytic astrocytoma developing at the site of a previously
treated medulloblastoma in a child. Childs Nerv Syst 24:289–292.
5. Pettorini B, Park YS, Caldarelli M, Massimi L, Tamburrini G, Di
Rocco C (2008) Radiation-induced brain tumours after central nervous
system irradiation in childhood: a review. Childs Nerv Syst 24:
793–805.
6. Selassie L, Rigotti R, Kepes JJ, Towfighi J (1994) Adipose tissue and
smooth muscle in a primitive neuroectodermal tumor of cerebrum.
Acta Neuropathol 87:217–222.
ABSTRACT
The occurrence of more than one brain tumor in a single patient is
not new, resulting from RT- or CT-induced neoplasms, syndromes
or casual association. We report on the exceptional case of a
12-year-old boy harboring three different brain tumors with no
definite correlation. The first MRI showed a medulloblastoma with
signs of infratentorial and supratentorial tumor spreading, includ-
ing a small frontal mass. Despite the good response to surgical and
adjuvant treatment, the frontal mass remained unchanged and was
excised, revealing a lipoastrocytoma. Finally, the possible local
recurrence of the original medulloblastoma was a pilocytic astro-
cytoma with post-radiation alterations. Explanations of this very
unusual association include radio-induced tumors, second tumors
developing from remnants of medulloblastoma cancer stem cells,
or the changing histology after adjuvant therapy.
Brain Pathology 20 (2010) 679–682