0110case1 Three Lesions

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C A S E O F M O N T H J A N U A R Y 2 0 1 0 bpa_381 679..682

12-YEAR-OLD BOY WITH MULTIPLE BRAIN MASSESLuca Massimi MD, Massimo Caldarelli MD, Quintino Giorgio DAlessandris MD, Massimo Rollo MD 1,

Libero Lauriola MD2, Felice Giangaspero MD3, Concezio Di Rocco MD

Institute of Neurosurgery, Division of Pediatric Neurosurgery, Catholic University of Rome, Italy1 Department of Bio-images and Radiological Sciences, Catholic University Medical School, Rome, Italy2 Institute of Pathology, Catholic University of Rome, Italy3

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, irregularlyshaped 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 compressedthe 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 patientunderwent 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 waspresent, 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,

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 booston 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.


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).


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.


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).


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).

doi:10.1111/j.1750-3639.2010.00381.x

679Brain Pathology 20 (2010) 679682

2010 The Authors; Journal Compilation 2010 International Society of Neuropathology


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Figure 2Figure 3

Figure 4Figure 5

Figure 6 Figure 7 Figure 8

Figure 1

Correspondence

680 Brain Pathology 20 (2010) 679682



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The patient was re-admitted on September 2008 because of recur-

rent vomiting and treated by surgical excision of these two cerebel-

lar masses, both infiltrating and quite vascularized. The patient is

currently going on with adjuvant chemotherapy.


The tumor was composed of compact elongated piloid cells withoccasional 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

Rosenthal fibers were present. No mitotic activity was observed.

Infiltration of the subarachnoid space was observed in the regions

were residual cerebellar tissue was present (Figure 12). By immu-

nohistochemistry, neoplastic cells were positive for GFAP and

negative for neuronal markers such as synaptophysin and neuro-

filaments. The Ki-67 labeling index did not exceed 3%. What is

diagnosis #3?

Figure 9

Figure 10

Figure 11

Figure 12

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681Brain Pathology 20 (2010) 679682



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DIAGNOSES AND DISCUSSION

Diagnosis #1Anaplastic medulloblastoma.

Diagnosis #2Low-grade lipoastrocytoma.

Diagnosis #3Pilocytic 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 26months (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 infiltratingthe tentorium and/orthe 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

suggestthatthe smallsubtentorialnodule inFigure 1 (black arrow)

considered as the expression of the tumor spreadingis separated

from the main tumor massand it reappears grossly unchanged more

than one year later (Figure 9) (white arrow). Moreover, this neoplasm showed areas largely composed of monstrous cells, with

irregular and hyperchromatic nucleiand without proliferative activ-

ity. Such features canbe related on theeffectsof radiationtherapyon

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

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 braintumors.

REFERENCES

1. Fan X, Eberhart CG (2008) Medulloblastoma stem cells. J Clin Oncol

26:28212827.

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 Neuropathol103:152156.

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 Syst22:12011207.

4. Koksal Y, Toy H, Unal E, Baysal T, Esen H, Paksoy Y, Ustun ME

(2008) Pilocytic astrocytoma developing at the site of a previouslytreated medulloblastoma in a child. Childs Nerv Syst24:289292.

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 Syst24:

793805.

6. Selassie L, Rigotti R, Kepes JJ, Towfighi J (1994) Adipose tissue and

smooth muscle in a primitive neuroectodermal tumor of cerebrum.

Acta Neuropathol87:217222.

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 nodefinite 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.

Correspondence

682 Brain Pathology 20 (2010) 679682


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