12‐YEAR‐OLD BOY WITH MULTIPLE BRAIN MASSES

PART 1

Clinical history‐1

This 12‐year‐old boy presented with a one‐month history of intracranial 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 (2, 3). Moreover, within the left frontal lobe was present a strongly contrast‐enhanced lesion considered as a possible metastasis (Figure 2).

Figure 1.

Figure 2.

Figure 3.

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 preoperative 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 hyperchromatic nuclei and high mitotic activity; apoptosis was prominent (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 expression 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?

Figure 4.

Figure 5.

PART 2

Clinical history‐2

The young boy underwent fractionated radiotherapy on the craniospinal 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 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 recurrences, 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).

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?

Figure 7.

Figure 8.

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).

Figure 9.

Surgical treatment and postoperative course‐3

The patient was re‐admitted on September 2008 because of recurrent vomiting and treated by surgical excision of these two cerebellar masses, both infiltrating and quite vascularized. The patient is currently going on with adjuvant chemotherapy.

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. Numerous 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 immunohistochemistry, neoplastic cells were positive for GFAP and negative for neuronal markers such as synaptophysin and neurofilaments. The Ki‐67 labeling index did not exceed 3%. What is diagnosis #3?

Figure 10.

Figure 11.

Figure 12.

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 adjuvant treatment to the appearance of this tumor (about 1 year) is too short compared with the criteria used to define a secondary malignancy, 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 possibly 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 originate from the medulloblastoma cancer stem cells (CSCs). Astrocytomas occurring after RT or CT for medulloblastoma, indeed, would represent the differentiation along glial lineage of the multipotent and multiresistant CSCs. Actually, CSCs have been demonstrated 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 surrounding cerebellar tissue, which was not excised during the first operation so that it was not appreciable at the first pathological examination. 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 neoplasm showed areas largely composed of monstrous cells, with irregular and hyperchromatic nuclei and without proliferative activity. Such features can be related on the effects of radiation therapy on a pre‐existing tumor, thus supporting the hypothesis that the pilocytic 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 suggested the diagnosis of supratentorial metastasis of medulloblastoma. 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 lipoastrocytoma, while the presence of monstrous, multinucleated cells describes the post‐radiation changes of the pilocytic astrocytoma.

A further hypothesis can be formulated considering the “changing 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 considered as the result of the occurrence of three synchronous brain tumors.

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, including 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 astrocytoma 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.