Radiation-induced anaplastic astrocytoma following treatment of medulloblastoma

Introduction

In 1945, at the Memorial Hospital for Cancer and Allied Diseases (nowadays called Memorial Sloan-Kettering Cancer Center), Bradley Coley amputated the lower leg of a 22-year-old man diagnosed with tibial sarcoma. Eight years earlier the patient had been treated with radium because of fibrous dysplasia found radiologically. The dose delivered to the bone was 15.5 Gy [4]. Three years later, in the publication coming from the same institution, Cahan et al. described 11 cases of bone sarcomas (located in the ribs, sternum and clavicle), which occurred in patients irradiated postoperatively for breast cancer. The authors referred to them as second radiation-induced cancer – SRIC and pointed out four essential criteria for their diagnosis: previous irradiation, latency period of several years, location of the neoplasm within the irradiated area, and histological proof of malignancy [5]. Until now, the dose needed to initiate carcinogenesis has not been established unequivocally. The results of meta-analyses including over 3000 patients diagnosed with SRIC revealed a linear correlation between the total radiation dose and the frequency of malignancies. The majority of SRIC were diagnosed in the proximity of tissues, which had received doses of 5 to 50 Gy [3,33].
Postoperative radiation therapy is an integral part of combined treatment of central nervous system tumours. Improving treatment results lead to prolongation of survival, which thus results in an increasing number of secondary brain malignancies. Malignant gliomas (radiation-induced malignant gliomas – RIMG) comprise more than a half of these neoplasms. The medium latency period varies between 9 and 19 years according to the literature [6,9,23,26,32]. We describe a case of secondary anaplastic astrocytoma which occurred 10 years after cerebro-spinal irradiation performed because of cerebellar medulloblastoma in a 10-year-old child.

Case report

In April 2000, a ten-year-old girl was admitted to the Surgery Department of the Children’s University Hospital in Cracow, presenting with a history of 2 months of intensifying headaches in the occipital region, nausea, vomiting and nystagmus. Diagnostic computed tomography (CT) and magnetic resonance imaging (MRI) visualised a tumour of the cerebellar vermis with a diameter of 8 cm. The tumour was excised totally with suboccipital craniectomy on 20 April 2000. The histological examination revealed a highly cellular tumour formed by small, uniform cells with only thin rims of cytoplasm, exceptionally rarely creating rosette-like structures but mostly crowded in compact featureless areas (Fig. 1).
Focally some glial fibrillary acidic protein (GFAP) and synaptophysin immunopositivity was observed. As a result, the diagnosis of medulloblastoma – “classical” variant was established. Cerebrospinal fluid was free from neoplastic cells. The patient received 4 cycles of chemotherapy (SIOP – vincristine, etoposide, cyclofosfamide). Systemic treatment ended on 21 August 2000. From 6 September to 20 October 2000, the patient received adjuvant irradiation. At the first step, a dose of 35.07 Gy in 21 fractions to the neuraxis was given. Subsequently, additional 18 Gy in 10 fractions to the posterior cranial fossa were given, resulting in the total dose of 53.07 Gy in this area. In July 2012, 12 years after the diagnosis of cerebellar medulloblastoma, at the age of 22, the patient was admitted to an emergency department because of an onset of seizures. MRI was performed and showed a tumour measuring 27×22×19 mm, located at the border of the left parietal and occipital lobe, and characterized with malignant features including heterogeneity of enhancement, digitate oedema, and mass effect (Fig. 2).
The patient was admitted to the Neurosurgery Department of the University Hospital in Cracow, where on 18 July 2012, a macroscopic resection of the tumour was performed. The histopathological examination revealed an anaplastic tumour of astrocytic type (immunopositivity to GFAP). Tumour cells were mostly of small or medium size, polymorphic and relatively loosely scattered, but somewhat more densely aggregated around numerous vessels, however, not in a “radiating”, rosette-like arrangement (Fig. 3A). Immunohistochemistry using a mouse monoclonal antibody targeting the IDH1 R132H mutation has given a negative result.
There were numerous mitoses and conspicuously high Ki67 labelling index of 20% was noted (Fig. 3B). Some scattered features of cell necrosis could be seen though without formation of palisades. Consequently, a diagnosis of anaplastic astrocytoma WHO III was adopted. From 10 September to 23 October 2012 at the Centre of Oncology in Cracow, adjuvant chemoradiotherapy was performed. The patient was treated with a dose of 50.4 Gy in 28 fractions with concurrent temozolomide. Subsequently she received 6 cycles of adjuvant temozolomide. At present, 5 years after the diagnosis of anaplastic astrocytoma, the patient remains asymptomatic in both clinical examination and imaging.

Discussion

Radiotherapy is an undisputed element of combined treatment of neoplasms located within the central nervous system. It is applied mainly in high-grade gliomas in adult patients and germinal tumours in children. Radiation therapy, like other methods of oncological treatment, is associated with early and late adverse effects. A lot of data have been collected on the most serious late complication, which is radionecrosis. Over the last decade, lots of reports regarding radiation-induced brain tumours have been published. The occurrence of secondary brain tumours depends on both institutions’ and authors’ experience. According to Paulino et al., a cumulative risk of secondary glioma is 1.7% at 10 years, rising to 2.7% at 15 years [23]. For over 70% of patients after neuraxis irradiation, who are diagnosed with a secondary tumour, the latency period does not exceed 10 years; however, Hamasaki describes a case, in which the latency period was 35 years [9,12,19]. Kamide et al. report a case of a 5-year-old patient diagnosed with medulloblastoma, treated with surgery for high-grade glioma and meningioma after 29 years. Both lesions were located in the cerebellum, thus in the high-dose region [14]. According to the literature, RIMG occur in the areas irradiated with a minimum dose of 30 Gy [10,17,25,34]. Table I presents cases of radiation-induced gliomas following treatment of medulloblastoma.
Van Calenbergh et al. define basic criteria of radiation-induced brain tumour: different histopathological features (not only higher grade), location in the irradiated area, latency period of several years (a minimum interval has not been determined yet), excluding tumours in patients with syndromes known to present with multiple neoplasms (e.g. neurofibromatoses) [30]. Our case meets all these criteria: primary neoplasm – medulloblastoma, the secondary one – anaplastic astrocytoma (the above-described astrocytoma apparently shows no IDH-1R132H mutation, at least tested by immunohistochemistry), development in the region irradiated with a dose of 35.07 Gy and latency period of 10 years. Although in our case, glioma was ultimately diagnosed as grade III astrocytoma, we are aware that to some extent its morphology may resemble pilomyxoid astrocytoma (which is grade II). However, this resemblance is only due to loose cellularity of the tumour and oedema. The tumour was devoid of any true “myxoid” features and although tumour cells were denser around vessels, no typical “radiating” rosette-like arrangements around vessels (quite characteristic in pilomyxoid astrocytoma) were noted and also neuroimaging features were not typical for pilomyxoid astrocytoma. Secondary gliomas may have different morphology and show a broad spectrum regarding their aggressiveness, including a high as well as a low grade and the relation between histopathology and clinical behaviour in secondary gliomas differs from what is observed in primary tumours [13,16,35]. In our case frequent mitoses and especially high Ki67 labelling index of 20% (Fig. 3B) pointed out to a rather truly aggressive course and this led to diagnosis of grade III astrocytoma. What additionally corroborated with neuroimaging features of grade III tumour was heterogeneity of enhancement, digitate oedema, and mass effect.
Standard treatment of primary high-grade gliomas consists of postoperative radiotherapy to a total dose of 60 Gy in 30 fractions given concurrently with temozolomide and followed by 6 cycles of temozolomide alone. Repeated irradiation of previously irradiated area seems controversial, thus in many institutions it is not performed [22]. The treatment of RIMG should take into account the dose delivered during the first radiotherapy, the irradiated volume and the latency period. The decision concerning repeated radiotherapy should be made taking these variables into account. Keeping in mind that medium latency period between the first and the repeated treatment is 9 years and relying on previous experience, we estimate that delivering the dose of 50-55 Gy concurrently with chemotherapy is safe [1,2,8,28,31].
Paulino et al. reviewed the literature from 1960 to 2005, finding 92 patients diagnosed with RIMG. The majority of patients (73%) were under 19 years old at the moment of diagnosis. The median time from irradiation to the occurrence of the secondary tumour was 8.75 years (range: 2.5 to 61 years) and was dependent neither on gender nor on age. There was also no difference in the latency period dependent on the irradiation dose and other methods of initial treatment. The authors noticed that in the case of neuraxis or whole brain irradiation, the latency period was shorter (median period of 7.1 years) comparing to local irradiation (median period of 10.2 years, p = 0.0350). Glioblastoma was found in 75% of cases of secondary tumours and anaplastic astrocytoma was diagnosed in the other 25% of cases. Table II presents different treatment modalities.
Median survival for the whole group was 11 months. Two-year overall survival was 13%. For the group of 35 patients treated with radiation therapy (median total dose 50 Gy, range from 30 to 76 Gy), the median survival was 13 months and 2-year overall survival was 20.5%, compared with 8 months and 3% for those who did not receive repeated irradiation. The difference in survival was statistically significant (p = 0.0009). Better prognosis was related to histology of anaplastic astrocytoma. Two-year overall survival was 30.3% for those diagnosed with anaplastic astrocytoma and 7.3% for patients diagnosed with glioblastoma (p = 0.0013). Acute toxicity of reirradiation was low. Episodes of brain oedema were treated with steroids, allowing completion of treatment. Serious late toxicity, e.g. brain radionecrosis, was seen in 2% of patients [1,2,8,31].
The data obtained suggest that reirradiation is the proper treatment option for patients diagnosed with RIMG. Neither surgery nor chemotherapy correlated with improvement in survival (p = 0.164, p = 0.536, respectively).

Conclusions

According to the literature and our own experience, concurrent chemoradiation is an effective treatment method for RIMG, leading to results comparable to treatment of primary high-grade gliomas.

Disclosure

The authors report no conflict of interest.

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