Radiation-induced spinal glioblastoma multiforme

Radiation-induced intracranial tumour has been well documented since 1950, of which the largest group was meningioma, followed by gliomas and sarcomas [1]. On the other hand, glioblastoma multiforme (GBM) of the brain is the most frequent primary brain tumor in adults. GBM of the spinal cord is a rare disease when compared with that of the brain. It only accounts for 1–5% of all glioblastoma multiforme and about 1.5% of all spinal cord tumours [2].

In the following, we report a Chinese female adult patient who developed spinal GBM at the C2–C7 level seven years after receiving conventional radiotherapy for nasopharyngeal carcinoma.

Our patient was diagnosed to have nasopharyngeal carcinoma (T2npN1M0) when she was at the age of 28. The histology of the nasopharyngeal biopsy was undifferentiated carcinoma. She received 43 doses of radiotherapy, with 2 Gy each time, to the nasopharynx and parapharynx (Figure 1). After receiving a total of 86 Gy of radiation, she was in complete remission. Seven years later, when she was 35 years old, she presented to us with neck pain, together with progressive weakness and numbness of all four limbs for one month. There was also difficulty in voiding. A MRI of the spine (Figure 2) and brain showed a contrast-enhancing lesion at the C2–C7 level with a suspicious leptomeningeal spread at the T10–T12 level, but no evidence of intracerebral tumour was demonstrated. C4–C6 laminotomy for biopsy of the intramedullary tumour was then performed. Histology examination of the specimen demonstrated a cervical cord glioblastoma multiforme. Further radiotherapy to the intramedullary tumour was not feasible, as the radiotherapy field would overlap with that of the previous NPC. Temozolamide, an oral chemotherapeutic agent, was then prescribed, with the dosage of 314 mg for five days, every 28 days as one cycle. A MRI of the spine was repeated after four cycles of chemotherapy. It showed marked improvement of cord oedema and a reduction of size of the cervical cord lesion by 20%. A further four cycles of chemotherapy was continued. She, however, progressed at eight-month follow up, both clinically and radiologically.

Figure 1.  Radiation field for NPC

Figure 2.  MRI cervical spine showed contrast enhancing cervical intramedullary lesion with cord expansion.

Radiation is an established carcinogen. It causes DNA damage and genomic instability, resulting in aberrant over expression of oncogenes or inactivation of tumor-suppression genes. There is never a safe dosage threshold for the development of secondary tumours. Experimental data shows that even a single photon can cause a base change leading to mutations. However, the carcinogenic effect does not go parallel with the radiation dosage. In fact, high doses of radiation may lower or even eliminate the carcinogenic potential of a tissue by killing the cells. Only those cells that are not killed progress towards malignant change by accumulating a series of mutations. Yet the dose-response curve for radiation associated second tumour is still not clearly understood. A biphasic rather than linear relationship was suggested by several experiments on small animals, which demonstrated that the incidence increased with dose up to a maximum between 3 to 10 Gy and a subsequent monotonic decrease followed [3]. Thus, dose reduction may not be an appropriate strategy for avoidance of secondary tumour. It depends on the position of the turning point.

Cahan et al. outlined the criteria for radiation-induced tumour in case series of sarcoma arising in irradiated bone [9]. First, there must be a latency interval between delivery of the radiation and tumour development. Second, the tumour must arise in the irradiated region. Third, the tumour must be histologically distinct from the original irradiated tumour. Forth, conditions such as immunodeficiency syndrome, xeroderma pigmentosum, retinoblastoma, that facilitate neoplastic growth must not be present. For our patient, the criteria mentioned above were all fulfilled. The GBM was located at the C2 to C7 level, which overlapped with the radiation field for the noasopharyngeal carcinoma. The latency period between the spinal irradiation and the subsequent GBM was seven years, which excluded the possibility that the glioblastoma was present in this location before the radiotherapy. Moreover, the pathology of the nasopharyngeal carcinoma was undifferentiated carcinoma, which was a totally different pathology of GBM.

The first clear demonstration of the role of radiation in the etiology of brain tumours in humans came from the Israel Retrospective Survey on 11 000 children who were treated with radiation in 1950 for tinea capitis [4]. The number of case reports documenting radiation-induced malignant gliomas in humans had risen sharply since 1970. It was estimated that the risk of developing a radiation-induced tumour after radiation therapy to the brain is approximately 1–3% [5], [16]. However, data is lacking in the literature concerning radiation-induced spinal tumour, not to mention spinal GBM. In fact, our understanding about the biological features of spinal GBM is still very limited. Histomorphologically, spinal and cerebral glioblastoma are identical [6]. In immunhistochemical studies of spinal GBM, an increase in the proliferation and accumulation of p53 protein was similar with that of cerebral GBM. The biological behaviour of spinal and cerebral GBM might therefore be alike [6].

The survival times of both spinal and cerebral GBM are short. In a survey of 21 patients with spinal glioblastoma who received post-operative irradiation, the rate of long-term survivors over 18 months was 32% [9]. The major causes of death in spinal GBM are meningeal seeding and/ or cerebral metastasis. The rate of leptomeningeal involvement in spinal GBM was higher than with the cerebral one [6], [9]. This is because of the relatively thin parenchyma column of the spinal cord and hence a short distance to the subarachnoid space. The spreading of the tumour cells into the CSF was thought to be the mechanism of cerebral metastasis [10–15].

However, the survival rate of radiation-induced malignant glioma appeared less favorable when compared with that of the nonradiation-induced ones. The poorer survival rates are apparently due to the lack of aggressive multimodality therapy, which should be recruited in the treatment of GBM [16]. Like our patient, the intramedullary C2–7 tumour makes aggressive excision not a beneficial option. Futher radiotherapy was not possible as it overlaps with the previous radiation field. Therefore, chemotherapy was the only treatment modality that can be offered to the patient. Oral Temozolamide may be one of the more tolerable options in this group of patients.