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Radiation-induced brain cavernomas in elderly: review of the literature and a rare case report

Radiation-induced brain cavernomas have been mainly reported in children who underwent radiotherapy for medulloblastoma, leukemia, or low-grade glioma. Otherwise, the “de novo” appearance of a cavernoma in an elderly long-survivor patient after resection and radiotherapy of a glioblastoma is a rare event. We report the case of a 62-year-old female patient who underwent surgical resection of a right temporal glioblastoma, followed by radiation therapy of the operative field and surrounding brain and concomitant adjuvant temozolomide. Four years after the operation, a follow-up Magnetic Resonance revealed a good tumor control and a small round lesion at the superior surface of the right cerebellar hemisphere, close to the margins of the previous irradiation field. The radiological items were consistent with a cavernous angioma. Because of the small size of the malformation and the absence of related symptoms, no treatment was performed. The patient died for tumor progression 86 months after the initial operation, with unchanged cerebellar cavernoma. The occurrence of a cavernous angioma in an elderly patient after radiotherapy for brain glioblastoma is an exceptional event; the distribution of radiotherapy-induced cavernous malformations reported in current literature is presented and the mechanism of their formation is discussed. (www.actabiomedica.it)


Introduction
Cavernous angiomas (CAs) are well-circumscribed vascular lesions composed of dilated thin walled venous channels without intervening normal brain tissue (1). Although benignant, CAs can be responsible for disabling neurological symptoms depending on their localization within the Central Nervous System (CNS). These lesions can be either acquired or congenital; multiple CAs (10% to 20%) are typically familiar or secondary to radiation therapy.
Acquired CAs may occasionally occur after radiotherapy, generally in addition to other more common complications such as white matter leukoencephalopathy, atrophy and dystrophic mineralization. The "de novo" presentation of CAs after radiation therapy is a relatively rare event, which may occur even after several years after the treatment, irrespective of the radiation dose and type of malignancy. Most of the reported cases (2, 3) mainly concern children (mean age 12 years) who underwent radiotherapy for medulloblastoma, leukemia or low-grade glioma (LGA); induced CAs after radiotherapy for high grade gliomas (HGG) are less common across older age groups.
We describe the unusual case of a cerebellar CA observed after radiation therapy for temporal glioblastoma in an elderly patient, reviewing current literature on the topic.

Case Report
A 62-year-old female patient was admitted to hospital because of a 2-month history of temporal lobe epilepsy. After a first-level neurological examination, further diagnostic investigations were required to exclude secondary epilepsy causes. Magnetic Resonance Imaging (MRI) showed the presence of a large right intracerebral temporal mass with intense and inhomogeneous contrast enhancement and perilesional oedema, suggestive for a HGG (Figure 1a). A gross total tumor resection was performed through a right temporal craniotomy. Histology was consistent with glioblastoma (WHO IV). Subsequent radiation therapy of the operative field and surrounding brain (60Gy for 30 days, 2Gy per daily fraction) and concomitant adjuvant therapy with multiple temozolomide administrations (during radiotherapy: 75 mg/m² per day, 7 days per week; post-radiotherapy: 150-200 mg/m² for 5 days during each 28-day cycle) were performed.
After 26 months the patient came to our attention because of tumor recurrence (Figure 1b). Thus, she underwent re-intervention remaining symptomfree for the following 2 years. Following examinations (4) did not show significant tumor recurrence, with a good disease control.
Almost 4 years after the initial diagnosis, a followup MRI confirmed the absence of recurrent disease; nevertheless a new round small lesion of the right cerebellar convexity was observed close to the margins of  showing the presence of an area of intense enhancement in the right temporal region, peripherally to the surgical cavity, consistent with tumor recurrence the previous irradiation field, showing central hyperintensity with a rim of signal loss due to hemosiderin ( Figure 2b); this asymptomatic lesion was not visible in the previous MRI control (Figure 2a). Radiological findings were strongly suggestive for CA, due to the typical berry appearance on unenhanced sequences.
Because of the small size of the malformation and the absence of related symptoms, no treatment was performed. After 1 year, a further follow-up MRI showed no tumor recurrence, as well as the unchanged right cerebellar CA. The patient died for tumor progression after a 7-year disease-free survival.

Discussion
CA is one of the possible complications of high dose radiation therapy, with a large number of cases reported in scientific literature at present (2,3,5). Almost all reported cases were described in paediatric population, whereas only a minority of case concerned adult patients. The most common primitive neoplasms associated with radiation-induced CAs include medulloblastoma and malignant hematopoietic neoplasms (2-5) as well as low grade gliomas (LGG) (3), whereas only anedoctal observations of CA in HGG are reported. The distribution of radiotherapyinduced cavernous malformations (RICMs) reported in current literature is represented in Figure 3. The radiation dose was very variable, ranging from 18 to 90 Gy; most patients (57%) received a high radiation dose of 40 up to 60 Gy. The time interval between the irradiation and the diagnosis of CAs was very variable (1 to 52 years), with most cases (65%) occurring within 10 years after irradiation. A correlation has been found between a radiation dose >30Gy and a shorter   (1). Multiple CAs were found in 36% patients, and clinical and/or radiological evidence of haemorrhage was reported in 38% of the radiation-induced cases, a significantly higher incidence compared with sporadic cavernomas (3, 6-8).
Our case presents several elements of distinctiveness being unusual due to the patient age, type of radio-treated tumour and CA location in the posterior fossa. The age of our patient, both at the irradiation (62 years) and at the appearance of the cavernoma (66 years), is very atypical. Indeed, among the 100 reviewed patients, at the diagnosis only 5 were older than 40 years (9), and none was older than 50 years. Moreover, at the CAs appearance only 5 patients (10) were older than 50 years and none was older than 60 years. Interestingly, all but one of these adult patients had received radiation doses greater than 60 Gy. On the other hand, the median latency time to diagnosis was 8.2 years, similarly in younger patients reports.
The present case is only the third reported in the literature of a brain cavernoma after HGG irradiation (11)(12)(13)(14)(15)(16)(17)(18)(19), although it is the first report of "de novo" appearance of a cavernous malformation in a patient who had radiation therapy for glioblastoma in such an advanced age (>60 years of age). Indeed, the higher incidence observed in LGGs is probably due to the longer mean survival of these patients compared with HGGs.
The infratentorial location of CAs at the superior surface of cerebellar hemispheres is unusual as well, being this region close to the margins but not included within the irradiation field. It has been suggested that low radiation doses are more efficient to induce CAs; indeed, higher radiation dose delivered at the centre of the field of irradiation may result in extensive cellular apoptosis, thus preventing the CA formation. Con- Figure 3. Distribution of CNS radiotherapy-induced cavernous malformations, according to primary tumours versely, the periphery of the field is at higher risk, as the radiation may modify the genetic stability, inducing abnormal vascular proliferation without substantial cell apoptosis (2).
The management of the radiation-induced CAs mainly depends on clinical manifestations and mean survival time associated with the primary lesion. Generally, when clinically silent, CAs may benefit from a regular MRI follow-up, especially in patients with small CAs and short life expectancy, as in the present case. Surgical treatment is indicated in cases with conspicuous haemorrhage or should be limited to younger patients with stable disease, low grade lesions and/or and long life expectancy.
On imaging, CAs have a distinctive appearance of the nidus with little or no surrounding edema (1). CT may show ring-like calcification with a core reticulation of variable attenuation, with usually no contrast enhancement (1,13). MRI imaging shows a reticulated core of heterogeneous signal intensity giving a typical "popcorn" appearance, with a dark peripheral rim of hemosiderin (14,15).
A comparison between patients with RICMs and those with non-radiotherapy-induced lesions showed that there are no significant differences in size, location and imaging appearance, although RICMs are more often multiple and present some different histologic features (13,16,(46)(47)(48).
Another difference lies in the possible clinicalradiological progression; variation in size and imaging characteristics is a more frequent feature of "de novo" cavernomas, that have significantly higher VEGF, MIB-1 and Ki-67 expression compared to congenital stable and indolent ones (17)(18)(19). Therefore, it may be suggested that the production of the angiogenic factors such as VEGF and TGF may play a crucial role in the formation of radiation-induced Cas (49)(50)(51)(52)(53)(54).
The mechanism of CAs formation is not completely defined. It is controversial whether radiation therapy causes enlargement of a pre-existing small cavernoma, or induces a "de-novo" cavernous malformation due to direct radiation-induced damage in blood vessels and DNA injury in predisposed pa-tients (13).
In conclusion, the occurrence of CAs in elderly patients after glioblastoma radiotherapy is exceptional, although its prevalence may change over time. In fact, this kind of complication could become more frequent because of new treatment lines with progressively increasing survival time of patients with HGG; in this light radiation field margins should be considered particularly susceptible to this kind of vascular damage.