Peritumoral and intratumoral hemorrhage after stereotactic radiosurgery for renal cell carcinoma metastasis to the brain

Abstract

Stereotactic Radiosurgery (SRS), provides in a single session, a high dose of radiation to a localized brain tumor volume. Acute adverse reactions after treatment are not uncommon, but are usually transient and generally are well controlled by medication. The authors wish to report this rare complication of intratumoral and peritumoral hemorrhage immediately after LINAC SRS treatment of single temporal lobe metastasis from renal cell carcinoma and discuss plausible causes for this case and its management. A review of the literature on acute intracranial hemorrhage after radiosurgery for metastatic lesions is provided. A 68-year-old man underwent SRS treatment for a single left temporal lobe metastasis. No complications were noticed during frame fixation, treatment itself, or frame removal. Thirty minutes after the end of treatment session the patient acutely became aphasic and right hemiplegic. An urgent CT-scan revealed peritumoral and intratumoral hemorrhage. Patient underwent urgent surgical treatment during which was performed gross total excision of the brain metastasis and total removal of the clot. The patient had a good recovery after surgery and he was discharged with moderate aphasia but able to walk with no other neurological deficits. Stereotactic radiosurgery for metastatic brain tumors should not be considered as a risk-free procedure, especially in cases of neoplasms with high propensity for intratumoral bleeding and, while extremely rare, hemorrhagic complications can occur after treatment. The possibility of acute complications and their consequences have to be discussed with the patient and his or her relatives before radiosurgical treatment.

INTRODUCTION

Brain metastasis is the most common type of intracranial tumor [1]. Each year the number of metastatic brain tumors diagnosed by far exceeds the combined total of other intracranial tumors. Renal cell carcinoma accounts for 90% of all primary kidney tumors, and the overall incidence of this cancer is rising for reasons beyond those accounted for increased use of imaging studies [2]. Four to 17% of patients with renal cell carcinoma develop brain metastasis [1,3,4,5,6,7,8,9]. Treatment options in patients with brain metastases from renal cell cancer include resection, whole-brain radiation therapy, and symptomatic medical management with corticosteroid agents, all of which lead to a median survival of 4 to 5 months [5,10,11,12]. Radiosurgery is a highly effective management option for both single and multiple metastatic brain tumors. Acute adverse reactions after treatment are not uncommon, but are usually transient and generally are well controlled by medication [13,14,15,16,17,18]. Development of neighboring radiation necrosis, increases in surrounding edema, and tumor hemorrhage are reported complications of radiosurgery for solitary metastatic lesions [19]. Hemorrhage into intracranial neoplastic lesions may occur spontaneously, as a sequelae of surgery, diagnostic procedures or trauma and potentially lead to catastrophic consequences due to acute compression of the eloquent brain structures [20,21]. In a small group of patients with 52 treated lesion from renal cell carcinoma, complications were very rare and none of them suffered a delayed hemorrhage [22]. In larger series, Sheehan et al [23] in a retrospective review of 69 patients underwent stereotactic radiosurgery for a total of 146 renal cell cancer metastases reported one patient with fatal intratumoral hemorrhage after treatment, while Wowra et al [24] in a series of 75 patients with 350 treated intracranial lesions, reported a delayed hemorrhage rate of 12%.

Acute hemorrhagic event taking place during a radiosurgery treatment session for metastatic lesion, or in the immediate post-treatment period, is extremely rare. The authors present in this case report the acute onset of neurological symptoms, in one patient treated with LINAC-based stereotactic radiosurgery for a single brain metastasis from renal cell carcinoma, due to intratumoral and peritumoral intraparenchymal hemorrhage, which occurred immediately after stereotactic radiosurgery.

CASE REPORT

The authors present the case of a 68-year-old man that was admitted for the management of a single renal cell carcinoma metastasis to the brain. The metastasis was located in the left temporal lobe, surrounded by edema and causing mass effect. In the Magnetic Resonance (MR) imaging the mass was well-demarcated, highly enhanced, 30 mm in diameter (Fig. 1). Previous treatment included systemic chemiotherapy, despite which by the time of patient’s admission the disease was disseminated. Neurological examination at admission did not reveal any neurological deficits. The Karnofsky performance scale score was 80, and patient’s hypertension was pharmacologically well managed (oral administration of 10 mg tablets of Amlodipina, Norvasc-Pfizer, once in a day), with no bleeding tendency in the hematological examination. The patient had received steroid therapy during the last two weeks before radiosurgery (Dexamethasone 4mg, intramuscular administration, twice in a day and Ranitidine 300 mg, once in a day, oral administration). After non-complicated frame fixation, which was done under local anesthesia, contrast enhanced Computed Tomography (CT) images were obtained for treatment planning and radiation dosimetry. Stereotactic radiosurgery (SRS) was performed to the brain tumor in a single session with main mass maximum dose of 20 Gy in the center and 80% isodose line in the margin of the tumor (Fig. 2). The volume of the lesion was 17,05 mL. Constant monitoring of the blood pressure during all stages of the procedure did not reveal any abnormalities and the patient was awake and collaborative throughout the 30-minute radiosurgery treatment. No complications were marked during frame fixation, pre-treatment neuroradiological investigation, the treatment session itself, and frame removal.

Figure 1.

Cerebral MR, gadolinium contrast enhanced, imaging demonstrating the left temporal renal cell carcinoma metastasis before LINAC stereotactic radiosurgery treatment.

Figure 2.

Treatment plan for LINAC stereotactic radiosurgery of the left temporal metastatic lesion. Isodose line of 80 (yellow line), 50 (light blue) and 30 % (dark blue) are shown. Homogeneous dose distribution within the lesion is well noted, without intratumoral or peritumoral intraparenchymal hemorrhage.

Thirty minutes after the end of treatment session, at the time of transportation to the ward, the patient acutely became aphasic and right hemiplegic. An urgent CT scan revealed peritumoral intraparenchymal and intratumoral hemorrhage (Fig. 3). Conservative therapy was undertaken without any improvement of his clinical conditions and the patient felt in coma. Patient underwent urgent surgical treatment during which was performed gross total excission of the brain metastasis and total removal of the blood clot (Fig. 4). Intraoperatively the clot was detected within the cystic metastatic lesion and the surrounding temporal white matter. Gross total resection of the neoplastic lesion and hemostasis were achieved without complications. The patient had a good recovery after surgery. He was discharged two weeks later, with moderate aphasia but able to walk with no other neurological deficits.

Figure 3.

Cerebral CT-scan, without contrast, obtained after neurological deterioration of the patient revealing intratumoral (arrows) and peritumoral intraparenchymal hemorrhage.

Figure 4.

Post-operative CT-scan, with contrast, revealing complete removal of the clot and gross-total tumoral excision.

DISCUSSION

In our Department of Neurological Surgery and Stereotactic Radiosurgery from 2000 to 2009 we performed stereotactic radiosurgery (SRS) treatment in 950 patients for a total of 2578 intracranial lesions. Nearly 85% of these patients were treated for brain metastases for a total of 2190 lesions. Ninty three patients (9,8%), had single or multiple metastases from renal cell carcinoma. In our Department constant monitoring of the vital signs and anesthesia team are available for the safety and comfort of the oncologic patients treated with LINAC-based stereotactic radiosurgery. This is the first case of peritumoral and intratumoral hemorrhage after radiosurgery in our 10-year experience of SRS management of metastatic intracranial lesions.

Early side effects after radiosurgery of intracranial lesions are encountered with an incidence of 24-67%, and in 13-18% of cases occur within 24 hours after treatment [13,15,17,18]. These usually corresponded to swelling of the neoplasm and/or peritumoral brain, or to the irradiation of the specific structures, such as area postrema [13,14,17]. Risk factors for clinically significant acute adverse reactions include large size of the lesion, its location in a critical brain area, prominent peritumoral edema, intracranial hypertension, and high irradiation dose [14,15,17,18]. Nevertheless, the symptoms are usually mild-to-moderate and only few patients need readmission to hospital or prolonged hospitalization [15,18]. Periprocedural administration of dexamethasone is considered as an effective prophylactic measure [13,14].

Spontaneous hemorrhage in brain tumors is encountered with an incidence of 5% and can be provoked by ventricular drainage, ventriculoperitoneal shunting, cerebral angiography, and head injury [20]. In prospective series, a given presenting spontaneous intracerebral hemorrhage can be associated with an intracranial tumor approximately 7% of the time [25]. Renal cell carcinoma metastatic lesions in particular have a propensity to undergo spontaneous hemorrhage [26,27]. A large prospective series of 350 metastases from renal cell carcinoma treated with Gamma Knife (GK) radiosurgery, revealed a delayed bleed rate of 12% of treated patients [24]. Motozaki et al [28], described peritumoral hemorrhage 6 weeks after non complicated radiosurgical management of the solitary metastasis of the breast adenocarcinoma in the basal ganglia. Uchino et al [29], reported peritumoral hemorrhage 2 hours after LINAC-based radiosurgery for multiple brain metastases of the breast cancer. In two previous case reports Izawa et al [30] and Anderson et al [31], described two fatal cases of oncologic patients underwent GK radiosurgery treatment for multiple intracranial metastatic lesions. In the first report [30], a 46-year-old woman was treated for multiple brain metastases from lung cancer (20 Gy to the 50% isodose line). Fifteen minutes post-treatment the patient became unresponsive and the head CT demonstrated a large intraparenchymal hemorrhage in the left cerebellar hemisphere where one of the treated metastases was located. No abnormal values of patient’s blood pressure were recorded during treatment. In the second case, Anderson et al [31] presenting a 71-year-old man underwent GK radiosurgery treatment for five intracranial metastatic lesions from renal cell carcinoma. The planned dosage was 20 Gy to the 50% isodose line for four of the five lesions and 16 Gy to the 40% isodose line for the fifth one. Because of patient’s ankylosing spondylitis, a system of sloped pads was slipped under his back on the radiosurgery treatment table, effectively putting the patient into 15-20° of Trendelenburg positioning. During the treatment, the patient suffered a focal motor seizure involving his left foot. Systemic hypertension during this focal seizure was detected and the patient lost consciousness suffering a generalized seizure. An emergent head CT examination revealed large hemorrhagic lesions at the site of the metastases. For Anderson et al [31], Trendelenburg positioning, possible bleeding disorder, predisposition for renal cell metastatic lesions to hemorrhage, and radiosurgery treatment could all of these or some combination of these factors explain this hemorrhagic complication. Additionally, in the large series of Wowra et al [24], one patient with a treated renal cell metastases did suffer an acute hemorrhage 5 h post-treatment.

The cause of the complication in the present case is not clear. Both acute necrosis of the vessel wall and acute thrombosis of the vessel with subsequent local ischemia could result in hemorrhage. Apoptosis of the endothelial cells, decrease of endothelin production, increase of thromboxan, prostacyclin, and prostaglandin synthesis can occur within few hours after irradiation of the brain tissue and may lead to the dilatation of the vessels and local reduction of the cerebral blood flow [11]. Impairment of tissue perfusion can be facilitated by the peritumoral brain edema. The later was present in our patient before treatment and could have been further augmented by radiosurgery. An underlying coagulopathy which contributed to his acute hemorrhage could not be excluded. The prothrombin time and activated partial thromboplastin times were normal before and after the hemorrhage, but this does not rule out all bleeding disorders. Also, it is known that malignant brain tumors by themselves can cause a local increase of fibrinolytic activity, which can facilitate bleeding [32]. Combination of these factors and concurrent radiosurgical treatment could explain this unfortunate case. Additionally, we could not exclude that spontaneous intratumoral and peritumoral intraparenchymal hemorrhage in our patient occurred at the time of radiosurgical treatment by coincidence.

CONCLUSION

Hemorrhagic complications after radiosurgery for metastatic brain tumors are extremely rare, but can lead to catastrophic events. The authors in this case report do not contend the causal relationship between radiosurgery and tumoral hemorrhage. Despite the timing of the hemorrhage and radiosurgery is tantamount to a causal relationship between the two, we hypothesize that patient’s cause of hemorrhage have been multifactorial and we advocate that the monitoring of blood pressure during all stages of the procedure and control of the coagulation status may be important for the reduction of the hemorrhagic risk, especially in cases of neoplasms with high propensity for intratumoral bleeding. Although, larger studies have shown that there is no substantive link between radiosurgery and hemorrhage in brain metastasis, in fact, some centers do not require cessation of anticoagulation agents prior to radiosurgery except for patients undergoing stereotactic angiography, the possibility of rare acute complications like intratumoral/peritumoral hemorrhage and their consequences have to be discussed with the patient and his or her relatives before radiosurgical treatment. Furthemore, the authors speculate that radiosurgery, at times like in our case, could induce fulminant breakdown of the fragile vessels of the tumor or the surrounding brain resulting in hemorrhage. This last conjecture reflects the fact that acute bleeding took place few minutes after radiosurgery. In any case, given the rarity of these hemorrhagic complications, and the lack of large multi-institutional studies on the subject, there is no definitive evidence of which was or were the factor(s), that contributed to the acute bleeding within the metastatic lesion and the surrounding brain. Finally, authors believe that in selective patients, hemorrhagic complications could be treated aggressively by surgical excision, like in our case, with good outcome.