Abbreviations

RIC — radiation-induced cyst

CA — contrast agent

Analysis of the mechanisms of radiation-induced damage to nervous system, methods of radioprotection, prevention and treatment of complications of radiotherapy are the key issues of radiobiology. Radiation-induced cyst is relatively rare complication that often occurs many years after irradiation in patients with intracranial diseases, head and neck tumors. Moreover, increased life expectancy and improvement of treatment result augmentation of the number of patients with this disease. Single or multiple radiation-induced cysts with progressive growth and focal or general cerebral symptoms usually require surgical treatment.

Radiotherapy is an important approach in the treatment of various intracranial diseases, head and neck neoplasms. This method is used as adjuvant treatment and isolated approach. Like any other method, radiotherapy is associated with certain complications. Fisher reported the first observation of radiation-induced necrosis 1930 [1]. In 1937, O’Connell and Brunshwig first described development of intracranial complications after irradiation of glial brain tumor [2]. To date, all radiation-induced brain lesions may be divided into several groups depending on terms of their development. These are acute (during treatment), subacute (within 6 months after radiotherapy) and delayed cysts [3]. Improving the methods of treatment and diagnosis, increased life expectancy of patients made it possible to observe radiation-induced brain lesions occurring in many years after radiotherapy. One of these delayed complications is radiation-induced cyst. Literature data on this disease are mainly presented by case reports or small samples (3—28 patients). Interestingly, the largest number of reports is devoted to cysts radiotherapy for brain AVM [4—13], nasopharyngeal cancer [1, 3, 14—17]. There are reports on the development of cysts after irradiation of pituitary tumors [2], meningiomas [18—22], cranial nerve neurinomas [23, 24], gliomas [25] and metastatic brain tumors [26]. Thus, brain RIC can develop after radiotherapy for primary and secondary intracranial or extracranial lesions of the head and neck.

Statistical data in various publications are significantly different. This may be explained by several significant reasons. Firstly, incidence of this lesion depends on follow-up period and systematic fashion of neuroimaging studies. Secondly, even patients with the same primary disease are heterogeneous regarding the type and parameters of irradiation. Finally, according to some researchers, there are no clear diagnostic criteria for determining RIC. For example, some specialists distinguish radiation-induced cavitation (small asymptomatic cysts) into a separate group [6]. Moreover, cysts can occur after previous hemorrhage or surgery and may not be associated with radiotherapy. Therefore, collection and analysis of data is significantly complicated.

Incidence of radiation-induced intracerebral cysts varies from 0.4% [7] to 28% [9]. According to the latest meta-analysis, cysts develop in 3% of patients undergoing radiotherapy for brain AVM [27]. These data are similar to the results obtained by Maryashev S.A. in the Research Center of Neurosurgery (2.9%) [28]. RICs were detected in 3.46% of patients after radiotherapy for nasopharyngeal carcinoma [14] and in 3.9% of patients with vestibular schwannomas [24]. Cysts were more common after irradiation of benign gliomas (9.8%) [25] and intracranial metastases (10%) [26]. On the contrary, this complication occurs only in 1—1.7% of patients with meningiomas [18, 19] and 0.9% in patients with pituitary tumors [2].

The terms of development of RICs also widely vary from 2 months [20] to 27 years [17]. Latent period varies depending on certain disease. This period is shorter in patients with meningiomas (1.5 years) [18—22], in patients with cerebral AVM — 6.5 years [27], nasopharyngeal carcinomas — 9.2 years [14].

As a rule, cysts are solitary formations. Descriptions of multiple cysts are extremely rare [14, 3].

It is difficult to determine the reliable relationship between symptomatic and asymptomatic RICs. In some series, clinical manifestations were observed in 100% of patients [14], in the others — only in 18% [28].

Symptomatic cysts require surgical treatment. There are only few descriptions of effective conservative therapy or self-regression of post-radiation cysts [8, 10]. Refusal of surgery in one case was followed by death of the patient due cyst enlargement [26]. Various surgeries have been proposed for the treatment of this lesion (single percutaneous puncture, Ommaya reservoir implantation, cystoperitoneal bypass surgery, fenestration or excision of the cyst walls). The choice of surgical method depends on surgeon’s preferences, there are no clear recommendations. However, many authors advise gradually increasing aggressiveness of treatment. Excision of cyst is recommended only for recurrence [5]. Some surgeons consider that inefficiency of bypass surgery is associated with high protein content in the cystic fluid [11, 18].

Differential diagnosis of tumor process and post-radiation changes is extremely difficult since both lesions are accompanied by disorders of blood-tissue barrier and abnormal contrast enhancement on T1WIs [29, 30]. For example, Lee reported a patient with RIC. The patient underwent surgery for suspected malignant glioma in 27 years after radiotherapy for basal cell epithelioma [1]. In this regard, follow-up examination should be supplemented by special diagnostic methods to assess tissue metabolic activity (PET-CT) or perfusion characteristics (KT perfusion, DSC perfusion, DCE perfusion and ASL perfusion). Non-contrast ASL perfusion is of great interest because this method does not require contrast agent administration and arterial blood protons are used as endogenous tracers. Recent studies have shown the high efficiency of this technique for differential diagnosis of continued tumor growth and post-radiation changes [31, 32].

RICs occur after radiotherapy [2—4, 15—17] and radiosurgery [4—13]. It is considered that predictors of cyst development after irradiation are total dose over 50—55 Gy with standard fractionation, single dose over 2 Gy, large volume of irradiated brain tissue and intake of cytostatic drugs [2, 4, 5]. Redo irradiation is associated with increased risk of RICs (1.3% vs. 10%) [11].

Pathogenesis of RICs is not completely understood. The most popular theory is based on endothelial damage to blood-brain barrier, blood cells extravasation and triggering autoimmune inflammatory process [14, 33, 34,].

Histological examination of the cyst walls revealed signs of extensive necrosis, reactive gliosis, neuronal degeneration, telangiectasia, hyalinization and calcification of the vascular walls [14]. The same authors found expression of tumor necrosis factor (TNF) and hypoxia-induced factor-2a (HIF-2a) in reactive astrocytes, while expression of vascular endothelial growth factor (VEGF) and cytokeratin (CK) was absent.

A modern view on versatility and complexity of pathological processes in brain matter after irradiation was comprehensively described by A. Piskunov [35]. An interesting aspect of report is prediction of radiation-induced complications and their severity via analysis of peripheral blood mediators of inflammation, markers of cellular activation and damage, markers of nuclear processes and endocrine mediators.

According to MRI data, morphogenesis of radiation-induced cysts covers a long period of several years and begins with the appearance of small focus of radiation-induced necrosis in white matter with uneven contrast enhancement [30]. Subsequently, focal necrosis is transformed into a cyst or cystic conglomerate with uneven and inconsistent contrast enhancement of the walls. Further enlargement of these cysts may be accompanied by hemorrhage, compression of adjacent structures and neurological symptoms. Giant cysts (up to 70 ml) were described [11].

Case report

A 27-year-old patient with complaints of severe headache accompanied by nausea, impaired gait and general weakness was hospitalized to Burdenko Neurosurgery Center in 2015. A nodular bright red tumor 3.5x2x1 cm with bloody discharge was diagnosed in 2010 on the background of birthmark in parietal-temporal zone. Regional cervical lymph nodes were intact. Skin melanoma of parietal-temporal zone (grade IIc, T4N0M0) was diagnosed. Combined treatment was carried out. Preoperative irradiation (linear accelerator SL-20) has been performed since May 5, 2010 (electron beam energy 12 MeV, 5 fractions by 10 Gy, normalized 90% isodose). Irradiation field dimension was 6x6 cm, emitter-surface distance — 96 cm. Tissue-equivalent bolus with a thickness of 2 cm was used for optimal dose distribution.

Resection of ulcerated pigmented epithelioid cell melanoma of the right parietal-temporal area together with parotid and lateral cervical fatty tissue was performed on May 13, 2010.

Morphological diagnosis: ulcerated pigmented epithelial cell melanoma with Clark invasion index IV, Breslow thickness 9.7 mm. Negative resection margins were observed. There was no evidence of tumor growth in the lymph nodes.

Courses of chemotherapy with Decarbosin 2000 mg i.v. every 3 weeks have been started since May 6, 2010. Postoperative adjuvant gamma-therapy was administered for right-sided cervical, supraclavicular and subclavian lymph nodes (single focal dose 3 Gy, total dose 30 Gy).

Generalized convulsive seizures occurred at the end of 2011 (a year after irradiation). MRI of the brain revealed right-sided contrast-enhanced zone in temporal and frontal lobes with perifocal edema and no median structures displacement (Fig. 1a—d).

CT-perfusion was performed for differential diagnosis between metastatic melanoma and radiation-induced necrosis. Radiation-induced transformation of the brain matter was confirmed (Fig. 1e—g). No significant clinical deterioration was observed until 2015 (5 years after irradiation). Elective MRI of the brain on May revealed a cyst within the radiation exposure area in the right temporal lobe. Cyst enlargement and left-sided displacement of the middle structures up to 20 mm followed by above-mentioned complaints have been diagnosed by September 2015 (Fig. 2a, b).

General cerebral symptoms, left-side hemiparesis up to 3—4 points and impaired gait were noted at admission. Neuroophthalmological examination revealed complete left-sided homonymous hemianopsia without signs of ICH. Cicatricial-atrophic changes of soft integument of the head were observed in frontotemporal area without signs of recurrent tumor (Fig. 3).

Ommaya reservoir was installed inside the cyst of the right temporal lobe on September 7, 2015. Punctures of the Ommaya reservoir with drainage of 30—35 ml of serous-hemorrhagic contents were performed in postoperative period (4 sessions). Regression of cerebral symptoms, improved gait and increased muscle strength in the left limbs were observed at discharge (4 days after surgery). Control neuroophthalmological examination confirmed moderate regression of visual pathway injury in the right hemisphere and no signs of ICH. According to CT data at discharge, significant reduction of the cyst (from 140 to 50 ml), decrease of lateral dislocation and straightening of the unilateral lateral ventricle were found (Fig. 2d, e). Patient's condition remained stable over the next two years. However, control CT in January 2017 (7 years after irradiation) revealed cystic transformation of radiation-induced necrosis in the right frontal lobe. As a result, two small cysts without mass-effect developed. Complete collapse of the cyst walls in the right temporal lobe was found (Fig. 4).

The patient was followed-up. Control CT of the brain was performed in November 2017 on the background of complete clinical well-being (no left-side hemiparesis) and the absence of neuroophthalmological symptoms. Significant cystic enlargement (over 140 ml) in the right frontal lobe with severe mass-effect and right-sided middle structures displacement up to 2 cm were diagnosed (Fig. 5).

The second Ommaya reservoir was installed inside the cyst of the right frontal lobe on November 13, 2017. A feature of this intervention was the use of Fiagon intraoperative magnetic navigation system. Both adjacent cysts were drained by a single ventricular catheter that required the exact selection of trajectory. Reservoir deployment was followed by drainage of a viscous cystic fluid with high protein content and cytosis. Postoperative period was uneventful. Puncture of the Ommaya reservoir was followed by withdrawal of up to 20 ml of fluid (6 procedures). However, repeated punctures of the Ommaya reservoir were not followed by significant reduction of cystic volume. Decrease of perifocal edema and lateral dislocation (from 20 mm to 7 mm) and partial straightening of the unilateral lateral ventricle were only noted (Fig. 6).

Surgical intervention was complicated by local radiation-induced cicatricial-atrophic changes of soft integuments in frontotemporal area. The patient was followed-up. His condition remains stable over the next 2 years despite a moderate MRI-confirmed cyst enlargement (there are no neurological symptoms).