Pathological Evaluation of Radiation-Induced Vascular Lesions of the Brain: Distinct from De Novo Cavernous Hemangioma

De novo cavernous hemangioma (CH) is the second most common vascular malformation of the central nervous system, with an incidence of approximately 0.5%.1 Patients present with headache, neurologic deficits, or seizures. Currently, magnetic resonance imaging (MRI) is the most sensitive and accurate diagnostic tool for de novo CH, and typically reveals an enhancing multiloculated cystic lesion with popcorn- or mulberry-like features on both T1- and T2-weighted images, due to clustered capillaries and venules that bleed periodically.2 Histologically, de novo CH is composed of proliferating ectatic, single-endothelial lined abnormal vessels that lack smooth muscle, and absence of intervening brain parenchyma within the lesion is also characteristic. Old hemorrhage and reactive gliosis are frequently found at the periphery of the lesion. Most de novo CHs occur sporadically, although some patients have a family history of CH related to mutations in the cerebral cavernous malformation (CCM) genes, CCM1, CCM2, and CCM3. So far, these mutations have been most frequently observed in Hispanic-Americans of Mexican descent. Briefly, these gene are thought to be involved in generation of abnormal vessels and affect brain parenchyma surrounding the endothelial cells.3

Some sporadic cases of CH have been described as late complications of cerebral radiation.4, 5 Stereotactic radiosurgery (SRS), initially introduced by Leksell,6 is now widely applied to patients with various brain lesions, including primary brain tumors,7, 8 metastatic lesions,9, 10 and vascular malformations.11, 12 Some patients who receive SRS develop a localized vascular, tumor-like lesion at the treatment site, months or even years after treatment.13 Together with hemorrhage after brain irradiation, these lesions described as a "radiation-induced cavernous hemangioma" (RICH),14, 15 although some authors refer to such lesions as "radiation-induced telangiectasia".16, 17 Similar to de novo CHs, RICHs present as enhancing lesions on MRI and are found to be composed of vasculature and hemorrhage upon histological examination. So far, there has been no thorough histologic review of RICHs following SRS in comparison to de novo CHs. In the present study, we compared the histological and MRI findings of RICHs following SRS to those of de novo CHs.

RICH has been studied in children with leukemia as a late complication of brain irradiation.15, 18, 19 In patients who underwent cranial irradiation during childhood for the treatment and prevention of hematologic malignancies, such as acute lymphoblastic leukemia, cerebral hemorrhage can develop after several years.18 Both CH and telangiectasia have been reported as possible complications of brain irradiation, and the terms have been used to describe vascular lesions.4, 18, 20 There have been studies about the relationship between brain irradiation during childhood and development of RICH.20, 21 Heckl, et al.15 concluded that the younger the patient was at the time of radiation treatment, the more likely a hemorrhagic event was to develop. In adults, a few RICHs following radiotherapy to treat arteriovenous malformation or a tumor have been reported,22, 23 and the dose of radiation seems to be associated with the risk of developing RICH.4 Regarding the development of RICH, two models have been proposed: one model suggests that RICH is a de novo response to the radiation. Another model suggests the possibility of bleeding from a preexisting occult CH.19 In a previous study of the role of structural proteins and angiogenic factors in CH, vascular endothelial growth factor (VEGF) and basic fibroblast growth factor were highly expressed in CH.24 Since radiation may induce deterioration of the brain blood barrier, hypoxia and subsequent release of VEGF may follow,25 and elevation of VEGF levels could play a role in the development of RICH.

Ionizing radiation and SRS are now widely used to treat a variety of brain lesions, from tumors to vascular malformations.26, 27 However, radiation induces variable histologic changes in the brain parenchyma, including edema, as an early effect, and spongionecrosis, reactive gliosis, and telangiectasia, as late effects.28, 29 Fibrinoid necrosis, hyaline fibrous degeneration, perivascular macrophage collection, telangiectasia, and hemorrhage are results of vascular alteration by radiation.30, 31, 32, 33 As a late complication of whole brain irradiation and SRS, cerebral hemorrhage has been grouped as RICHs34, 35 or radiation-induced telangiectasia.16, 17 Diagnoses thereof are made based on MRI findings rather than histologic examination.23, 36, 37 Unlike ionizing radiation, SRS emits a much higher dose of radiation to a small target area, leading to the shrinkage of the target lesion,38, 39, 40 which in turn results in a small cavitary lesion in the center of the focal area. We hypothesized that RICH may originate from this cavitary lesion rather than malformation of vessels. After tissue destruction, this newly-made small cavity would be filled with blood. Spillage of fibrin would then inhibit further extension of the hemorrhage, and finally, a stabilized hematoma would be made. In support of our hypothesis, the locations of RICHs were identical to the sites of SRS, where prior tumors or vascular malformations existed. The proliferation of thin-walled vasculature and macrophage collection in RICHs are more likely to be radiation-related changes, and greatly different from de novo CH.

Although RICHs have been diagnosed with MRI, radiologic findings of RICHs differed from de novo CHs. While all de novo CHs in current study were typical multiloculated lesions with a popcorn-like appearance and a complete hemosiderin rim, none of the RICHs satisfied these features. Instead, most RICHs showed mixed intensity with an enhancing cystic and/or solid component and an incomplete hemosiderin rim, findings that would be insufficient for a diagnosis of de novo CH.

In terms of patient treatment, de novo CH warrants immediate treatment through surgical removal, because of the risk of intracranial hemorrhage. However, the treatment algorithm for RICH is not well established. Several studies have shown that a sizable proportion of patients with a RICH present with a seizure due to intracranial hemorrhage,5, 21 although some authors have suggested that RICH tends to more often be asymptomatic and have a relatively low risk of intracranial hemorrhage.15, 16 Although surgical intervention is required to remove de novo CH and/or RICH, surgery itself involves the risk of a neurologic deficit. We hypothesized that, since RICH is an inactive hematoma-like lesion, it may follow a more asymptomatic and safe course than de novo CHs, which harbor abnormal vessels bearing shear stress from circulating blood flow. However, the natural course of RICH has yet to be established, and a more precise study with a larger cohort is needed.

In summary, we reviewed hemorrhagic lesions following SRS that have been referred to as RICH. We found that these lesions are distinct from de novo CH in regards to their histologic and radiologic features. Since RICH is a rare condition and a small number of cases were included in current study, well-established radiologic and histologic features should be investigated. Further validation with a larger cohort accompanied with molecular studies, such as CCM gene mutation analysis, would help to elucidate the pathogenesis of RICH and its clinical implications. In conclusion, we suggest that RICH following SRS is more likely to be an inactive organizing hematoma rather than to involve the proliferation of malformed vasculature. Accordingly, the term "radiation-induced cavernous hemangioma" is inappropriate to describe this lesion, and we carefully suggest the term "radiation-induced organizing hematoma."