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Abstract：
BACKGROUND: Radiation treatment for diseases of the brain can result in hemorrhagic adverse radiation effects. The underlying pathologic substrate of brain bleeding after irradiation has not been elucidated, nor potential associations with induced somatic mutations.
METHODS: We retrospectively reviewed our department\'s pathology database over 5 years and identified 5 biopsy specimens (4 patients) for hemorrhagic lesions after brain irradiation. Tissues with active malignancy were excluded. Samples were characterized using H&E, Perl\'s Prussian Blue, and Masson\'s Trichrome; immunostaining for B-cells (anti-CD20), T-cells (anti-CD3), endothelium (anti-CD31), macrophages (anti-CD163), α-smooth muscle actin, and TUNEL. DNA analysis was done by two panels of next-generation sequencing for somatic mutations associated with known cerebrovascular anomalies.
RESULTS: One lesion involved hemorrhagic expansion among multifocal microbleeds that had developed after craniospinal irradiation for distant medulloblastoma treatment. Three bleeds arose in the bed of focally irradiated arteriovenous malformations (AVM) after confirmed obliteration. A fifth specimen involved the radiation field distinct from an irradiated AVM bed. From these, 2 patterns of hemorrhagic vascular pathology were identified: encapsulated hematomas and cavernous-like malformations. All lesions included telangiectasias with dysmorphic endothelium, consistent with primordial cavernous malformations with an associated inflammatory response. DNA analysis demonstrated genetic variants in PIK3CA and/or PTEN genes but excluded mutations in CCM genes.
CONCLUSIONS: Despite pathologic heterogeneity, brain bleeding after irradiation is uniformly associated with primordial cavernous-like telangiectasias and disruption of genes implicated in dysangiogenesis but not genes implicated as causative of cerebral cavernous malformations. This may implicate a novel signaling axis as an area for future study.
METHODS: We retrospectively reviewed our department\'s pathology database over 5 years and identified 5 biopsy specimens (4 patients) for hemorrhagic lesions after brain irradiation. Tissues with active malignancy were excluded. Samples were characterized using H&E, Perl\'s Prussian Blue, and Masson\'s Trichrome; immunostaining for B-cells (anti-CD20), T-cells (anti-CD3), endothelium (anti-CD31), macrophages (anti-CD163), α-smooth muscle actin, and TUNEL. DNA analysis was done by two panels of next-generation sequencing for somatic mutations associated with known cerebrovascular anomalies.
RESULTS: One lesion involved hemorrhagic expansion among multifocal microbleeds that had developed after craniospinal irradiation for distant medulloblastoma treatment. Three bleeds arose in the bed of focally irradiated arteriovenous malformations (AVM) after confirmed obliteration. A fifth specimen involved the radiation field distinct from an irradiated AVM bed. From these, 2 patterns of hemorrhagic vascular pathology were identified: encapsulated hematomas and cavernous-like malformations. All lesions included telangiectasias with dysmorphic endothelium, consistent with primordial cavernous malformations with an associated inflammatory response. DNA analysis demonstrated genetic variants in PIK3CA and/or PTEN genes but excluded mutations in CCM genes.
CONCLUSIONS: Despite pathologic heterogeneity, brain bleeding after irradiation is uniformly associated with primordial cavernous-like telangiectasias and disruption of genes implicated in dysangiogenesis but not genes implicated as causative of cerebral cavernous malformations. This may implicate a novel signaling axis as an area for future study.
摘要：
背景：脑部疾病的放射治疗可导致出血性不良放射作用。照射后脑出血的潜在病理基础尚未阐明，与诱导的体细胞突变也没有潜在的关联。
方法：我们回顾性回顾了我们部门5年的病理数据库，确定了5个活检标本（4例）为脑照射后出血性病变。排除有活动性恶性肿瘤的组织。使用H&E对样品进行表征，Perl\的普鲁士蓝,和Masson的三色；B细胞免疫染色（抗CD20），T细胞（抗CD3），内皮（抗CD31），巨噬细胞（抗CD163），α-平滑肌肌动蛋白，还有TUNEL.DNA分析是通过两组与已知脑血管异常相关的体细胞突变的下一代测序进行的。
结果：一个病变与多灶性微出血中的出血性扩张有关，该多灶性微出血是在颅骨照射治疗远处髓母细胞瘤后形成的。证实闭塞后，在局灶性照射的动静脉畸形（AVM）的床上出现了三处出血。第五个样本涉及的辐射场与辐照的AVM床不同。从这些,确定了2种出血性血管病理模式：包裹性血肿和海绵状畸形。所有病变包括毛细血管扩张与内皮畸形，与伴有炎症反应的原始海绵状畸形一致。DNA分析显示PIK3CA和/或PTEN基因中的遗传变异，但排除了CCM基因中的突变。
结论：尽管病理异质性，照射后的脑出血与原始海绵状毛细血管扩张和与血管生成障碍有关的基因的破坏一致相关,但与引起脑海绵状畸形的基因无关.这可能暗示了一个新的信号轴作为未来研究的领域。
方法：我们回顾性回顾了我们部门5年的病理数据库，确定了5个活检标本（4例）为脑照射后出血性病变。排除有活动性恶性肿瘤的组织。使用H&E对样品进行表征，Perl\的普鲁士蓝,和Masson的三色；B细胞免疫染色（抗CD20），T细胞（抗CD3），内皮（抗CD31），巨噬细胞（抗CD163），α-平滑肌肌动蛋白，还有TUNEL.DNA分析是通过两组与已知脑血管异常相关的体细胞突变的下一代测序进行的。
结果：一个病变与多灶性微出血中的出血性扩张有关，该多灶性微出血是在颅骨照射治疗远处髓母细胞瘤后形成的。证实闭塞后，在局灶性照射的动静脉畸形（AVM）的床上出现了三处出血。第五个样本涉及的辐射场与辐照的AVM床不同。从这些,确定了2种出血性血管病理模式：包裹性血肿和海绵状畸形。所有病变包括毛细血管扩张与内皮畸形，与伴有炎症反应的原始海绵状畸形一致。DNA分析显示PIK3CA和/或PTEN基因中的遗传变异，但排除了CCM基因中的突变。
结论：尽管病理异质性，照射后的脑出血与原始海绵状毛细血管扩张和与血管生成障碍有关的基因的破坏一致相关,但与引起脑海绵状畸形的基因无关.这可能暗示了一个新的信号轴作为未来研究的领域。
