Pathology of Cavernous Malformations in Children

Pathophysiology

De novo formation

• De novo formation possible: Several studies have quantified the incidence of de novo formation of cavernous malformations, with results ranging from 0.1–0.6 new lesions per patient-year (26, 31, 70).
• De novo formation most common in familial form: De novo formation is much more common in the familial than in the sporadic form of the disease. Over time, 27.5–30% of patients with the familial form developed de novo cavernous malformations, while only 4.1% of patients with sporadic lesions developed de novo cavernous malformations (31, 32, 48).

GRE axial MRI of multiple cavernous malformations: The patient is a 1-year-old boy who presented after a seizure.

T2-weighted MRI of multiple cavernous malformations: The image is that of the same boy as above at age 7 years, showing at lease 3 new cavernous malformations.

Growth

• Growth possible due to serial microhemorrhages: The size of a cavernous malformation can change over time. Pozzati et al. presented three cases in which the cavernous malformation grew substantially over time (48). The authors theorized the mechanism to be serial microhemorrhages followed by organization, fibrosis, and calcification. Clatterbuck et al. observed 68 patients with 114 cavernous malformations (11). Serial imaging over a mean period of 3.7 years found that 22% of lesions were stable in size, 43% of lesions increased in size, and 35% of lesions decreased in size. Many of these lesions had periods of both increase and decrease in size.

Molecular/Genetic Pathology

• Familial form with autosomal dominant inheritance: The familial form is inherited in an autosomal dominant fashion with an incomplete clinical and neuroradiological penetrance. About 50% of the decedents are affected by the disease. It is a germline mutation, and molecular genetic screening tests are available for diagnosis. The natural history of the familial form of cavernous malformations parallels that of their sporadic counterpart.
• Proportional distribution: Lesions occur throughout the CNS in rough proportion to the tissue volume of the various compartments (80% supratentorial, 15% posterior fossa, and 5% spinal cord). De novo lesions were observed at a rate of 0.4 new lesions per patient-year (70).

Histopathology

• Endothelial-lined, large, anomalous vessels: Cavernous malformations consist of clusters of cavernous anomalous vessels lined by endothelial cells. Russel and Rubinstein defined cavernous malformations as vascular malformations with abnormally dilated blood vessels (56).
• Intervening collagen matrix: The endothelial cells are embedded in a dense collagenous matrix. Because of this nature, Cavernous malformations are classified not as a tumor but as a congenital anomaly. Compared to AVMs, cavernous malformations do not contain brain parenchyma.
• Endothelium lacks watertight junctions: Ultrastructural examination of cavernous malformations reveals gaps between endothelial cells due to a lack of watertight junction. There is also a lack of cells such as pericytes, smooth muscle cells, or astrocytes. These findings are thought to be why the leakage of blood cells into the surrounding brain tissue occur.
• Hemosiderin and thrombosis found in lesion: Some part of the mass may be thrombosed. The reason remains unclear, but one hypothesis is the low flow of the blood and the exposure of the basal lamina inside the lumen. Hemosiderin and reactive gliosis are also found in the adjacent brain.
• No capsule: There is no capsule surrounding the anomaly (56).

Cavernous malformation of the brain: H&E stained photomicrograph shows a complex of vascular space without intervening brain parenchyma. (Courtesy of Professor Ho-Keung Ng, Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, the Chinese University of Hong Kong)