2020 NPA-04

This case was originally published in 2020. The information provided in this case was accurate and correct at the time of initial program release. Any changes in terminology since the time of initial publication may not be reflected in this case.

A 73-year-old woman with a remote history of mucinous breast carcinoma and recent discovery of metastatic carcinoma to the lung complained of worsening balance and memory changes as well as arm numbness for two months. CT imaging of the head without contrast revealed a 1.5-cm right frontal lobe lesion exhibiting increased attenuation but no evidence of mass effect or acute infarct. The lesion was favored to represent metastatic disease. The patient underwent biopsy of the lesion.

Tissue Site
Brain, right frontal lobe

The whole slide image provided is an H&E-stained image of the brain from a right frontal lobe biopsy.

The diagnosis is cerebral amyloid angiopathy (CAA). Although termed cerebral amyloid angiopathy, vascular amyloid deposition also occurs in the cerebellum and brainstem. Amyloid-ß (Aß) deposition in the cerebral vasculature is a major contributor to cognitive decline and is the most common cause of lobar intracerebral hemorrhage (ICH) in the elderly. Radiographic imaging may demonstrate a single, lobar hemorrhage but may also show multiple microinfarcts and microhemorrhages. Occasionally, severe CAA can lead to rapidly-progressive dementia, even in the absence of Alzheimer disease. CAA can occur sporadically, may be familial (eg, meningovascular amyloidosis, hereditary cerebral hemorrhage with amyloid, familial British dementia), and is strongly, but not invariably, associated with Alzheimer disease. Aß deposition and a decrease in smooth muscle cells within vascular media is seen in CAA. Aß is generated by cleavage of the amyloid precursor protein, and mutations of the amyloid precursor protein (APP) gene found in some familial forms of Alzheimer disease result in development of CAA. The affected age ranges from the third decade (in hereditary forms) to the sixth decade (sporadic and age-related forms). Small and large lobar hemorrhages in the absence of other causes (trauma, tumor, coagulopathy) suggest the presence of CAA in elderly patients and fulfill criteria for antemortem diagnosis of CAA (the Boston criteria). The risk of CAA increases in individuals harboring the apolipoprotein epsilon APOE2 and APOE4 genotypes. Familial forms of CAA include hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D) and hereditary cystatin C amyloid angiopathy-Icelandic type (HCCAA-I), both of which are autosomal dominant and are commonly associated with brain hemorrhage. HCHWA-D is caused by a mutation in the APP gene, and HCCAA-I is caused by a mutation in the CST3 gene.

Gross and microscopic examination of brain specimens in CAA may reveal hemorrhagic tissue with surrounding reactive changes and no definite mass. The small arteries and arterioles are preferentially affected, and CAA can exhibit a patchy distribution. The leptomeningeal and cortical vessels in and around the areas of hemorrhage may demonstrate amorphous eosinophilic thickening due to amyloid deposition (Image A, Image B, and Image C). Additional vascular findings include vessel splitting, microaneurysms, vessel wall fibrosis, fibrinoid necrosis, and thrombosis. Parenchymal neuritic plaques and neurofibrillary tangles may also be present and can be highlighted by Bielschowsky silver stain (Image D and Image E). The vessels are congophilic, exhibiting birefringence under polarized light, and are positive by fluorescence microscopy using Thioflavin T/S. IHC for Aß is positive within the vessels of sporadic CAA, Down syndrome-associated CAA, Alzheimer disease-associated CAA, and some forms of familial CAA (Image F and Image G). Aß vascular immunoreactivity can be diffuse or focal. It is important to note that not all forms of CAA will exhibit immunoreactivity for Aß, as the type of amyloid may not derive from the amyloid precursor protein. For example, HCCAA-I exhibits positive Congo red and Thioflavin T/S but is negative by Aß IHC. Amyloid angiopathy with granulomatous inflammation (Aß-related angiitis) can occur and shows perivascular to transmural inflammation comprised of histiocytes and lymphocytes. This form of Aß vasculopathy manifests in the seventh to eighth decades and may respond to immunosuppressive therapy.

The differential diagnosis includes other small vessel vasculopathies such as hypertensive-related arteriolar sclerosis and hereditary small vessel disease (CADASIL/CARASIL, RVCL, COL4A1). Importantly, although plaques and neurofibrillary tangles might be seen in cases of CAA and should be reported, it is not appropriate to diagnose Alzheimer disease on surgical material due to limited sampling. Management of patients with CAA is aimed at the prevention of hemorrhagic events. ICH related to CAA is treated similarly to sporadic ICH. Disease-specific treatment for CAA is not available to date, and prognosis is dependent on the extent of hemorrhage.

• CAA can present with lobar and/or microhemorrhages or infarcts, and CAA with hemorrhage can appear as a mass lesion on neuroimaging.
• The cerebral vasculature is congophilic in all forms of CAA and positive for Aß in most forms of CAA.
• Sporadic forms of CAA predominate, but hereditary forms exist.
• Alzheimer disease is often, but not invariably, associated with CAA, and vice versa. The diagnosis of Alzheimer disease should not be established on surgical material alone.
• Management of CAA is centered around prevention of ICH.

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