Case 5 -

Abeta Related Angiitis (Primary CNS Angiitis Associated with Amyloid Angiopathy) Causing a Mass Like Lesion Caterina Giannini, Mayo Clinic, Rochester, MN

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Clinical History The patient is a 74-year-old man, who began noting intermittent difficulty with expressive language. He had problems coming up with the name of a familiar neighbor as well as remembering the name of an ingredient for stew. There was no associated weakness, alteration in awareness, vision, or sensation. A brain CT and subsequently an MRI were obtained. The CT showed an area of low attenuation in the left temporal lobe with tiny associated area of hyperattenuation. A subsequent MRI showed a left temporal large mildly enhancing lesion with mass effect as well as several other areas of abnormal T2 signal in both hemispheres. He underwent a stereotactic biopsy of the left temporal lobe lesion with the clinical suspicion of low- to intermediate-grade glioma, likely multifocal. Case 5 - Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer Case 5 - Slide 2 Click to view with ImageScope Click to view with a Web-Based Viewer Case 5 - Figure 1 Case 5 - Figure 2 Case 5 - Figure 3 Case 5 - Figure 4 Case 5 - Figure 5 Preoperative-CT Case 5 - Figure 6 Preoperative-MRI Case 5 - Figure 7 A-beta amyloid immunostain shows marked A-beta deposits in the vascular walls as well as a moderate number of amyloid plaques surrounding the vessels. Macrophages are present in the vascular walls. Tau protein is negative. There is no evidence of neuritic plaques or neurofibrillary tangles. Introduction: Elderly patients presenting with central nervous system mass lesions are biopsied with the concerns of malignancy. Pathological/Microscopic Findings and any Immunohistochemical or Other Studies: Two H&E slides are submitted for examination, each containing multiple small gray and superficial white matter tissue fragments admixed with a moderate amount of fresh blood. The tissue appears to be relatively normal with normal cellularity. There is some diffuse non specific gliosis, but no evidence of atypia to suggest a primary infiltrative glial neoplasm, as clinically suggested. Several small cortical vessels have thickened walls with an eosinophilic homogeneous appearance. Some in addition show presence of a cellular infiltrate composed mostly of pale histiocytes. On slide A, a small tissue fragment shows two adjacent vessels, one cut longitudinally with prominent histiocytes and scattered giant cells. The vascular lumens are nearly occluded and fibrin seems to permeate the vascular wall. Immunohistochemical studies reveal intense A- beta amyloid positivity in the vascular wall of most cortical small vessels, in which presence of histiocytes is confirmed by the macrophage stain KP1. A-beta amyloid deposits are present in the cortex as diffuse plaques. A tau protein stain for neurofibrillary tangles is completely negative. Differential Diagnoses: - Incidental finding of age related cerebral amyloid angiopathy (CAA) in an otherwise non diagnostic biopsy – Advise rebiopsy - Cerebral amyloid angiopathy (CAA) causing a mass like lesion - Abeta related angiitis (ABRA) / primary CNS angiitis associated with amyloid angiopathy causing a mass like lesion - Amyloidoma Final Diagnosis: Abeta Related Angiitis (Primary CNS Angiitis Associated with Amyloid Angiopathy) Causing a Mass Like Lesion Case Discussion: Non-neoplastic lesions are not infrequently encountered in patients presenting with an intracerebral mass and undergoing biopsies with a clinical diagnosis of tumor, typically high grade. Cerebral amyloid angiopathy (CAA) is a relatively common and important disorder occurring predominantly in older patients. It is characterized by the extracellular deposition in the blood vessel walls of highly insoluble amyloid fibrils with beta-pleated secondary structures (Ferrer et al). The most common form of CAA is sporadic and associated with deposition of A- beta, a cleavage product of amyloid-beta precurson protein (APP), normally expressed in endothelial cells, pericytes and smooth muscle cells of CNS blood vessels. Prevalence of sporadic CAA increases with age over age 60 and is high among patients with Alzheimer's disease to which is highly interrelated. Inherited CAA is rare and associated with seven different amyloidogenic proteins, including APP. Sporadic A-beta CAA is responsible for up to 12% of primary non traumatic parenchymal hemorrhages. Based on our institutional experience, intracerebral hemorrhage represents the most common manifestation of amyloid angiopathy diagnosed in a surgical biopsy accounting for approximately 50% of patients. Typically patients present with large life treatening parenchymal "lobar" hemorrhages, which are evacuated surgically while surrounding parenchyma is biopsied. The remaining patients instead present with a mass and/or mental status changes and are frequently thought to have a tumor. It is important to entertain this diagnostic possibility in the differential diagnosis, since ordering key immunohistochemical tests allows for a specific diagnosis in this setting. Angiocentric inflammatory infiltrates have been described in a subset of A-beta CAA and associated with a distinct clinical syndrome, which may respond to immunosuppressive treatment (Eng et al). Primary angiitis of the CNS (PACNS), predominantly granulomatous , also occurs in association with CAA. In our series of PACNS, beta-A4 amyloid deposition was present in approximately 50% of the granulomatous vasculitis group, which was the most common pattern of vasculitis observed in surgical biopsies (Miller et al, Salvarani et al). Scolding et al reported a group of these patients with stereotyped clinical, radiological and pathological features under the name of A-beta-related angiitis (ABRA). The patients are older (60-70 years) than other PACNS patients, often present with altered mental status, headaches or seizures and focal neurological deficits associated frequently with white matter hyperintensities on MRI and seems to show a favorable response to immunosuppression. It is unclear if/how A-beta amyloid deposits induce inflammation and/or vasculitis or if A-beta deposits represent just bystander products of vasculitis causing chronic increase in vascular permeability, leakage of first soluble A-beta and ultimately deposition of A-beta amyloid in the wall of damaged vessels. The occurrence of ABRA at an earlier age as compared to CAA favors the first hypothesis. Localized accumulation of AL lambda light chain-derived amyloid resulting in mass like amyloidomas can also occur in the central nervous system and usually involves white matter and choroid plexus (Laeng et al). Amyloid deposits occur within white matter interstitium and perivascularly and typically result from AL lambda deposition. In these cases, amyloid can be characterized by histochemical stains (e.g. Congo red) and more specific immunohistochemistry for kappa and lambda immunoglobulin light chains. The recent introduction of mass spectrometry– based proteomics provides an additional powerful tool with exquisite sensitivity and specificity that may help in evaluating the composition of amyloid deposits in cases that are equivocal by immunohistochemistry (Rodriguez et al). Most cases of primary CNS amyloidoma are secondary to localized monoclonal plasma cell proliferations and are often associated with a scant perivascular infiltrate of light chain restricted plasma cells in most cases. Conclusion(s): Cerebral amyloid angiopathy (CAA) and primary angiitis of the CNS associated with cerebral amyloid angiopathy (ABRA) are relatively common and important disorders occurring predominantly in older patients. It is important for the pathologist to entertain this diagnostic possibility when examining biopsies from elderly patients presenting with CNS mass lesions. While findings may be subtle and could be easily overlooked, appropriate immunohistochemical tests may easily allow for a specific diagnosis in this setting. The recognition that at least a subset of these patients significantly benefit from immunosuppressive treatment makes CAA and ABRA important pathological diagnoses. References: Briceno CE, Resch L, Bernstein M Cerebral amyloid angiopathy presenting as a mass lesion, Stroke 1987;18:234-9 Eng JA, Frosch MP, Choi K, Rebeck GW, Greenberg SM Clinical manifestations of cerebral amyloid angiopathy-related inflammation Ann Neurol 2004;55:250-6 Ferrer I, Kaste M, Kalimo H Vascular diseases in Greenfield's Neuropathology 8th Ed (Editors Love S, Louis DN, Ellison DW), London 2008;1: 142-6 Rodriguez FJ, Gamez JD, Vrana JA, Theis JD, Giannini C, Scheithauer BW, Parisi JE, Lucchinetti CF, Pendlebury WW, Bergen HR 3rd, Dogan A. Immunoglobulin derived depositions in the nervous system: novel mass spectrometry application for protein characterization in formalin-fixed tissues. Lab Invest 2008;88:1024-37 Laeng RH, Altermatt HJ, Scheithauer BW, Zimmermann DR. Amyloidomas of the nervous system: a monoclonal B-cell disorder with monotypic amyloid light chain lambda amyloid production. Cancer 1998;82:362–374. Miller DV, Salvarani C, Parisi JE, et al. Primary central nervous system vasculitis: a clinicopathologic study of 51 patients. Am J Surg Pathol. 2009;33:35-43. Salvarani C, Brown Jr RD, Calamia KT, Christianson TJ, Weigand SD, Miller DV, et al. Primary central nervous system vasculitis: analysis of 101 patients. Ann Neurol 2007; 62(5):442–51. Scolding NJ, Joseph F, Kirby PA, Mazanti I, Gray F, Mikol J, Ellison D, Hilton DA, Williams TL, MacKenzie JM, Xuereb JH, Love S. Abeta-related angiitis: primary angiitis of the central nervous system associated with cerebral amyloid angiopathy. Brain. 2005;128:500-15.