A 71‐Year‐Old Man Presenting with Headache, Blurry Vision and Alexia without Agraphia

CLINICAL HISTORY

A 71‐year‐old man presented with a two‐day history of periodic severe left‐sided occipital headache, blurry vision, alexia without agraphia and occasional nausea without vomiting. His past medical history is significant for hypertension, for which he takes lisinopril, hydrochlorothiazide and verapamil. He also takes meloxicam for arthritis and pantoprazole for gastroesophageal reflux. He has no personal history of malignancy, but does have a family history significant for esophageal cancer. He does not smoke or use alcohol or drugs, and has no known environmental exposures. Physical examination was remarkable only for a right visual field deficit. MRI showed a 5.2 × 4.6 × 4.0 cm area of complex signal abnormality in the left occipital/posterior parietal region, with some cortical effacement and white matter edema, but no significant mass effect (T2‐weighted MRI; Figure 1a). All sequences showed serpiginous and punctate foci of low signal, suggestive of hypervascularity, but revealed no large feeding or draining vessels. There was no diffusion restriction. Irregular contrast enhancement involved a 4.3 × 3.8 × 3.2 cm region of the abnormality (T1‐weighted postgadolinium MRI; Figure 1b). CT scan revealed an associated area of calcification near the sagittal sinus. A stereotactic left occipital brain biopsy was performed.

Figure 1.

 

MICROSCOPIC PATHOLOGY

H&E stained sections of the FFPE biopsy specimen show abundant irregular lobules of acellular, pale eosinophilic material, variably separated by modest amounts of brain parenchyma with rare entrapped neurons and scattered atypical glial cells (Figure 1c). Small vessels with thickened and hyalinized walls are numerous and, in some areas, merge into pale eosinophilic lobules. Several small patches with multinucleated giant cells, lymphocytes, plasma cells and modest hemosiderin are present (Figure 1d and 1e). Calcification and focal incipient ossification are present, but only in intraoperative frozen sections. A section stained with Congo Red and examined with polarized light microscopy reveals apple‐green birefringence (Figure 1f) within the pale eosinophilic deposits; on a section stained with thioflavin S and examined with fluorescence microscopy, the proteinaceous deposits fluoresce intensely (Figure 1g). Immunostains for endothelial marker CD34 highlights viable small caliber vessels within a subset of the proteinaceous deposits. GFAP highlights gliotic brain parenchyma between the deposits, in which NF reveals very sparse axons. IHC for lambda light chain shows very strong reactivity within the deposits (Figure 1h), and to a lesser extent, within the brain parenchyma. In contrast, IHC for kappa light chain showed variable weak reactivity, and IHC for amyloid‐beta peptide was nonreactive. The presence of abundant lambda light chain within microdissected Congo Red positive areas was subsequently confirmed by liquid chromatography tandem mass spectrometry (LC MS/MS). What is your diagnosis?

DIAGNOSIS

Cerebral Amyloidoma.

DISCUSSION

Cerebral Amyloidoma (CA) is very rare; approximately 40 cases have been reported in the literature. Mostly found near ventricles within the white matter, these intracerebral masses appear as single or multiple macroscopic nodules formed by amyloid deposits of monoclonal immunoglobulin light chains. The etiology remains poorly understood.

The clinical course of CA is generally, but not universally, favorable 1, 2, 3. Some authors advocate complete resection, when possible, to avoid continued expansion and associated neurological complications. Clinical features, most completely described in a review of 27 total patients by Fischer et al 1, include a slight male to female predominance (1.17:1) and a mean age at diagnosis of 48.9 years (range 15–71 years). Presenting symptoms vary and include seizure, hemiparesis, gait disturbance, impaired vision and cognitive disturbance. While no cases to date have described concomitant systemic amyloidosis, most authors still recommend a complete evaluation to investigate this possibility.

Radiographic findings for CA are variable and not specific 1. In our case, the leading radiographic diagnosis was primary CNS neoplasm, with a broad differential diagnosis that included glioblastoma, lymphoma, metastatic disease, cerebritis and subacute infarction. In reported cases, CA is usually hyperdense on CT; reported MRI findings are more variable and describe hypo‐, iso‐ or hyperintense lesions on T1‐ and T2‐weighted images, commonly with surrounding edema on T2‐weighted scans. On post‐contrast CT and MRI, CA shows enhancement. All reported cases have been supratentorial, though rare examples also show infratentorial involvement.

The histomorphologic features of our case are similar to those of reported cases, and suggest a differential diagnosis that may include: Calcifying Pseudoneoplasm of the Neuraxis, Cerebral Amyloid Angiopathy, Cerebral Amyloidoma or other infectious/inflammatory entities. Nonspecific features such as lymphoplasmacytic cells and macrophages are often present. Focal foreign body giant cell reaction to the amyloid, noted only focally in our case, might also suggest a diagnosis of Amyloid Beta Related Angiitis. The most reliable histochemical features for diagnosis include apple green birefringence with Congo Red staining under polarized light, bright yellow‐green fluorescence with thioflavin S staining, and immunoreactivity for immunoglobulin light chain.

Most cases of CA that have been characterized by immunohistochemistry (14/16 cases, 88%) have been found to be of the AL lambda light chain subtype 1. A minority of cases (2/16 cases, 12%) has been described as a composition of mixed lambda and kappa light chains, without any significant predominance. In a separate report by Rodriguez and colleagues, five cases were analyzed by liquid chromatography‐electrospray tandem mass spectrometry (LC‐MS/MS) 4; all five were found to harbor lambda, with no kappa, light chains. Other constituents variably detected in the amyloid deposits included serum amyloid P, ApoE, Apo‐AI, Apo‐AII, Apo‐AIV, IgG, IgA and immunoglobulin J polypeptide.