Brain aggregoma with clonal B-cell perivascular proliferation detected by next-generation sequencing. A case report and review of the literature

Introduction

Monoclonal immunoglobulin deposition disorders (MIDDs) are well-known clinicopathological entities related to the deposition of monoclonal immunoglobulins in fibrillar amyloidotic and, much more rarely, in granular or amorphous non-amyloidotic form (Randall type) [2]. Systemic MIDDs in both forms, light chain amyloidosis (AL), and, in non-amyloidotic form designated light and/or heavy chain deposition disease (LCDD/HCDD), always affect the kidneys, but other organs can be affected. The only functionally preserved organ in systemic MIDDs is the brain, due to the blood-brain barrier (BBB), with an exception to this rule [6]. Localized MIDDs have been described in respiratory and gastrointestinal tracts, lymph nodes, bones, and brain, usually as tumour-like amyloid deposits designated amyloidomas or, much more rarely, as tumour-like non-amyloid deposits called aggregomas [19]. Diffuse LCDD restricted to a single organ has also been described [16]. Only 10 cases of LCDD restricted to the brain have so far been described [1,4,5,10-13,15,17,18]. The majority of them were aggregomas, with or without vascular involvement. Only 1 case manifested as multifocal cerebral light chain vasculopathy (CLCV) [13]. Herein we describe a female patient with brain aggregoma and further compare it with 10 reported cases.

Case report

The patient was admitted to the neurological department after a first generalized epileptic seizure without neurological deficits. Magnetic resonance imaging (MRI) showed a focal lesion in the right occipital lobe (Fig. 1). Surgical complete excision of a firm lesion, sharply demarcated from oedematous brain tissue, was performed. The postoperative head MRI revealed postoperative changes after complete excision of the lesion (Fig. 1). The patient had no signs of systemic lymphoproliferative disease.
Microscopic examination revealed abundant multifocal homogenous material with crack-like artefacts (Fig. 2A), which was Congo red negative (Fig. 2B) but Thioflavin T moderately positive (Fig. 2C). Immunofluorescence on lambda (l) and kappa (k) light chain (LC) showed aggregates to be l-positive (Fig. 2D) and k-negative (figure not shown). Mild perivascular lymphoplasmacytic infiltrates in the intervening brain tissue were composed mostly of T- and B-lymphocytes and very few plasma cells with no LC restriction (figures not shown). A small piece of formalin-fixed, paraffin-embedded (FFPE) tissue was processed for electron microscopy, as previously described [7], revealing electron-dense finely granular material in the brain tissue but not in the vessel walls (Fig. 2E, F). A diagnosis of tumour-like LCDD or aggregoma was made. We isolated total DNA from perivascular lymphocytic infiltrates, which were present between the abundant aggregates of l-LC, enriched in the sample as previously described [9]. Next-generation sequencing (NGS)-based clonality testing of B-lymphocytes was performed using commercially available LymphoTrack assays (Invivoscribe Technologies) targeting immunoglobulin heavy (IGH) and k light (IGK) chain, following the manufacturer’s protocols. We detected a monoclonal B-lymphocyte population with rearrangements in IGH-FR2 and IGK (see Fig. 3), further supporting l-LC deposits and the aggregoma diagnosis.

Discussion with review of previously reported cases

The presented case of cerebral LCDD is similar to some, but different from others, of 10 previously reported cases (Table I). The range of age at presentation was 19 to 72 years (mean age 52 years), which is only slightly younger than the age of appearance of primary central nervous system lymphomas (PCNSL) in immunocompetent patients [3], with a male predilection (male-to-female ratio 7 : 4). Another similarity between brain LCDD and PCNSL is the periventricular location in the majority of cases. In 7 cases, including the presented case, the lesion was located in the right occipital lobe close to the ventricle [1,4,5,11,12,18]. Even in the case with post-mortem brain examination, the largest lesion was in the same location [13]. In the other 3 cases, the locations were right cerebellar [17], right fronto-parietal [10], and right frontal [18]. The lesions were multifocal in 2 cases [12,13]. The leading symptom of disease in the presented case was epileptic seizure, as it was in the additional 2 with similar locations [4,12]. Otherwise, there were hemiparesis with or without hemihypesthesia [10,11,15], headache with speech and visual disturbances [1,5], gait instability in the case with cerebellar location [17], and bulbar signs in the case with multifocal CLCV with severe medullary involvement [13]. The MRI presentation of all cases was very similar.
Specimens for microscopic observation of the lesions were obtained by stereotactic biopsy in 6 cases [4,10-12,15,18], by craniotomy followed by excision of the lesion in 4 cases, including the presented one [1,5,17], and whole brain examination was performed in 1 case [13]. In stereotactic biopsy specimens, the exact location of the aggregates could not always be determined, while in the excised specimens after craniotomy, the location of aggregates was well defined: in 3 cases, including the presented one, the aggregates were parenchymal, sparing the vessel walls [5,17], and giving tumour-like LCDD called aggregoma, while in 1 case the aggregates were only in the vessel walls [1], giving focal CLCV. Multifocal CLCV with no parenchymal aggregates was clearly observed only in the case of whole brain examination [13]. In the presented case, NGS clonality testing showed monoclonal B-cell lymphocytes. In all other cases, monoclonal lymphoplasmacytic infiltrate was observed with k-LC restriction in 4 cases [1,5,11,17], and l-LC restriction in 2 cases [10,15], in contrast to amyloidomas of CNS, in which almost exclusively l-LC have so far been described [8]. LC restriction in the lymphoplasmacytic infiltrate was not mentioned in the other 3 cases [4,12,13]. In 3 cases, the infiltrate was defined as primary cerebral low-grade lymphoma [4,12,15]. Cerebrospinal fluid (CSF) examination was done in all cases except 2 [5,10]. CSF oligoclonal bands were found in only 2 cases [12,13]. A whole-body work up was performed in all cases except 1 [15], showing no sign of systemic immune dyscrasia.
To summarize, LCDD restricted to the brain is a very rare disease, radiologically mimicking a tumour or multiple sclerosis. We propose the name aggregoma only in cases with deposition of LC inside the brain tissue, with or without deposition in the vessel walls. The nature of monoclonal lymphoplasmacytic infiltrate, reactive or neoplastic, accompanying the deposits in all cases, remains questionable.

Ethics approval 

The publication of the case report was approved by an institutional review board.

Availability of data and material

The data and the participation consent for the current case are not publicly available due to privacy concerns but are available from the corresponding author upon reasonable request.

Acknowledgments

The authors are grateful to Nina Hauptman, Ph.D. and Metod Perme for their technical support. Martin Cregeen provided language editing.

References