Correspondence comprehensive characterization of a brainstem aggregoma (light and heavy chain deposition disease)

Monoclonal immunoglobulin (Ig) deposition diseases are classified as heavy chain deposition disease (HCDD); light chain deposition diseases (LCDD); and light and heavy chain deposition disease (LHCDD)—deposits of both light [kappa (κ) and lambda (λ)], and heavy [alpha (α), delta (δ), epsilon (ε), gamma (γ), and mu (μ)] Ig chains. These are frequently related to onco-hematological diseases and may form space-occupying lesions (“aggregomas”), rarely reported in the central nervous system (CNS).1-3 We present the first comprehensive report of an infratentorial aggregoma composed by κ light chain, IgA, and J chain deposits, confirmed by liquid chromatography tandem mass spectrometry (LC–MS/MS), RNA-sequencing, and exome sequencing (ES) which will help to build the body of knowledge about this rare and intriguing disease. In 2015, a 19-year-old female presented with slight left-hand tremors and slurred speech. Magnetic resonance imaging (MRI) scan revealed a well-limited 2.1 cm intramedullary mass with mild contrast enhancement, lacking diffusion restriction (Figure 1A–C). The lesion, totally removed en bloc (confirmed by intraoperative ultrasound and postoperative MRI), expanded the brainstem sparing cranial nerves and contained grayish gelatinous material. Histopathology showed hypocellular, eosinophilic, amorphous, colloid-like material Congo red negative under polarized light (controls showing appropriate reactivity), with scant neural cell elements and perivascular chronic inflammation (lymphocytes, plasma cells, and macrophages) (Figure 1D–E). Absence of epithelial lining ruled out the diagnosis of a cyst. Immunohistochemistry (IHC) showed focal GFAP and S100 stain in reactive brain tissue, p53 negative, and low Ki-67 mitotic index making the diagnosis of a neuroepithelial tumor unlikely. CD45 and CD68 stained lymphocytes and macrophages, respectively. Langerin stained scant perivascular cells and CD1a was negative, excluding the diagnosis of Langerhans histiocytosis. Antibodies anti-light Ig chains κ and λ stained inflammatory cells within and around blood vessels, not suggesting a monoclonal process. Bone marrow biopsy was normal, and positron emission tomography/computed tomography with 2-deoxy-2-[fluorine-18]fluoro-d-glucose (18F-FDG) demonstrated non-specific hypermetabolic bilateral cervical lymph nodes, tonsils and posterior nasopharynx (Figure 1F). Colony-stimulating factor (CSF) analyses showed oligoclonal bands absent in the patient's serum, indicating abnormal, non-specific, synthesis of gammaglobulins in the CNS. A comprehensive biochemical workup for infectious, autoimmune, and hematologic diseases returned negative. The patient was treated with steroids and underwent extensive neurorehabilitation. In 2019, she presented with clinical and radiological signs of recurrence, with increase in size of the lesion, involvement of medial right cerebellum and bulbous extension into the right cervical medullary junction and into the lower pontine dorsum at MRI (Figure 1G-I). The supratentorial brain remained stable in appearance. Histopathological aspects were similar to the initial lesion. IHC showed heterogeneous expression of B-cells and plasma cells (CD19 and CD79a), T-cells (CD3, CD4, and CD8, with CD4 > CD8), and macrophages (CD163) markers. Blasts/immature immune cells (TdT and CD34) markers were negative. The κ light chain was diffusely positive and much more obvious than the λ light chain by IHC (Figure 1J–M) and by in situ hybridization. IgM, IgG, and IgG4 stained the background. Polymerase chain reaction of the CSF for Ig heavy chain showed oligoclonal pattern, with multiple peaks, not supporting a diagnosis of lymphoproliferative disease. IgG, IgA, and IgM were within normal ranges in peripheral blood; κ free light chains levels were normal, with decreased λ free light chains levels (4.1—normal: 6.4–22.1 mg/L), and increased κ:λ ratio (1.93—normal: 0.51–1.72), consistent with findings in the histopathologic exam. Hepatic and renal function were always normal. Paired comparator germline/disease-involved enhanced ES was performed on DNA extracted from a comparator germline specimen (peripheral blood) and snap frozen lesional tissue to identify single nucleotide variations, small insertion–deletion (indel) events, and copy number (CN) alterations. No medically meaningful germline alterations in the setting of cancer or other known disease-associated genes were detected. The pass-filter somatic variant with the highest frequency within the lesional tissue was NM_003966.3(SEMA5A):c.2275G>A:p.Gly759Ser (8.8% variant allele frequency [VAF]). Only two pass-filter variants were observed in cancer-associated genes: NM_139215.3(TAF15):c.52T>C:p.Ser18Pro (5.2% VAF) and NM_005228.5(EGFR):c.549C>A:p.His183Gln (4.5% VAF). Each of these variants would be considered a variant of uncertain significance. Fresh frozen sample of the lesion content was submitted to LC/MS–MS, which detected 475 abundant proteins, compared to thousands typically detected in neoplastic tissue. The top 10 most abundant proteins are shown in Figure 2A, including increased abundance of IgA and κ light chain. The increased κ light chain was previously seen by IHC and retrospective IHC for IgA showed diffusely positive stain in the lymphoplasmacytic infiltrate (Figure 1K). The diagnostic was of a LHCDD constituted by κ light chain, IgA, and J chain. RNA-sequencing was performed from the lesional tissue to evaluate for gene overexpression and aberrantly activated pathways. This analysis confirmed overexpression of IGHA1, IKGC, and JCHAIN relative to an institutional cohort of pediatric CNS tumors (N = 43) (Figure 2B), and consistent with the prior proteomics and IHC results. Ingenuity pathway analysis performed from RNA-sequencing of the lesional tissue identified multiple inflammatory pathways to be activated, including the neuroinflammation signaling pathway (Figure 2C). Herein we describe a unique case of LHCDD presenting as an aggregoma in the brainstem of a young adult. LCDD and LHCDD of the brain have multiple radiologic and histopathologic overlaps and are frequently reported together in small series.2, 3 The largest series of CNS LHCDD reported six adult patients (34–70 years) all with supratentorial lesions, in which three out of five brain hemisphere lesions were associated CNS/systemic lymphoma and κ light chain/IgG deposits.2 Recently a LHCDD with κ light chain/IgA deposits was reported in a 31-year-old patient with multiple large, non-enhancing intracerebral lesions, which recurred after only 7-month follow-up which demanded treatment with radiation therapy (RT) analogous to the scheme used for plasmacytoid malignancy1 despite not having a definite diagnosis of lymphoproliferative disease. Although ES did not identify any clearly medically meaningful variants associated with the disease, the variants in SEMA5A and TAF15 are intriguing given the biology of these genes; however, the contribution of these variants to the disease process for this patient is unclear at present. SEMA5A encodes Semaphorin-5A, an integral membrane protein involved in inflammation, immunity, and axonal guidance during neurodevelopment. SEMA5A upregulation has been related to enhanced T-cell activation in rheumatoid arthritis4 and several psychiatric and neurodegenerative diseases.5 Alterations of TAF15, which encodes a member of the TET family of RNA-binding proteins, have been described in amyotrophic lateral sclerosis and frontotemporal dementia.6, 7 In oncology, high SEMA5A expression was related to poor prognosis in multiple myeloma patients8 and TAF15-ZNF384 gene fusion have been described in a rare form of acute lymphoblastic leukemia.9 Comprehensive molecular profiling, including proteomics, ES, and RNA-sequencing, and extensive histopathological workup helped to refine the diagnosis for this individual to LHCDD constituted by κ light chain, IgA, and J chain. Taken together, our findings suggest that the pathogenesis of CNS LHCDD is inflammatory rather than neoplastic in nature, and a proposed mechanism of the lesion is shown in Figure 2D. As caveats of this report, the gene variants occurred at very low allelic frequency and given the specimen quality, an artifact could not be ruled out. Therefore, the meaning of the variants identified on ES remain indeterminate. In addition, the transcriptional consequences of the gene variants were not observed at protein level by LC–MS/MS because only the colloid-like material was analyzed, therefore the results most probably simply reflect the secreted products of the plasma cell infiltration. In 2020, the patient presented signs of local recurrence at MRI and received treatment with low dose (2400cGY) RT. Currently, she presents only stable postsurgical changes at MRI after 7 months of completing the RT treatment. Her motor and coordination deficits secondary to the surgeries persist, however, her cognitive functions are preserved, and she achieved a graduate school-level education after the diagnosis. The patient does not have the diagnosis of neurodegenerative or hematological disease after long-term follow-up. However, the implication of SEMA5A in plasmacytic neoplasia outcome probably warrants the need of close clinical surveillance for the patient. Our results highlight the genomic, transcriptomic, and proteomic landscape as observed in a patient with LHCDD of the CNS and set forward a path for future validation of the observed findings in additional patients. Performed critical analysis of the LC–MS/MS results and histopathologic correlation: Aline P. Becker. Performed critical analysis of the LC–MS/MS results and pathway analysis: Erica H. Bell, Jessica L. Fleming, and Arnab Chakravarti. Provided pediatric and adult onco-hematological care to the patient: Diana S. Osorio, Pierre Giglio, and Don Benson. Performed and analyzed the genomic workup, RNA sequencing, and DNA sequencing: Catherine E. Cottrell, Elaine R. Mardis, Katherine E. Miller, Kathleen M. Schieffer, and Benjamin J. Kelly. Performed the interpretation of the radiological exams (MRI and PET/CT): Mina S. Makary and Wayne Slone. Performed both surgeries and clinical follow-up of the patient: Jeffrey Leonard. Performed the histopathological analyses of the primary and recurrent lesion: Samir B. Kahwash and Daniel R. Boué. Proposed mechanism of LHCDD: Samir B. Kahwash. All authors had major contributions in writing the manuscript, read and approved the final version submitted to publication. The authors thank David W. Ellison, MD, PhD at St. Jude's Children's Research Hospital, for the pathology review, important for consensus diagnosis in this case; Joshua Palmer, MD, for the support with the Radiation Oncology reports; Blake E. Sells, MD, PhD candidate for the support in pathway analysis, and Jennifer Thurmond, for the support in the consent and authorization form signature. This study received funding from R01CA108633, R01CA169368, RC2CA148190, U10CA180850-01 (NCI), Brain Tumor Funders Collaborative Grant, and the Ohio State University CCC (all to Arnab Chakravarti). The authors declare no conflict of interest. The patient consented to the study in protocols from both NCH (IRB17-00206) and OSU (2019C0084) and provided written consent to publication of the case. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to nature of the study (case report), as the containing information would compromise the privacy of the patient.