Pathogenesis of primary central nervous system lymphoma: invasion of malignant lymphoid cells into and within the brain parenchyme

✓ Intraocular primary central nervous system lymphoma (PCNSL), also called primary intraocular lymphoma (PIOL), is a subset of PCNSL in which lymphoma cells invade the subretinal pigment epithelial space and vitreous cavity with or without central nervous system involvement at the time of ocular diagnosis. The frequency of this rare condition has increased over the past years in immunosuppressed as well as immunocompetent patients. The authors review the current status of PIOL and elaborate on their group's experience with its diagnosis and treatment. The incidence of PIOL is increasing. There is evidence that chronic antigenic stimulation may result in the development of PIOL. Recent advancements in the diagnosis of PIOL include better handling of vitreous specimens for cytological studies, immunocytological investigation for lymphoid cells, flow cytometry, cytokine evaluation, and molecular analysis. Because PIOL has a nonspecific presentation, the differential diagnosis should include infectious and noninfectious causes presenting with vitreitis and/or subepithelial infiltration as well as paraneoplastic syndromes including CRMP-5 optic neuropathies. Given that therapy is long-term and has significant systemic and ocular complications, tissue diagnosis is important. Treatment of PIOL may include systemic chemotherapy in which high-dose methotrexate-based regimens are used as well as intraocular injections of methotrexate and rituximab (anti-CD20 antibody). Cranial and ocular external-beam radiotherapy is being used less often today. Further studies are needed to prevent the tumor formation in terms of eliminating antigenic load and inhibiting B-cell chemokines as well as to determine the optimal local and systemic chemotherapy and immunotherapy options in the management of PIOL.

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Ibrutinib in Refractory or Relapsing Primary Central Nervous System Lymphoma: A Systematic Review

Neurology International ◽

10.3390/neurolint14010009 ◽

2022 ◽

Vol 14 (1) ◽

pp. 99-108

Author(s):

Gaurav Nepal ◽

Mahika Khurana ◽

Domenica Herrera Bucheli ◽

Siddhartha Bhandari ◽

Utsav Joshi ◽

...

Keyword(s):

Systematic Review ◽

Central Nervous System ◽

Nervous System ◽

Significant Proportion ◽

Central Nervous System Lymphoma ◽

The Novel ◽

Non Hodgkin Lymphoma ◽

Frequent Relapses ◽

Btk Inhibitor ◽

The Brain

Primary Central Nervous System Lymphoma (PCNSL) is a rare variant of Non-Hodgkin Lymphoma (NHL) representing 1–2% of all NHL cases. PCNSL is defined as a lymphoma that occurs in the brain, spinal cord, leptomeninges, or eyes. Efforts to treat PCNSL by traditional chemotherapy and radiotherapy have generally been unsuccessful as a significant proportion of patients have frequent relapses or are refractory to treatment. The prognosis of patients with Refractory or Relapsed (R/R) PCNSL is abysmal. The optimal treatment for R/R PCNSL is poorly defined as there are only a limited number of studies in this setting. Several studies have recently shown that ibrutinib, a Bruton tyrosine kinase (BTK) inhibitor, has promising results in the treatment of R/R PCNSL. However, these are preliminary studies with a limited sample size. In this systematic review, we explored and critically appraised the evidence about the efficacy of the novel agent ibrutinib in treating R/R PCNSL.

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Nonglial Central Nervous System Tumors

10.1093/med/9780197512166.003.0104 ◽

2021 ◽

pp. 931-948

Author(s):

Akanksha Sharma ◽

Alyx B. Porter

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Highly Active Antiretroviral Therapy ◽

Central Nervous System Lymphoma ◽

Non Hodgkin Lymphoma ◽

Highly Active ◽

Acquired Immunodeficiency ◽

Immunodeficiency Syndrome ◽

Adjusted Incidence ◽

The Brain

Primary central nervous system lymphoma (PCNSL) is a rare variant of extranodal non-Hodgkin lymphoma that may involve the brain, leptomeninges, eyes, or spinal cord and accounts for up to 5% of all adult primary brain neoplasms. Age-adjusted incidence has increased in the past 3 decades. Infection with HIV and acquired immunodeficiency syndrome increase the risk of PCNSL by 3,600-fold. However, with highly active antiretroviral therapy, the frequency of immune system compromise sufficient for HIV-associated PCNSL (CD4 count ≤50) is dramatically reduced, along with the risk of this disorder.

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Rare pathological variants and presentations of primary central nervous system lymphomas

Neurosurgical FOCUS ◽

10.3171/foc.2006.21.5.8 ◽

2006 ◽

Vol 21 (5) ◽

pp. 1-6 ◽

Cited By ~ 8

Author(s):

Arnaldo Neves Da Silva ◽

Maria Beatriz Lopes ◽

David Schiff

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Cell Lymphoma ◽

Central Nervous System Lymphoma ◽

B Cell Lymphoma ◽

Brain Parenchyma ◽

Low Grade ◽

Rare Form ◽

Large B Cell Lymphoma ◽

The Brain

✓ Primary central nervous system lymphoma (PCNSL) is a rare form of primary brain neoplasm, accounting for less than 3% of all primary brain tumors. Ninety percent of cases involve a large B-cell lymphoma that presents as a homogeneously enhancing lesion or lesions, typically deep-seated in the brain parenchyma. The authors describe unusual pathological forms of PCNSLs, including low-grade, T-cell, and Burkitt types, and also rare presentations such as neurolymphomatosis and pituitary lymphomas.

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Panhipopituitarismo y diabetes insípida central como primera manifestación de linfoma primario del sistema nervioso central en una paciente inmunocompetente

Revista Colombiana de Endocrinología, Diabetes & Metabolismo ◽

10.53853/encr.3.1.24 ◽

2017 ◽

Vol 3 (1) ◽

pp. 43-46

Author(s):

Edwin A. Wandurraga Sánchez ◽

William J. Morales Camacho ◽

Jessica E. Plata Ortiz

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Diabetes Insipidus ◽

Anterior Pituitary ◽

Central Nervous System Lymphoma ◽

Definitive Diagnosis ◽

Loss Of Function ◽

Paraventricular Nuclei ◽

Definition Of ◽

The Brain

El panhipopituitarismo (PH) hace referencia a la pérdida total de la función de la hipófisis anterior (adenohipófisis) que incluye los ejes somatótropo, tirótropo, corticótropo, gonadótropo, entre otros. La diabetes insípida central (DIC) no está contemplada en la definición de PH y su asociación simultánea implica la destrucción o degeneración de las neuronas localizadas en los núcleos supraóptico y paraventricular a nivel hipotalámico, es decir, un compromiso más extenso, dicha asociación se ha reportado hasta en 27% de los casos de linfoma primario del sistema nervioso central (LPSNC), la presencia de esta alteración obliga siempre a descartar enfermedades de carácter hematológico, infiltrativo, infeccioso y autoinmune. Presentamos el caso de una paciente de 19 años quien debutó con PH y DIC en la que no se pudo esclarecer un diagnóstico definitivo en su abordaje inicial, luego de casi tres años de evolución, una segunda biopsia realizada a nivel cerebral permitió confirmar el diagnóstico de linfoma primario del SNC. El curso lento y progresivo observado en nuestra paciente es propio de dicha neoplasia; sin embargo, el efecto citorreductor de los corticoides utilizados para el manejo de su déficit hormonal, favoreció el retraso en la identificación de esta enfermedad hematológica.Abstract The panhypopituitarism (PH) refers to total loss of function of the anterior pituitary (adenohypophysis), which ultimately can lead to commitment at differents endocrine axes involved at this level. Central diabetes insipidus (CDI) is not covered by the definition of PH and its simultaneous association involves the destruction or degeneration of neurons located in the supraoptic and paraventricular nuclei of the hypothalamus, it means a greater and more extent commitment. We present the case of a 19 years old female who debuted with PH and CDI in which failed to elucidate a definitive diagnosis in its initial approach. Finally, after nearly three years of evolution and a second biopsy performed in the brain the diagnosis of primary central nervous system lymphoma was confirmed.

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Discovery of HBW-3-20, the first potent reversible inhibitor of Bruton’s tyrosine kinase (BTK) with high brain exposure.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e15068 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e15068-e15068

Author(s):

Ning Lee ◽

Yingfu Li ◽

Chester Yuan ◽

Guanfeng Liu ◽

Chunchao Yue

Keyword(s):

Central Nervous System ◽

Nervous System ◽

B Cell ◽

Central Nervous System Lymphoma ◽

Autoimmune Disorders ◽

Wild Type ◽

High Brain ◽

Brain Exposure ◽

Btk Inhibitor ◽

The Brain

e15068 Background: It has been an on-demand task to develop a BTK inhibitor of significant brain exposure, a critical property for extending its usages to treat Primary Central Nervous System Lymphoma (PCNSL) and autoimmune disorders. PCNSL is an aggressive extra nodal non-Hodgkin lymphoma that exclusively invades the central nervous system (CNS). Tirabrutinib, an irreversible BTK inhibitor with limited brain exposure, is the first BTK inhibitor approved for the treatment of recurrent or refractory primary central nervous system lymphoma recently. PRN2246 is another irreversible BTK inhibitor claimed to be of brain exposure, and is currently in clinical trials for the treatment of multiple sclerosis. Methods: New reversible BTK inhibitors were designed, synthesized and tested for enzymatic activities against wild-type and C481S-mutated BTK. Highly active compounds were confirmed for growth effects in diffuse large B-cell lymphoma derived TMD8 cells. Their microsomal stability and ADME properties were also assessed. Potent and bioavailable compounds were further measured for brain exposures in rats. Results: HBW-3-20 has excellent potency against both wild-type and C481S-mutated BTK, with IC50 of 2.5 and 3.8 nM, respectively. Its TMD8 cellular potency is 72 nM. In a head-to-head direct comparison of brain exposure experiment, HBW-3-20, tirabrutinib and PRN2246 were all dosed at 10mg/kg orally. The brain and plasma concentration were measured after 1 hour and the data are shown in the table below. The brain to plasma ratio for HBW-3-20, tirabrutinib and PRN2246 are 58%, 11.8% and 4.2% respectively. Our results show that HBW-3-20 has much greater brain permeability than tirabrutinib or PRN2246 in rats. Conclusions: HBW-3-20 is the first potent reversible BTK inhibitor that shows promisingly high brain permeability. HBW-3-20 provides a very valuable clinical candidate for treating B-cell malignancies in brain and autoimmune disorders![Table: see text]

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VH Gene Sequences From Primary Central Nervous System Lymphomas Indicate Derivation From Highly Mutated Germinal Center B Cells With Ongoing Mutational Activity

Blood ◽

10.1182/blood.v94.5.1738.417k10_1738_1746 ◽

1999 ◽

Vol 94 (5) ◽

pp. 1738-1746 ◽

Cited By ~ 3

Author(s):

Andrew R. Thompsett ◽

David W. Ellison ◽

Freda K. Stevenson ◽

Delin Zhu

Keyword(s):

Central Nervous System ◽

Nervous System ◽

B Cell ◽

Germinal Center ◽

Central Nervous System Lymphoma ◽

Mechanism Analysis ◽

Cell Of Origin ◽

B Cell Lymphomas ◽

Vh Gene ◽

The Brain

Primary central nervous system lymphoma (PCNSL) represents 1% to 3% intracranial tumors. Most PCNSL are located in the brain, and 75% are large B-cell lymphomas. The largest subgroup of these tumors contains cells that resemble centroblasts and has been labelled diffuse centroblastic (polymorphous) lymphoma. To investigate the cell of origin and the clonal history of these tumors, we have analyzed VH gene of 5 cases of PCNSL, all confirmed by histological studies to be Epstein-Barr virus (EBV)-negative, high-grade diffuse B-cell lymphomas. The V4-34 gene of the VH4 family was used in 4 of 5 cases. All VHgenes were found to have accumulated very high levels of somatic mutation (14% to 25%). In 3 of 5 cases, intraclonal nucleotide heterogeneity, including codon deletion in some clones in 1 case, was observed, indicating that the VH genes were still under the influence of the somatic hypermutation mechanism. Analysis of the distribution of silent and replacement mutations showed evidence for preservation of immunoglobulin structure in all cases. These results suggest that, although there is no evidence for germinal center formation in the brain tissue, PCNSL is derived from a B cell with features associated with location in a germinal center environment.

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Primary central nervous system lymphoma of the brain stem responding favorably to radiosurgery: A case report and literature review

Surgical Neurology ◽

10.1016/j.surneu.2004.12.028 ◽

2005 ◽

Vol 64 (5) ◽

pp. 400-405 ◽

Cited By ~ 7

Author(s):

Peter G. Campbell ◽

Ajay Jawahar ◽

Marjorie R. Fowler ◽

Allyson DeLaune ◽

Anil Nanda

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Case Report ◽

Literature Review ◽

Brain Stem ◽

Central Nervous System Lymphoma ◽

The Brain

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Comparative Molecular Analysis of Primary Central Nervous System Lymphomas and Matched Vitreoretinal Lymphomas by Vitreous Liquid Biopsy

International Journal of Molecular Sciences ◽

10.3390/ijms22189992 ◽

2021 ◽

Vol 22 (18) ◽

pp. 9992

Author(s):

Daniel A. Balikov ◽

Kevin Hu ◽

Chia-Jen Liu ◽

Bryan L. Betz ◽

Arul M. Chinnaiyan ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Precision Medicine ◽

Liquid Biopsy ◽

Brain Lesion ◽

Central Nervous System Lymphoma ◽

Genetic Alterations ◽

Liquid Biopsies ◽

Diagnostic Strategies ◽

The Brain

Primary Central Nervous System Lymphoma (PCNSL) is a lymphoid malignancy of the brain that occurs in ~1500 patients per year in the US. PCNSL can spread to the vitreous and retina, where it is known as vitreoretinal lymphoma (VRL). While confirmatory testing for diagnosis is dependent on invasive brain tissue or cerebrospinal fluid sampling, the ability to access the vitreous as a proximal biofluid for liquid biopsy to diagnose PCNSL is an attractive prospect given ease of access and minimization of risks and complications from other biopsy strategies. However, the extent to which VRL, previously considered genetically identical to PCNSL, resembles PCNSL in the same individual with respect to genetic alterations, diagnostic strategies, and precision-medicine based approaches has hitherto not been explored. Furthermore, the degree of intra-patient tumor genomic heterogeneity between the brain and vitreous sites has not been studied. In this work, we report on targeted DNA next-generation sequencing (NGS) of matched brain and vitreous samples in two patients who each harbored VRL and PCSNL. Our strategy showed enhanced sensitivity for molecular diagnosis confirmation over current clinically used vitreous liquid biopsy methods. We observed a clonal relationship between the eye and brain samples in both patients, which carried clonal CDKN2A deep deletions, a highly recurrent alteration in VRL patients, as well as MYD88 p.L265P activating mutation in one patient. Several subclonal alterations, however, in the genes SETD2, BRCA2, TERT, and broad chromosomal regions showed heterogeneity between the brain and the eyes, between the two eyes, and among different regions of the PCNSL brain lesion. Taken together, our data show that NGS of vitreous liquid biopsies in PCNSL patients with VRL highlights shared and distinct genetic alterations that suggest a common origin for these lymphomas, but with additional site-specific alterations. Liquid biopsy of VRL accurately replicates the findings for PCNSL truncal (tumor-initiating) genomic alterations; it can also nominate precision medicine interventions and shows intra-patient heterogeneity in subclonal alterations. To the best of our knowledge, this study represents the first interrogation of genetic underpinnings of PCNSL with matched VRL samples. Our findings support continued investigation into the utility of vitreous liquid biopsy in precision diagnosis and treatment of PCNSL/VRL.

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