Hematolymphoid tumors involving the CNS

2025-01-30 Paola Dal Cin, PhD , Scott Ryall, PhD Affiliation

1.Brigham and Women's Hospital , Harvard Medical School, Boston , MA (USA)
2.Brigham and Women's Hospital, Harvard Medical School, Boston , MA (USA)

Keywords

CNS CNS lymphomas, CNS-diffuse large B-cell lymphoma, CNS histiocytic neoplasms, rare CNS lymphomas

Classification

Definition

Hematolymphoid tumors involving the CNS are cancers arising from a blood cell lineage that develop within the central nervous system (CNS), primarily in the parenchyma and meninges. Critically, the distinction of primary versus secondary manifestations of the tumors is essential for their accurate diagnosis given than virtually all hematolymphoid tumors involving the CNS may also arise in other organs. Collectively, these are the second most frequent primary brain tumors in adults, second only to glioma. ¹

The 2021 World Health Organization (WHO) classification of hematolymphoid tumors involving the CNS categorizes tumors into two major groups: i) Lymphomas and ii) Histiocytic Tumors, the former further segregated into “CNS Lymphomas” and “Miscellaneous Rare Lymphomas in the CNS” to permit expansion of the less common CNS lymphoma subtypes. Of primary CNS lymphoma, diffuse large B-cell lymphoma (CNS-DLBCL) is the most common. ^2-4 In contrast, histiocytic neoplasms are extremely rare, thought to be a manifestation of their broad clinical spectrum and variable histology. ⁵

Historically, the genetic underpinnings of hematolymphoid tumors involving the CNS have been largely unexplored due to limited tissue availability and diagnostic ambiguity. However, recent work has begun to uncover the genetic differences between tumors with immense potential to refine and optimize the current diagnostic strategies and identify therapeutic susceptibilities not previously appreciated.

Hematolymphoid tumors involving the CNS
Lymphomas involving CNS	Genetic marker(s)
Primary diffuse large B-cell lymphoma of the CNS (CNS-DLBCL)	CNS-DLBCL are comprised of B cells derived from self-reactive precursor cells confined to the CNS microenvironment. These cells ubiquitously carry rearranged and somatically mutated immunoglobulin (IG) genes. Evidence of ongoing somatic hypermutation is also noted, and expands to multiple gene targets beyond IG, including BCL6, BCL2, MYC, PIM1, PAX5, RHOH, KLHL14, OSBPL10, and SUSD2. ^6-8 Translocations involving the IG genes, BCL6, and ETV6 are common, whereas those affecting MYC and BCL2 are rare and absent, respectively. ^9-12 Genetic alterations affecting CD79B and MYD88 are frequently observed, while alterations in INPP5D, CBL, BLNK, CARD11, MALT1 (in 43%), and BCL2 are less frequent and are thought to promote proliferation whilst inhibiting apoptosis. ^13-20 Cytogenetic analysis also identified recurrent gains of chromosome 18q (including BCL2 and MALT1, chromosome 12, and chromosome 10q. ¹³ Recurrent losses include chromosome 6 (including HLA-DRB1, HLA-DQA1, and HLA-DQB1), 8q, and 9p ,including CDKN2A/CDKN2B. ^13,21-23 Epigenetic studies have identified changes that may potentially impact tumorigenesis including enhancer silence and hypomethylation of DAPK1, CDKN2A, MGMT, and RFC1, although methylation-based classifiers still struggle with differentiating primary and secondary neoplasms. ^13,21,24-26
Immunodeficiency-associated CNS lymphomas	Immunodeficiency-associated CNS lymphomas are a rare clinical entitity, typically associated with Epstein-Barr virus (EBV+). These tumors lacked the MYD88, CD79B, and PIM1 missense variants typically associated with CNS-DLBCL as well as copy number losses of CDKN2A or the HLA genes. Rather, they harbored mutations in SOCS1 of the JAK/STAT pathway and mutually exclusive gain-of-function variants in the NOTCH pathway. Copy number gains were enriched on chromosome 11q23.3 and losses of chromosomes 5q and 17q. ²⁷ Other immunodeficiency syndromes including ataxia telangiectasia, Wiskott–Aldrich syndrome, and IgA deficiency as well as other underlying conditions such as systemic lupus erythematosus, Sjögren syndrome, neoplastic diseases, iatrogenic immunosuppression and infectious disorders such as HIV and HTLV may also increase the risk of CNS lymphomas.
Lymphomatoid granulomatosis (LYG)	Lymphomatoid granulomatosis (LYG) is a very rare Epstein-Barr virus (EBV)-driven lymphoproliferative disease in which atypical lymphoid cells accumulate within the affected tissue(s). Most often this includes the lungs, but may also arise in the CNS and kidneys, although no clear association between disease grade and dissemination to the CNS has been observed. ^28,29 Isolated EBV-negative cases have also been described. ^29,30 The underlying genetics of LYG are largely unknown.
Intravascular large B-cell lymphoma (IVLBCL)	Intravascular large B-cell lymphoma (IVLBCL) is a rare and aggressive cancer primarily affecting the CNS and skin. Diagnosis of IVLBCL is challenging due to variable clinical manifestations and nonspecific laboratory findings and is often made at autopsy due to limited availability of biopsy material. ³¹ Similar genetic underpinnings to those observed in DLBCL are noted in IVLBCL including mutations in MYD88, CD79B, SETD1B, and HLA-B and rearrangements of CD274/PDCD1LG2 involving the 3' untranslated region, the latter critical for immune evasion. ^32,33
Miscellaneous rare lymphomas in the CNS
MALT lymphoma of the dura	MALT lymphoma of the dura are low-grade lymphomas of mucosa-associated lymphoid tissue composed of marginal zone B cells that sometimes present with plasmacytic differentiation. Inactivation of TNFAIP3 is common in cases with plasmacytic differentiation ³⁴, while activating NOTCH2 mutations paired with inactivating TBL1XR1 mutations are common in cases with monocytoid morphology. ³⁴ Cytogenetic studies have identified recurrent gains of chromosome 6p and losses of chromosome 1p. Translocations involving IGH and/or MALT1 are rare. ^35-37
Other low-grade B-cell lymphomas of the CNS	Low-grade B-cell lymphoma is exceptionally rare, with most corresponding to extranodal marginal zone lymphoma, small lymphocytic lymphoma, follicular lymphoma or lymphoplasmacytic lymphoma. ^37-43 Clonal rearrangements of IGH and/or IGK, loss of heterozygosity on 6q (including the locus for TNFAIP3, and MALT1 rearrangements have been identified in isolated cases, but recurrent events are uncommon.^37,44,45 In specimens tested, MYD88 variants were not observed. ³⁷
Anaplastic large cell lymphoma (ALK+/ALK−)	Primary anaplastic large cell lymphoma (ALCL) arising in the CNS is extremely rare. ALK-positive ALCL constitute ~70-80% of ALCL as defined by ALK-positivity via immunohistochemistry and are gentically driven by oncogenic ALK gene fusions, most commonly with NPM1. ^46-49 These ALK fusions result in increased ALK expression, leading to aberrant activation of downstream signalling pathways such as RAS/MAPK and JAK/STAT3 and others. ⁵⁰ ALK-negative ALCL are thought to harbor mutations or fusions in other receptor tyrosine kinase that activate similar signalling pathways to those in ALK-positive ALCL. A single case with an IRF4/DUSP22 rearrangement has been reported. ⁵¹
T-cell and NK/T-cell lymphomas	Primary lymphomas of peripheral T-cell lineage in the CNS are rare and mainly classifiesd as peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), but may also include anaplastic large cell lymphoma, and extranodal natural killer (NK)/T-cell lymphoma (ENKTL). ^52,53 A genetic study of 18 primary lymphomas of peripheral T-cell lineage identified somatic mutations in 36% of cases, although none were recurrent. These includes mutations in NMT3A, KRAS, JAK3,STAT3,STAT5B, GNB1, and TET2. ⁵² A more recent study identified additional pathogenic alterations including those in KMT2C, TET2, NRAS and JAK3 as well as homozygous deletions of CDKN2A and CDKN2B. A single ENKTL case harbored mutations in ARID1B, FAS, TP53, BCOR, KMT2C, POT1, and PRDM1. ⁵⁴
Histiocytic tumors
Erdheim-Chester disease	Erdheim–Chester disease of the CNS or the meninges manifests as widespread infiltrative parenchymal lesions or a meningioma-like mass and can arise throughout the neuroaxis. Genetics alterations primary target the RAS/MAPK pathway and include BRAF p.V600E, or mutations in MAP2K1, KRAS, NRAS, and PIK3CA. ^55-59 Other less common genetic events targeting the RAS/MAPK pathway include ARAF mutations or fusions involving BRAF, NTRK1, ALK, or ETV3 fusions. ^58,60
Rosai-Dorfman disease	Studies on Rosai-Dorfman disease are lacking and most large scale studies were unsuccessful at identifying a genetic driver of the disease. However, rare instances of BRAF p.V600E, mutations in KRAS, NRAS, ARAF, MAP2K1, and CSF1R have been described. ^58,60 Of note, these lesions often have a low proportion of neoplastic cells, likely resulting in underestimations on their genetic underpinnings.
Juvenile xanthogranuloma	Juvenile xanthogranuloma of the CNS is a rare condition typically affecting children and adolescents. Mutations in ARAF, KRAS, and NRAS are common, sometimes arising concurrently whereas the frequency of BRAF p.V600E is unknown. ^58,60 Mutations of CSF1R and fusions involving NTRK 1/2/3 are more comonly associated with peripheral juvenile xanthogranuloma and suggest a non-CNS origin.
Langerhans cell histiocytosis	BRAF p.V600E is noted in ~50% of langerhans cell histiocytosis while additional isolated cases of p.V600D or mutations in ARAF have also been described. ^60-64 Cases without alterations in BRAF often contain variant in other RAS/MAPK pathway genes including MAP2K1, NRAS, KRAS, and PIK3CA. ^{58,60,61,64-66}
Histiocytic sarcoma	Histiocytic sarcoma is an extremely rare and aggressive cancer primarily affecting adults. Genetic aberrations, primarily in the RAS/MAPK pathway, have been identified including those in MAP2K1, KRAS, BRAF, NRAS, PTPN11, NF1, and CBL. ^60,67,68 In addition, mutations affecting the PI3K/AKT/mTOR pathway have also been noted including those in PTEN, MTOR, PIK3R1, and PIK3CA sometimes co-ocurring with the aforementioned RAS/MAPK variants. ^60,67,68 Deletions of CDKN2A and/or CDKN2B have also been described in a subset of cases. Of note, compared to other histiocytic tumors, BRAF p.V600E is rare in histiocytic sarcoma.

Article Bibliography

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External Links

Citation

Paola Dal Cin ; Scott Ryall

Hematolymphoid tumors involving the CNS

Atlas Genet Cytogenet Oncol Haematol. 2025-01-30

Online version: http://atlasgeneticsoncology.org/solid-tumor/209309