HAEM4Backup:Splenic Marginal Zone Lymphoma

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Primary Author(s)*

  • Snehal Patel, MD, PhD

Cancer Category/Type

Cancer Sub-Classification / Subtype

  • Splenic Marginal Zone Lymphoma (SMZL)

Definition / Description of Disease

  • Indolent mature B-cell neoplasm of adults involving the spleen, blood, and bone marrow
  • Splenic white pulp effacement by small lymphocytes and pale marginal zone involved by larger cells
  • Likely originating from mature B-cells of the marginal zone
  • The synonyms derive from circulating lymphocytes with cytoplasmic villous projections

Synonyms / Terminology

  • Splenic B-cell marginal zone lymphoma
  • Splenic lymphoma with villous lymphocytes
  • Splenic lymphoma with circulating villous lymphocytes

Epidemiology / Prevalence[1][2]

  • 1 to 2% of lymphoid neoplasms
  • Median age: mid to late 60's
  • Males ~ Females

Clinical Features[1][2]

Signs & Symptoms

  • Splenic enlargement and discomfort
  • Lymphadenopathy (rare)
  • Autoimmune hemolytic anemia or thrombocytopenia
  • Association with Hepatitis C virus

Laboratory findings

  • Cytopenias
  • Lymphocytosis (low level)
  • Small paraprotein

Sites of Involvement[1][2]

  • Spleen (white pulp)
  • Perihilar lymph nodes
  • Blood
  • Bone marrow
  • liver (less common)
  • peripheral lymph nodes (rare)

Morphologic Features[1][2]

  • Marked expansion splenic white pulp by neoplastic B-cells
  • Effacement of mantle zone and germinal center by small neoplastic B-cells
  • Residual germinal centers may be present
  • Small cells and large cells with more cytoplasm are seen in the marginal zone
  • Neoplastic B-cells show cytoplasmic projections in smear preparations

Immunophenotype[1][2]

Finding Marker
Positive (B-cell lineage markers) CD19, CD20 (bright), CD22, PAX5, FMC7, sIg (bright, monotypic)
Positive (subset) CD5, CD11c, CD70, CD103
Negative CD10, CD21, CD35, CD42, CD123, BCL1, BCL6, SOX11, LEF1, IRTA1, BRAF V600E

Chromosomal Rearrangements (Gene Fusions)

  • Rare but (some) recurrent translocations/gene fusions:
    • t(8;14)(q24;q32)/IGH-MYC[3][4]
    • KMT2A fusion in large cell transformation of SMZL[5]
    • t(2;7)(p11.2;q21.2/IGK-CDK6[6][7]
      • Also reported in CD5-negative monoclonal B-cell lymphocytosis[8]
    • t(14;18)(q32;q21)/IGH-BCL2[9]
    • t(5;7)(p15.33;p11)/TERT fusion[10]
    • t(9;14)(p13;q32)/IGH-PAX5[11][12][13]

Characteristic Chromosomal Aberrations / Patterns

  • Ig gene rearrangements

Genomic Gain/Loss/LOH

Chromosome Number Gain/Loss/Amp/LOH Significance Prevalence
7q31-32 Loss (heterozygous) Unknown; possible haploinsufficiency of IRF5 tumor suppressor[14] 26–45%[1][15][16]
3/3q Gain (trisomy) Unknown 15%[1][16][15]

Gene Mutations (SNV/INDEL)

Gene* Oncogene/Tumor Suppressor/Other Presumed Mechanism (LOF/GOF/Other) Prevalence (COSMIC)
NOTCH2 Oncogene or Tumor Suppressor[17] Other 21%
MYD88 Oncogene GOF 7%
KLF2 Likely tumor suppressor in most contexts[18] LOF 20%[19]
TNFAIP3 Tumor Suppressor LOF 8%
TP53 Tumor Suppressor LOF 7%
BIRC3 Oncogene or Tumor Suppressor[20] Other 5%
CARD11 Oncogene GOF 4%
IKBKB Oncogene GOF 4%
SPEN Tumor Suppressor LOF 6%
NOTCH1 Oncogene or Tumor Suppressor[17] Other 11%
TBL1XR1 Oncogene or Tumor Suppressor[21] Other 7%
NFKBIE Tumor Suppressor LOF 2%

*Specific mutations in these genes may be found in cBioPortal or COSMIC.

Epigenomics (Methylation)

  • Epigenetic dysregulation expected on basis of genetic alterations in histone modifying and chromatin remodeling factors:
    • TBL1XR1 is a member of nuclear receptor corepressor (N-CoR) and histone deacetylase 3 (HDAC3) complexes
    • CREBBP is a histone acetyltransferase
    • ARID1A is a member of SWI-SNF complexes
    • EP300 is a histone acetyltransferase
    • DNMT3A is a DNA methyltransferase
  • Promoter methylation and gene expression study revealed two clusters of SMZL[22]
    • high methylation group compared to low methylation group showed
      • Methylated/repressed tumor suppressor genes and unmethylated/overexpressed prosurvival genes
      • Association with NOTCH2 mutations, 7q31-32 loss, and histologic transformation
      • Reduced overall survival
      • Reduced proliferation and reversion of phenotype in response to demethylating agents in vitro

Genes and Main Pathways Involved

Molecular Feature Pathway Pathophysiologic outcome
NOTCH2, NOTCH1, DTX, and SPEN mutations NOTCH signaling[23] Increased proliferation and survival
MYD88, TNFAIP3, BIRC3, CARD11, IKBKB, NFKBIE, and TRAF3 mutations NF-κB signaling[24][25][26] Lymphocyte development
TP53 mutations TP53 pathway Dysregulation of genomic stability and apoptosis
TBL1XR1, CREBBP, ARID1A, EP300, and DNMT3A mutations Histone modification and chromatin remodeling[23] Abnormal gene expression program

Diagnostic Testing Methods

  • Clinical, morphologic, and immunophenotypic findings and exclusion of other low-grade B-cell lymphomas are generally sufficient for diagnosis
  • No established specific diagnostic test currently exists
  • Molecular testing may help exclude other entities in some cases (see below)

Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)

Alteration Clinical Significance Note
BRAF mutations Diagnostic (exclusion) Present in hairy cell leukemia (HCL) and absent in SMZL[27]
MYD88 mutations Diagnostic (exclusion) Present in lymphoplasmacytic lymphoma (LPL) and rare but not absent in SMZL
t(11;14)(q13;q32)/IGH-CCND1* Diagnostic (exclusion) Present in mantle cell lymphoma (MCL) and absent in SMZL
t(14;18)(q32;q21)/IGH-BCL2 Diagnostic (exclusion) Present in follicular lymphoma (FL) and rare but not absent in SMZL[9]
t(11;18)(q21;q21)/BIRC3-MALT1 Diagnostic (exclusion) Present in MALT lymphoma and absent in SMZL
t(14;18)(q32;q21)/IGH-MALT1 Diagnostic (exclusion) Present in MALT lymphoma and absent in SMZL[28]
t(1;14)(p22;q32)/IGH-BCL10 Diagnostic (exclusion) Present in MALT lymphoma and absent in SMZL

*Cases previously reported as SMZL with IGH-CCND1 fusion should now be classified as MCL

Familial Forms

  • None

Other Information

  • None

Links

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 Salido, Marta; et al. (2010). "Cytogenetic aberrations and their prognostic value in a series of 330 splenic marginal zone B-cell lymphomas: a multicenter study of the Splenic B-Cell Lymphoma Group". Blood. 116 (9): 1479–1488. doi:10.1182/blood-2010-02-267476. ISSN 0006-4971.
  2. ↑ 2.0 2.1 2.2 2.3 2.4 Tsd, Santos; et al. (2017). "Splenic Marginal Zone Lymphoma: A Literature Review of Diagnostic and Therapeutic Challenges". doi:10.1016/j.bjhh.2016.09.014. PMC 5457460. PMID 28577652.CS1 maint: PMC format (link)
  3. ↑ Shi, Xiaofeng; et al. (2018). "A rare case of B-lymphoproliferative disorder with villous lymphocytes harboring t(8;14)(q24;q32) translocation". Frontiers of Medicine. 12 (3): 324–329. doi:10.1007/s11684-017-0558-z. ISSN 2095-0217.
  4. ↑ Scapinello, Greta; et al. (2018). "Splenic marginal zone lymphoma with a de novo t(8;14)(q24;q32) and a prolymphocytoid evolution responsive to rituximab-bendamustine". Annals of Hematology. 97 (10): 2001–2003. doi:10.1007/s00277-018-3351-4. ISSN 0939-5555.
  5. ↑ Gindin, Tatyana; et al. (2015). "MLL / KMT2A translocations in diffuse large B-cell lymphomas: MLL / KMT2A translocations in diffuse large B-cell lymphomas". Hematological Oncology. 33 (4): 239–246. doi:10.1002/hon.2158.
  6. ↑ Remstein, E D; et al. (2008). "The prevalence of IG translocations and 7q32 deletions in splenic marginal zone lymphoma". Leukemia. 22 (6): 1268–1272. doi:10.1038/sj.leu.2405027. ISSN 0887-6924.
  7. ↑ Corcoran, M M; et al. (1999). "Dysregulation of cyclin dependent kinase 6 expression in splenic marginal zone lymphoma through chromosome 7q translocations". Oncogene. 18 (46): 6271–6277. doi:10.1038/sj.onc.1203033. ISSN 0950-9232.
  8. ↑ Parker, Edward; et al. (2011). "Molecular characterization of a t(2;7) translocation linking CDK6 to the IGK locus in CD5− monoclonal B-cell lymphocytosis". Cancer Genetics. 204 (5): 260–264. doi:10.1016/j.cancergen.2011.03.004.
  9. ↑ 9.0 9.1 Baseggio, Lucile; et al. (2012). "In non-follicular lymphoproliferative disorders, IGH/BCL2-fusion is not restricted to chronic lymphocytic leukaemia". British Journal of Haematology. 158 (4): 489–498. doi:10.1111/j.1365-2141.2012.09178.x.
  10. ↑ Nagel, Inga; et al. (2010). "Deregulation of the telomerase reverse transcriptase (TERT) gene by chromosomal translocations in B-cell malignancies". Blood. 116 (8): 1317–1320. doi:10.1182/blood-2009-09-240440. ISSN 0006-4971.
  11. ↑ Kelly, Richard J.; et al. (2007). "The t(9;14)(p13;q32) is a recurrent but rare abnormality in splenic marginal zone lymphoma". Leukemia & Lymphoma. 48 (8): 1636–1637. doi:10.1080/10428190701474415. ISSN 1042-8194.
  12. ↑ Sole, F.; et al. (2006). "Translocation t(9;14)(p13;q32) in cases of splenic marginal zone lymphoma". Haematologica. 91 (9): 1289–1291. ISSN 0390-6078. PMID 16956840.
  13. ↑ K, Kawakami; et al. (1998). "A Case of Primary Splenic Large Cell Lymphoma With a t(9;14)(p13;q32)". PMID 9631587.
  14. ↑ Fresquet, Vicente; et al. (2012). "High-throughput sequencing analysis of the chromosome 7q32 deletion reveals IRF5 as a potential tumour suppressor in splenic marginal-zone lymphoma". British Journal of Haematology. 158 (6): 712–726. doi:10.1111/j.1365-2141.2012.09226.x.
  15. ↑ 15.0 15.1 Baró, Cristina; et al. (2008). "New chromosomal alterations in a series of 23 splenic marginal zone lymphoma patients revealed by Spectral Karyotyping (SKY)". Leukemia Research. 32 (5): 727–736. doi:10.1016/j.leukres.2007.09.012.
  16. ↑ 16.0 16.1 Gruszka-Westwood, Alicja M.; et al. (2003). "Deletion mapping on the long arm of chromosome 7 in splenic lymphoma with villous lymphocytes". Genes, Chromosomes and Cancer. 36 (1): 57–69. doi:10.1002/gcc.10142. ISSN 1045-2257.
  17. ↑ 17.0 17.1 Lobry, Camille; et al. (2011). "Oncogenic and tumor suppressor functions of Notch in cancer: it's NOTCH what you think". The Journal of Experimental Medicine. 208 (10): 1931–1935. doi:10.1084/jem.20111855. ISSN 1540-9538. PMC 3182047. PMID 21948802.CS1 maint: PMC format (link)
  18. ↑ Wang, Chunmei; et al. (2017). "Krüppel-like factor 2 suppresses human gastric tumorigenesis through inhibiting PTEN/AKT signaling". Oncotarget. 8 (59): 100358–100370. doi:10.18632/oncotarget.22229. ISSN 1949-2553. PMC 5725026. PMID 29245984.CS1 maint: PMC format (link)
  19. ↑ Jaramillo Oquendo, Carolina; et al. (2019). "Systematic Review of Somatic Mutations in Splenic Marginal Zone Lymphoma". Scientific Reports. 9 (1). doi:10.1038/s41598-019-46906-1. ISSN 2045-2322. PMC 6639539. PMID 31320741.CS1 maint: PMC format (link)
  20. ↑ Yamato, Azusa; et al. (2015). "Oncogenic activity of BIRC2 and BIRC3 mutants independent of nuclear factor-κB-activating potential". Cancer Science. 106 (9): 1137–1142. doi:10.1111/cas.12726. PMC 4582982. PMID 26094954.CS1 maint: PMC format (link)
  21. ↑ Cao, Qinghua; et al. (2018). "TBL1XR1 promotes migration and invasion in osteosarcoma cells and is negatively regulated by miR-186-5p". American Journal of Cancer Research. 8 (12): 2481–2493. ISSN 2156-6976. PMC 6325474. PMID 30662805.
  22. ↑ Arribas, Alberto J.; et al. (2015). "DNA methylation profiling identifies two splenic marginal zone lymphoma subgroups with different clinical and genetic features". Blood. 125 (12): 1922–1931. doi:10.1182/blood-2014-08-596247. ISSN 0006-4971. PMC 4416938. PMID 25612624.CS1 maint: PMC format (link)
  23. ↑ 23.0 23.1 Rossi, Davide; et al. (2012). "The coding genome of splenic marginal zone lymphoma: activation of NOTCH2 and other pathways regulating marginal zone development". The Journal of Experimental Medicine. 209 (9): 1537–1551. doi:10.1084/jem.20120904. ISSN 1540-9538. PMC 3428941. PMID 22891273.CS1 maint: PMC format (link)
  24. ↑ Spina, Valeria; et al. (2016). "NF-κB deregulation in splenic marginal zone lymphoma". Seminars in Cancer Biology. 39: 61–67. doi:10.1016/j.semcancer.2016.08.002.
  25. ↑ Yan, Q.; et al. (2012). "BCR and TLR signaling pathways are recurrently targeted by genetic changes in splenic marginal zone lymphomas". Haematologica. 97 (4): 595–598. doi:10.3324/haematol.2011.054080. ISSN 0390-6078. PMC 3347666. PMID 22102703.CS1 maint: PMC format (link)
  26. ↑ Rossi, Davide; et al. (2011). "Alteration of BIRC3 and multiple other NF-κB pathway genes in splenic marginal zone lymphoma". Blood. 118 (18): 4930–4934. doi:10.1182/blood-2011-06-359166. ISSN 0006-4971.
  27. ↑ Naseem, Shano; et al. (2020). "BRAF V600E mutation detection in hairy cell leukemia-utility of archival DNA from bone marrow aspirate/imprint smear and amplification refractory mutation system". Molecular Biology Reports. doi:10.1007/s11033-020-05509-0. ISSN 0301-4851.
  28. ↑ Streubel, Berthold; et al. (2003). "T(14;18)(q32;q21) involving IGH andMALT1 is a frequent chromosomal aberration in MALT lymphoma". Blood. 101 (6): 2335–2339. doi:10.1182/blood-2002-09-2963. ISSN 1528-0020.

EXAMPLE Book

  1. Arber DA, et al., (2017). Acute myeloid leukaemia with recurrent genetic abnormalities, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Arber DA, Hasserjian RP, Le Beau MM, Orazi A, and Siebert R, Editors. IARC Press: Lyon, France, p223-225.

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