Nodular Sclerosis Classic Hodgkin Lymphoma
Xiaolin Hu, PhD, Sema4 OpCo Inc.
Cancer Sub-Classification / Subtype
Nodular sclerosis classic Hodgkin lymphoma
Definition / Description of Disease
Hodgkin lymphomas (HL) are a group of B-cell neoplasms that arise in lymph nodes, categorized mainly into nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) and classic Hodgkin lymphoma (CHL). CHL accounts for approximately 90% of HL and is subdivided into four histologic types, nodular sclerosis CHL (NSCHL), lymphocyte-rich CHL, mixed cellularity CHL, and lymphocyte-depleted CHL. NSCHL is the most common type of CHL and is characterized by the appearance of nodular growth surrounded by prominent collagen bands and the presence of lacunar type Hodgkin/Reed-Sternberg cells (HRS).
Synonyms / Terminology
Hodgkin disease, nodular sclerosis, NOS
Hodgkin lymphoma, nodular sclerosis, grade 1
Hodgkin lymphoma, nodular sclerosis, grade 2
Hodgkin lymphoma, nodular sclerosis, cellular phase
Epidemiology / Prevalence
CHL has an incidence of 2-3 cases per 100000 people every year in developed country . NSCHL is the most common type of CHL in developed countries, accounting for 70% of diagnosed cases. It is seen most in individuals between 15 and 35 years old, affecting both males and females at similar frequency. Concurrent Epstein-Barr virus infection is found in approximately 25%-40% CHL but the percentages vary in different subtypes . EBV-positivity is not as common in the context of NSCHL as it is in mixed cellularity and lymphocyte-depleted subtypes of CHL. Reported frequencies of EBV positive NSCHL range from 10-40%  , some of this variation may be accounted for by differences in detection techniques used.
Clinical staging is based on the revised Ann Arbor system (stage I to IV), with incorporation of clinical signs/symptoms and CT/PET scan data . 40% of patients at diagnosis are at stage II (lymphoma involves two or more lymph nodes on the same side of the diaphragm) with B symptoms. Patients may present with a mediastinal mass, including bulky disease where the mediastinal mass exceeds 1/3 of the width of the thoracic cavity, or any mass ≥ 10 cm in any dimension when measured via CT scan.
Sites of Involvement
Mediastinum - 80%
Spleen/lung - 5%
Bone marrow - 3%
Liver - 2 %
The lymph node capsule is thickened with prominent collagen bands dividing the lymph node into variable nodules, which are composed of highly variable mixture of neoplastic and inflammatory cells, including small lymphocytes, eosinophils, histiocytes and neutrophils.
The neoplastic cells do not have the classical binucleate appearance of Reed-Sternberg cells seen in other types of HL. Instead they tend to have multilobated nuclei, smaller nucleoli than classical Reed Sternberg cells, coarse chromatin, and when formalin-fixed the cells have the appearance of being surrounded by an empty space (lacuna) due to the retraction and condensation of the cytoplasm. These lacunar cells can form large clusters attracting aggregation of inflammatory cells especially eosinophils and histiocytes, resembling necrotizing granulomas. This is called syncytial variant of NSCHL.
Nodular necrosis can be seen in higher grade lymphoma and cystic degeneration is commonly seen with thymic involvement.
R-S cells, including lacunar cells, have a typical immunophenotype as CD30+, CD15+/−, CD20−/+, CD19−, CD45−, EBV/EBER−/+, PAX5+, EMA−, and MUM1.
|Positive (universal)||CD30, PAX5,|
|Positive (subset)||CD15, CD20, CD79a, CD4, CD2, EBV|
|Negative (universal)||CD19, CD45, EMA|
|Negative (subset)||CD15, CD20, EBV|
Chromosomal Rearrangements (Gene Fusions)
Translocation breakpoints involving immunoglobin loci have been reported in approximately 20% of CHL. Some translocations may involve known oncogenes such as BCL1, BCL2, BCL3, BCL6, REL and MYC, but most of partners are unknown . Disease-specific translocations have not been characterized in NSCHL. t(14;18) is common in certain types of non-Hodgkin lymphoma but is a rare event in HL. CIITA rearrangements have been detected in 15% of CHL by fluorescence in situ hybridization (FISH) .
Individual Region Genomic Gain/Loss/LOH
Chromosome analysis usually renders a normal karyotype, due to the paucity of neoplastic cells. Studies have shown that HRS cells may exhibit complex karyotypes including triploidy, tetraploidy, multiple aneuploidies and copy number variations (CNV) . Recurrent CNVs have been reported in 5-20% of CHL, involving chromosome 1p, 2p, 6q, 7q, 8q, 9p, 11q, 12q, 13q, 14q, 16p, 17q, 19 and 20q . Among these, deletions are associated with loss of function in 6q (TNFAIP3) , 14q (IKBA) and 16p (SOCS1), duplications are associated with gain of function in 2p (REL)  and 9p (JAK2, PDL1 and PDL2) .
Characteristic Chromosomal Patterns
Gene Mutations (SNV/INDEL)
Recurrent sequencing mutations have been detected in genes involved in several cell signaling pathways that promote proliferation and growth in CHL. STAT6 and SOCS1 are the most commonly involved genes, and are associated with the JAK-STAT signalling pathway . TNFAIP3, NFKBIA variants are associated with dysregulation of the NF-kB pathway. ITPKB and GNA13 variants are associated with disruption of the PI3K/AKT pathway . Other reported common variants in HL include XPO1, B2M and TP53 . Studies using genomic profiling report that HL has an overall increased mutational burden .
|Gene; Genetic Alteration||Presumed Mechanism (Tumor Suppressor Gene [TSG] / Oncogene / Other)||Prevalence (COSMIC / TCGA / Other)||Concomitant Mutations||Mutually Exclusive Mutations||Diagnostic Significance (Yes, No or Unknown)||Prognostic Significance (Yes, No or Unknown)||Therapeutic Significance (Yes, No or Unknown)||Notes|
|TNFAIP3||TSG||20% (COSMIC) in HL||NA||NA||Unknown|
|SOCS1||TSG||47% (COSMIC) in HL||NA||NA||Unknown|
|GNA13||G protein||24%  in CHL||NA||NA||Unknown|
|ITPKB||Kinase||16%  in CHL||NA||NA||Unknown|
|STAT6||Oncogene||32%  in CHL||NA||NA||Unknown|
|XPO1||protein transporter||18%  in CHL||NA||NA||Unknown|
|B2M||MHC class I molecule||26%  in CHL||NA||NA||Unknown|
Note: A more extensive list of mutations can be found in cBioportal (https://www.cbioportal.org/), COSMIC (https://cancer.sanger.ac.uk/cosmic), ICGC (https://dcc.icgc.org/) and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.
Promoter hypermethylation may play a role in silencing B-cell specific genes such as SYK, PU.1, CD19, and CD79B  as well as genes involved in a variety of biological functions . Some isoforms of histone deacetylases (HDAC) are highly expressed in HL .
Genes and Main Pathways Involved
Both canonical and non-canonical NF-kB pathways have been reported to be constitutively activated, resulting in HRS cell proliferation and survival. The deregulation of NF-kB signaling may be influenced by the tumor microenvironment but can also be caused by genetic alterations in components of the B-cell receptor (BCR), Toll-like receptor signaling (TLR), and the NF-kB pathway itself . TNFAIP3, a NF-kB inhibitor, is commonly mutated in HL not associated with concurrent EBV infection, suggesting NF-kB activation and EBV are two different mechanisms to transform HRS cells .
The JAK/STAT signaling pathway is constitutively activated in CHL, which is likely an aberration caused by both deregulated cytokines/chemokines, and/or genetic lesions in the JAK/STAT pathway. The cytokine and chemokines produced by the HRS cells could further stimulate the proinflammatory environment to promote tumor growth and proliferation . Other signaling pathways that may play a role in the pathogenesis include Notch1 signaling, PI2K/AKT pathway and MAPK/ERK pathway .
|Gene; Genetic Alteration||Pathway||Pathophysiologic Outcome|
|TNFAIP3 inactivating mutations
NFKBIA, NFKBIE inactivating mutations
|NF-kB signalling||Promotes HRS cell survival|
|JAK2, chromosome gain, translocation
SOCS1, inactivating mutation
STAT6, STAT3, STAT5b, activating mutations
|JAK/STAT signalling||Promotes HRS cell growth and survival|
|PD1, PDL1, chromosome gain||immune checkpoint||Creates an immunosuppressive microenvironment|
Genetic Diagnostic Testing Methods
There is no definitive genetic diagnostic testing for NSCHL. The diagnosis is mainly based on clinical symptoms and histopathological findings.
Familial Hodgkin Lymphoma Predisposing Genes are under investigation.
Overall, NSCHL has good prognosis when compared to other subtypes of CHL, with a 5-year survival rate over 80% . Bulky disease at diagnosis is an adverse prognostic indicator.
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- ↑ Brice, Pauline; et al. (2021-10-23). "Classical Hodgkin lymphoma". Lancet (London, England). 398 (10310): 1518–1527. doi:10.1016/S0140-6736(20)32207-8. ISSN 1474-547X. PMID 33493434 Check
- ↑ Zanelli, Magda; et al. (2021-09-12). "EBV-Driven Lymphoproliferative Disorders and Lymphomas of the Gastrointestinal Tract: A Spectrum of Entities with a Common Denominator (Part 1)". Cancers. 13 (18): 4578. doi:10.3390/cancers13184578. ISSN 2072-6694. PMC 8465149 Check
|pmc=value (help). PMID 34572803 Check
- ↑ Campos, Antonio Hugo Jose Froes Marques; et al. (2018-01-30). "Frequency of EBV associated classical Hodgkin lymphoma decreases over a 54-year period in a Brazilian population". Scientific Reports. 8 (1): 1849. doi:10.1038/s41598-018-20133-6. ISSN 2045-2322. PMC 5789833. PMID 29382865.
- ↑ Cheson, Bruce D.; et al. (2014-09-20). "Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification". Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology. 32 (27): 3059–3068. doi:10.1200/JCO.2013.54.8800. ISSN 1527-7755. PMC 4979083. PMID 25113753.
- ↑ Martín-Subero, José I.; et al. (2006-11-01). "Chromosomal breakpoints affecting immunoglobulin loci are recurrent in Hodgkin and Reed-Sternberg cells of classical Hodgkin lymphoma". Cancer Research. 66 (21): 10332–10338. doi:10.1158/0008-5472.CAN-06-1992. ISSN 0008-5472. PMID 17079453.
- ↑ Szymanowska, Natalia; et al. (2008-10-15). "BCL2 and BCL3 are recurrent translocation partners of the IGH locus". Cancer Genetics and Cytogenetics. 186 (2): 110–114. doi:10.1016/j.cancergencyto.2008.06.007. ISSN 1873-4456. PMID 18940474.
- ↑ Steidl, Christian; et al. (2011-03-17). "MHC class II transactivator CIITA is a recurrent gene fusion partner in lymphoid cancers". Nature. 471 (7338): 377–381. doi:10.1038/nature09754. ISSN 1476-4687. PMC 3902849. PMID 21368758.
- ↑ Weber-Matthiesen, K.; et al. (1995-08-15). "Numerical chromosome aberrations are present within the CD30+ Hodgkin and Reed-Sternberg cells in 100% of analyzed cases of Hodgkin's disease". Blood. 86 (4): 1464–1468. ISSN 0006-4971. PMID 7632954.
- ↑ Falzetti, D.; et al. (1999-04). "Genomic instability and recurrent breakpoints are main cytogenetic findings in Hodgkin's disease". Haematologica. 84 (4): 298–305. ISSN 0390-6078. PMID 10190942. Check date values in:
- ↑ Steidl, Christian; et al. (2010-07-22). "Genome-wide copy number analysis of Hodgkin Reed-Sternberg cells identifies recurrent imbalances with correlations to treatment outcome". Blood. 116 (3): 418–427. doi:10.1182/blood-2009-12-257345. ISSN 1528-0020. PMID 20339089.
- ↑ 12.0 12.1 Schmitz, Roland; et al. (2009-05-11). "TNFAIP3 (A20) is a tumor suppressor gene in Hodgkin lymphoma and primary mediastinal B cell lymphoma". The Journal of Experimental Medicine. 206 (5): 981–989. doi:10.1084/jem.20090528. ISSN 1540-9538. PMC 2715030. PMID 19380639.
- ↑ Barth, Thomas F. E.; et al. (2003-05-01). "Gains of 2p involving the REL locus correlate with nuclear c-Rel protein accumulation in neoplastic cells of classical Hodgkin lymphoma". Blood. 101 (9): 3681–3686. doi:10.1182/blood-2002-08-2577. ISSN 0006-4971. PMID 12511414.
- ↑ Green, Michael R.; et al. (2010-10-28). "Integrative analysis reveals selective 9p24.1 amplification, increased PD-1 ligand expression, and further induction via JAK2 in nodular sclerosing Hodgkin lymphoma and primary mediastinal large B-cell lymphoma". Blood. 116 (17): 3268–3277. doi:10.1182/blood-2010-05-282780. ISSN 1528-0020. PMC 2995356. PMID 20628145.
- ↑ 15.0 15.1 15.2 15.3 15.4 15.5 15.6 Tiacci, Enrico; et al. (2018-05-31). "Pervasive mutations of JAK-STAT pathway genes in classical Hodgkin lymphoma". Blood. 131 (22): 2454–2465. doi:10.1182/blood-2017-11-814913. ISSN 1528-0020. PMC 6634958. PMID 29650799.
- ↑ Spina, Valeria; et al. (2018-05-31). "Circulating tumor DNA reveals genetics, clonal evolution, and residual disease in classical Hodgkin lymphoma". Blood. 131 (22): 2413–2425. doi:10.1182/blood-2017-11-812073. ISSN 1528-0020. PMID 29449275.
- ↑ 17.0 17.1 Liang, Winnie S.; et al. (2019-02). "Comprehensive Genomic Profiling of Hodgkin Lymphoma Reveals Recurrently Mutated Genes and Increased Mutation Burden". The Oncologist. 24 (2): 219–228. doi:10.1634/theoncologist.2018-0058. ISSN 1549-490X. PMC 6369943. PMID 30108156. Check date values in:
- ↑ Ushmorov, Alexey; et al. (2006-03-15). "Epigenetic processes play a major role in B-cell-specific gene silencing in classical Hodgkin lymphoma". Blood. 107 (6): 2493–2500. doi:10.1182/blood-2005-09-3765. ISSN 0006-4971. PMID 16304050.
- ↑ Dhiab, Myriam Ben; et al. (2015-12). "DNA methylation patterns in EBV-positive and EBV-negative Hodgkin lymphomas". Cellular Oncology (Dordrecht). 38 (6): 453–462. doi:10.1007/s13402-015-0242-8. ISSN 2211-3436. PMID 26350502. Check date values in:
- ↑ Adams, Heiner; et al. (2010-06). "Class I histone deacetylases 1, 2 and 3 are highly expressed in classical Hodgkin's lymphoma". Expert Opinion on Therapeutic Targets. 14 (6): 577–584. doi:10.1517/14728221003796609. ISSN 1744-7631. PMID 20415600. Check date values in:
- ↑ Weniger, Marc A.; et al. (2016-08). "NF-κB deregulation in Hodgkin lymphoma". Seminars in Cancer Biology. 39: 32–39. doi:10.1016/j.semcancer.2016.05.001. ISSN 1096-3650. PMID 27221964. Check date values in:
- ↑ Steidl, Christian; et al. (2011-05-10). "Molecular pathogenesis of Hodgkin's lymphoma: increasing evidence of the importance of the microenvironment". Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology. 29 (14): 1812–1826. doi:10.1200/JCO.2010.32.8401. ISSN 1527-7755. PMID 21483001.
- ↑ Jundt, F.; et al. (2008-08). "Aberrant expression of Notch1 interferes with the B-lymphoid phenotype of neoplastic B cells in classical Hodgkin lymphoma". Leukemia. 22 (8): 1587–1594. doi:10.1038/leu.2008.101. ISSN 1476-5551. PMID 18449208. Check date values in:
- ↑ Dutton, Amanda; et al. (2005-03). "Constitutive activation of phosphatidyl-inositide 3 kinase contributes to the survival of Hodgkin's lymphoma cells through a mechanism involving Akt kinase and mTOR". The Journal of Pathology. 205 (4): 498–506. doi:10.1002/path.1725. ISSN 0022-3417. PMID 15714459. Check date values in:
- ↑ Zheng, Bei; et al. (2003-08-01). "MEK/ERK pathway is aberrantly active in Hodgkin disease: a signaling pathway shared by CD30, CD40, and RANK that regulates cell proliferation and survival". Blood. 102 (3): 1019–1027. doi:10.1182/blood-2002-11-3507. ISSN 0006-4971. PMID 12689928.
- ↑ Allemani, Claudia; et al. (2006-07-15). "Hodgkin disease survival in Europe and the U.S.: prognostic significance of morphologic groups". Cancer. 107 (2): 352–360. doi:10.1002/cncr.21995. ISSN 0008-543X. PMID 16770772.
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