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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