Nodular Sclerosis Hodgkin Lymphoma

Nodular Sclerosis Hodgkin Lymphoma

C. Cameron Yin, MD, PhD

Lymph node partially effaced by nodular sclerosis Hodgkin lymphoma (NSHL). Multiple nodules image are surrounded by thick fibrous bands image.

A case of NSHL shows effacement of lymph node architecture by neoplastic nodules image surrounded by dense fibrous bands image.



  • Nodular sclerosis Hodgkin lymphoma (NSHL)


  • Nodular sclerosis classical Hodgkin lymphoma

  • Nodular sclerosis (or sclerosing) Hodgkin disease


  • Classical Hodgkin lymphoma (CHL) is a lymphoid neoplasm composed of Hodgkin and Reed-Sternberg (HRS) cells in a variable inflammatory background

  • Nodular sclerosis is a type of CHL composed of lacunar-type HRS cells and inflammatory cells forming nodules surrounded by fibrous bands


Infectious Agents

  • Epstein-Barr virus (EBV) is present in HRS cells in ˜ 20% of cases and has a probable pathogenetic role

    • Expression of EBNA1 and latent membrane proteins LMP1 and LMP2a

      • LMP1 mimics active CD40 receptor

      • LMP2a mimics B-cell receptor


  • HRS cells arise from late germinal center or early postgerminal center B-cells that

    • Have undergone immunoglobulin (Ig) gene rearrangements with somatic mutations

    • Have undergone crippling Ig mutations in subset of cases

    • Lack B-cell antigen receptors

  • HRS cells lose much of normal B-cell immunophenotype due to

    • Severe impairment of transcription factor network regulating B-cell gene expression

    • Low or undetectable levels of transcription factors: OCT2, BOB1, PU.1, and early B-cell factor (EBF)

      • Leads to low level of Ig transcripts in HRS cells

      • Made worse by epigenetic silencing (promoter hypermethylation) of Ig transcription

    • Impaired function of early B-cell development transcription factors: pax-5, E2A, and EBF

      • pax-5 and E2A are expressed in HRS cells

      • Aberrant overexpression of NOTCH1, ABF1, and ID2 inhibit overall B-cell development

      • Also leads to decreased or absent expression of CD19, CD20, and CD79a

  • Overall, these abnormalities physiologically should lead to apoptosis

    • However, HRS cells are rescued from undergoing apoptosis

  • Development of antiapoptotic mechanisms to achieve survival

    • Inhibition of executors of apoptosis by expression of X-linked inhibitor of apoptosis (XIAP)

    • Expression of FLICE-like inhibitory protein

    • Deregulation of Bcl-2 family proteins

    • Protection from Fas-induced cell death

    • Deregulation of signaling pathways

      • Poorly understood causes

      • Include paracrine and autocrine feedback loops in addition to genetic lesions of HRS cells

      • Constitutive activation of NF-κB pathway: Canonical and alternative pathways

      • Activation of Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway

  • Role of microenvironment

    • Reactive cellular infiltrate is induced, in part, by HRS cells

      • Protects HRS cells from apoptosis

      • Suppresses T-cell and NK-cell immune response against HRS cells

    • HRS cells produce a variety of molecules

      • Th2 cytokines, chemokines, growth factors, and their receptors

      • IL-1, IL-10, TNF-α, TGF-β, and eotaxin

      • Most cytokines signal via JAK/STAT pathway

    • HRS cells in NSHL show increased production of IL-13

      • May be responsible for broad bands of birefringent collagen

Possible Origin

  • Thymic B cell in patients with mediastinal involvement



  • Incidence

    • Represents ˜ 70% of CHL cases in developed countries

      • Relatively less frequent in underdeveloped nations

  • Age

    • Peak at 15-34 years

  • Gender

    • Slightly more prevalent in women

  • Ethnicity

    • More common in whites than in African-Americans or Latino-Americans


  • Mediastinal or cervical lymph nodes


  • Mediastinal involvement in ˜ 80% of cases

    • Bulky disease in ˜ 50% of cases

  • B symptoms in ˜ 40% of cases

  • Associated predominantly with clinical stage II


  • Current chemotherapy &/or radiation can cure disease in many patients

  • Chemotherapy with or without radiation

    • ABVD: Adriamycin (doxorubicin), bleomycin, vinblastine, and dacarbazine

    • Chemotherapy alone or reduced cycles for early stage NSHL


  • > 90% survival at 5 years in patients with early stage disease

  • Therapy modifies prognosis

  • Adverse prognostic factors

    • Advanced stage

    • Massive mediastinal involvement

    • Older age, usually > 45 years

    • Male gender

  • Histologic grading of NSHL is predictive but less important than clinical factors

  • Recurrent disease with multiple adverse factors results in 56% overall survival at 5 years

  • Deaths mostly related to 2nd malignancy, therapeutic toxicity, and older age


General Features

  • Current imaging techniques have made staging laparotomy obsolete


General Features

  • Nodular surface; nodules often surrounded by bands of fibrosis


Histologic Features

  • Lymph node architecture effaced by neoplastic nodules surrounded by broad collagen bands

    • Originate in thickened capsule

    • Dissect lymph node into nodules of various sizes

    • Lacunar cells formed due to retraction artifact of HRS cells in formalin-fixed tissue sections

      • Nuclei tend to be lobated with smaller lobes, less prominent nucleoli than HRS of other CHL types

    • Number of HRS cells and lacunar cells highly variable

      • Lacunar cells may form cell aggregates associated with necrosis and histiocytes

  • Background of inflammatory cells

    • Eosinophils, histiocytes, &/or neutrophils are often numerous

      • Occasional eosinophilic abscesses are noted

Cytologic Features

  • Lacunar cells in an inflammatory background can be appreciated in fine needle aspiration smears

    • Immunophenotype can be assessed in cell block

Syncytial Variant of NSHL

  • Confluent aggregates of lacunar cells

  • Cohesive appearance may resemble large cell non-Hodgkin lymphoma or metastatic carcinoma

  • Limited number of birefringent collagen bands and occasional necrosis

Grading of NSHL

  • British National Lymphoma Investigation (BNLI) system developed in 1989

    • Based on amount of HRS cells, anaplasia of HRS cells, and fibrosis features

      • Grade 1 NS: Scattered HRS cells in lymphocyte-rich or mixed cellular infiltrate

      • Grade 2 NS: Aggregates of HRS cells or pleomorphic cytology in > 25% of nodules

      • Grade showed differences in outcome for patients with advanced disease only

      • Lack of prognostic significance with current chemotherapeutic regimens

  • German Hodgkin Lymphoma Study Group system reported in 2003

    • Similar to BNLI system but also includes tissue eosinophilia (> 5% of cell infiltrate)

    • Controversial results; prognostic value for intermediate and high-stage disease

Extranodal Involvement of NSHL

  • Spleen

    • ˜ 30% of patients with NSHL

    • Usually presents as solitary or multiple nodules

    • Tumor nodules surrounded by sclerosis that effaces splenic architecture

      • Incipient lesions are periarteriolar or at periphery of marginal zone

      • Nodules of NSHL in spleen do not necessarily show fibrous bands

  • Liver

    • ˜ 10% of patients with NSHL; usually microscopic clusters

      • Mainly detected in wedge biopsies of staging laparotomy (procedure now obsolete)

    • Infiltrates with preferential portal or portal to central vein distribution

      • Associated with constitutional symptoms and biochemical abnormalities

    • Sometimes nondiagnostic inflammatory changes, without HRS cells

  • Bone marrow (BM)

    • ˜ 5-10% of cases of NSHL, up to 70% in necropsies

    • Can be detected during staging of CHL or may be presenting finding

      • CHL presenting in BM usually manifests with cytopenias

      • Unlikely involvement in young patients with normal blood counts and low-stage disease

      • Likely involvement in older patients with cytopenias, B symptoms, and high-stage disease

    • Variable extent of involvement, amount of neoplastic cells, and stromal changes

      • Eosinophilia may be prominent including microabscesses

      • Diffuse stromal fibrosis and histiocytic infiltrate may obscure HRS cells

  • Thymus

    • NSHL is type of CHL most frequently associated with mediastinal involvement

    • Thymus is commonly involved and may be cystic

    • In some cases, granulomatous inflammation can obscure neoplastic cells



  • CD30(+) in > 95%; CD15(+) in 70-80% of cases

    • Characteristic membranous pattern with accentuation in Golgi area

  • pax-5(dim +) ˜ 90%, CD20(variably +) ˜ 20%, CD79a(+) ˜ 10-20%

  • Ki-67(+), p53(+), MUM1(+)

  • CCL17(+), Fascin(+/-), Bcl-2(+/-)

  • CD45/LCA(-), EMA(-), Ig(-), clusterin(-)

  • OCT2(-/+), BOB.1(-/+), PU.1(-)

  • EBV(+) with latency type II pattern in ˜ 20% of cases

    • LMP-1(+), LMP2a(+), EBNA1(+), EBNA2(-)

  • T-cell antigens can be aberrantly expressed by HRS cells in up to 15% of cases

  • Background CD4(+) T cells form rosettes around HRS cells

Flow Cytometry

  • Polytypic B cells and T cells with normal immunophenotype, CD4:CD8 ratio often elevated

  • Useful to exclude non-Hodgkin lymphoma


  • Data derived from HL cell lines and primary HRS cells

  • Aneuploidy and hypertetraploidy

  • Random numerical chromosomal aberrations

In Situ Hybridization

  • EBER(+) in ˜ 20% of cases

Array CGH

  • Many recurrent chromosomal abnormalities

    • Gains of 2p, 9q34, 12q13

    • Losses of Xp21, 6q23, 13q22

    • Amplification of 4p16, 4q23-24, 9p23-24

Molecular Genetics

  • Monoclonal Ig gene rearrangements of HRS cells

  • Rearranged Ig genes harbor somatic mutations in IgH variable regions

    • Rare (˜ 2%) cases reported with monoclonal T-cell receptor gene rearrangements

      • Unclear if these cases are truly examples of CHL

  • REL gene on 2p16 that encodes 1 component of NF-κB shows gains or amplifications in 50% of CHL

  • Inactivating mutations of NF-κB inhibitor IκBα in 10-20% of CHL

Gene Expression Profiling

  • Signature of NSHL shares features with primary mediastinal large B-cell lymphoma


Primary Mediastinal Large B-cell Lymphoma (PMBL)

  • Nodal and soft tissue effacement

  • Interstitial collagen deposition surrounding clusters or sheets of large lymphoma cells

    • Large cells often exhibit cytoplasmic retraction artifact

  • Immunophenotype of neoplastic B cells

    • CD19(+), CD20(+), CD22(+), CD45/LCA(+), CD79a(+)

      • CD30(+/-) and often dim; MAL(+/-)

    • Surface Ig(-), CD10(-), CD15(-)

B-cell Lymphoma, Unclassifiable, with Features Intermediate Between DLBCL and CHL

Jul 8, 2016 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Nodular Sclerosis Hodgkin Lymphoma

Full access? Get Clinical Tree

Get Clinical Tree app for offline access