Nodular Sclerosis Hodgkin Lymphoma



Nodular Sclerosis Hodgkin Lymphoma


C. Cameron Yin, MD, PhD





Key Facts


Terminology



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


Etiology/Pathogenesis



  • Hodgkin and Reed-Sternberg (HRS) cells arise from late germinal center B cells


  • Ig gene rearrangements positive; many defects in B-cell differentiation


Clinical Issues



  • Represents ˜ 70% of CHL cases in developed countries


  • 15-34 years; mediastinal or cervical lymph nodes


  • Current chemotherapy ± radiation can cure many patients


Microscopic Pathology



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


  • HRS cells have features of lacunar cells


  • Background of inflammatory cells


Ancillary Tests



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


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


  • EBV(+) ˜ 20%, CD45/LCA(-)


Top Differential Diagnoses



  • Primary mediastinal large B-cell lymphoma


  • B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and CHL


  • Lymphocyte-rich classical Hodgkin lymphoma


  • Nodular lymphocyte predominant HL







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.


TERMINOLOGY


Abbreviations



  • Nodular sclerosis Hodgkin lymphoma (NSHL)


Synonyms



  • Nodular sclerosis classical Hodgkin lymphoma


  • Nodular sclerosis (or sclerosing) Hodgkin disease


Definitions



  • 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


ETIOLOGY/PATHOGENESIS


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


Pathogenesis



  • 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


CLINICAL ISSUES


Epidemiology



  • 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


Site



  • Mediastinal or cervical lymph nodes


Presentation



  • Mediastinal involvement in ˜ 80% of cases



    • Bulky disease in ˜ 50% of cases


  • B symptoms in ˜ 40% of cases


  • Associated predominantly with clinical stage II


Treatment



  • 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


Prognosis



  • > 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


IMAGE FINDINGS


General Features



  • Current imaging techniques have made staging laparotomy obsolete


MACROSCOPIC FEATURES


General Features



  • Nodular surface; nodules often surrounded by bands of fibrosis


MICROSCOPIC PATHOLOGY


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


ANCILLARY TESTS


Immunohistochemistry



  • 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


Cytogenetics



  • 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


DIFFERENTIAL DIAGNOSIS


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

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

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