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

are surrounded by thick fibrous bands

A case of NSHL shows effacement of lymph node architecture by neoplastic nodules

surrounded by dense fibrous bands

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(-)