Nodular Lymphocyte Predominant Hodgkin Lymphoma

Nodular Lymphocyte Predominant Hodgkin Lymphoma

Pei Lin, MD

Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) in a lymph node. There are multiple nodules of variable size image throughout the lymph node parenchyma.

NLPHL involving lymph node. The nodal architecture is effaced by multiple expansile nodules image with compressed interfollicular zones image. The nodules have a “moth-eaten” appearance.



  • Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL)


  • Nodular lymphocyte predominant Hodgkin disease (REAL, 1994)

  • Lymphocytic-predominant Hodgkin disease (Rye, 1966)

  • Lymphocytic &/or histiocytic predominance Hodgkin disease (Lukes and Butler, 1966)

  • Paragranuloma (Jackson and Parker, 1944)


  • Nodular proliferation of scattered large neoplastic B cells associated with numerous inflammatory cells

    • Neoplastic cells are designated as lymphocyte-predominant (LP) cells

      • a.k.a. “popcorn” cells because of their hyperlobated nuclei with vesicular chromatin

      • Formerly called L&H (lymphocytic &/or histiocytic) cells

    • Neoplastic cells are usually confined within follicular dendritic cell meshworks

    • Background infiltrate of nonneoplastic small lymphocytes and histiocytes

      • Inflammatory cells greatly outnumber neoplastic LP cells

  • Diffuse form of NLPHL

    • Term derived from Lukes and Butler classification, but its existence has been challenged

    • Most cases in this category have been reclassified as

      • T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL)

      • NLPHL with diffuse THRLBCL-like areas

      • Classical Hodgkin lymphoma (CHL)

    • Rare cases of diffuse NLPHL probably exist, i.e., “moth-eaten” B-cell-rich pattern of NLPHL


Postulated Normal Counterpart

  • Germinal center B lymphocyte at centroblast stage of differentiation

Associated Lesions

  • NLPHL is associated with progressive transformation of germinal centers (PTGC)

    • PTGC and NLPHL can involve same lymph node biopsy specimen

    • In past, PTGC often identified in staging laparotomy specimens of NLPHL patients

    • However, prospective studies of patients with PTGC show no increased risk of NLPHL



  • Incidence

    • 5-6% of all Hodgkin lymphomas

  • Age

    • Median: 35 years

    • All age groups are affected

  • Gender

    • Male predominance

    • Male to female ratio > 2:1


  • Lymph nodes

  • Most commonly affected groups include cervical, axillary, or inguinal lymph nodes

    • Paraaortic and iliac lymph nodes less often involved

  • Liver &/or spleen involved in ˜ 10% of cases

  • Mediastinum involved in ˜ 7%

  • Bone marrow rarely involved (˜ 2%)

    • Bone marrow involvement is usually evidence of transformation to large B-cell lymphoma


  • Peripheral lymphadenopathy

    • Stage I or II in ˜ 80% of patients

  • B symptoms are uncommon (˜ 10%)

Laboratory Tests

  • Normal complete blood count; no leukemic phase

  • Serum lactate dehydrogenase (LDH) or β-2-microglobulin levels are rarely elevated

Natural History

  • NLPHL is clinically indolent disease with frequent relapses

  • Relapse-free survival curves show “staircase”

    • No plateau suggestive of cure

    • Early and late (> 10 years) relapses occur

    • Risk of relapse is independent of stage of disease or therapy

    • Relapse can be localized or generalized (˜ 20%) disease

  • ˜ 3-5% of NLPHL transform to large B-cell lymphoma (LBCL)

    • Large B-cell lymphoma typically follows NLPHL but can coexist with or precede NLPHL

      • Subset of transformed cases resembles diffuse large B-cell lymphoma (DLBCL)

      • Clinically indolent when compared with de novo diffuse large B-cell lymphoma

    • 2nd subset resembles THRLBCL

  • ˜ 15% of patients die of disease with prolonged followup

    • Deaths related to therapy-refractory disease or 2nd malignancies

    • 2nd malignancies represent ˜ 4% of all deaths

      • Acute leukemia (2%), non-Hodgkin lymphoma (1%), solid organ tumors (1%)


  • Options, risks, complications

    • “Watch and wait” has been advocated for pediatric patients with localized disease

  • Drugs

    • Combination chemotherapy employed most often

    • Recommended regime: Doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD)

    • Rituximab (anti-CD20) monoclonal antibody is often used

      • As part of ABVD regimen, upfront (R-ABVD)

      • At time of refractory disease

  • Radiation

    • Localized disease may be treated with involved field radiation alone

      • This option is avoided in pediatric and adolescent patients to avoid injuring growth plates of bones


  • Good prognosis with > 80% 10-year survival

    • Better survival for patients with low- vs. high-stage disease

    • Patients with NLPHL have better survival than patients with classical Hodgkin lymphoma

  • Transformation to diffuse large B-cell lymphoma or THRLBCL is often associated with poorer prognosis

    • Bone marrow involvement is associated with aggressive clinical behavior

    • Prognosis may not be impacted if large B-cell lymphoma is localized and treated appropriately


Radiographic Findings

  • Peripheral lymphadenopathy

  • NLPHL lesions are not FDG-PET avid


Histologic Features

  • Complete or partial effacement of lymph node architecture

    • Nodular or nodular and diffuse patterns

    • Expansile nodules composed mostly of small lymphocytes and fewer histiocytes

      • Reactive lymphoid follicles usually absent within nodules

      • Absent or rare centrocytes or centroblasts within nodules

    • Nodules larger than normal lymphoid follicles

  • LP cells are large and scattered amongst abundant small lymphocytes and histiocytes

    • Represent ˜ 1% of all cells

    • LP cells have variety of appearances

      • Multilobated “popcorn” cells with vesicular chromatin and multiple small nucleoli

      • Multinucleated or mummified cells

      • LP cells also can be round without multilobation

  • Various architectural patterns have been described

    • Classical nodular pattern is most common

    • Serpiginous nodular pattern

      • Confluent irregular nodules

    • Nodular with extranodular LP cells

      • Pattern more commonly seen in patients with recurrence

    • Nodular pattern with T-cell-rich background

    • THRLBCL-like

      • Always associated with at least 1 typical nodule of NLPHL

      • Diffuse areas indistinguishable from primary THRLBCL

      • Most background lymphocytes are T cells and histiocytes

      • Absence of underlying follicular dendritic cell meshworks

      • Associated with B symptoms and higher clinical stage

    • Diffuse, B cell-rich with “moth-eaten” appearance

      • Uncommon pattern (< 5% of cases)

      • Most background lymphocytes are B cells

      • Underlying follicular dendritic cell meshworks positive

  • Histiocytes may be epithelioid &/or form small granulomas

  • Features common in classical Hodgkin lymphoma are usually absent in NLPHL

    • Eosinophils, neutrophils, and plasma cells are unusual

    • Classical Hodgkin and Reed-Sternberg (HRS) cells are absent or rare

    • Necrosis is rare; no fibrous bands around nodules

  • Residual/uninvolved lymph node in biopsy specimens of NLPHL

    • Reactive follicular hyperplasia is usually present

    • PTGC commonly present

  • Recurrent/relapsed NLPHL

    • Depletion of small lymphocytes with increased histiocytes

    • Fibrosis in up to 40% of cases with recurrence

    • Diffuse areas present; often increased in size

Cytologic Features

  • Diagnosis of NLPHL difficult to establish in fine needle aspirate specimens

    • Nodular architecture difficult to appreciate in smears

    • Small lymphocytes, histiocytes, and large LP cells present

    • No granulocytes or plasma cells

Transformation of NLPHL to Large Cell Lymphoma

  • Large cell lymphoma may coexist with or follow NLPHL

    • Large cells may form sheets, as in de novo diffuse large B-cell lymphoma, or be scattered, as in THRLBCL

  • No consensus on pathologic criteria to distinguish between

    • NLPHL with diffuse THRLBCL-like areas vs. transformation to THRLBCL

  • Transformation of NLPHL to THRLBCL can be diagnosed when

    • Diffuse areas of THRLBCL are identified, and

    • Patients have high-stage disease, including bone marrow involvement, &/or other clinical evidence of transformation, such as

      • High serum lactate dehydrogenase or β-2-microglobulin levels

      • Lytic bone lesions

    • Bone marrow involvement in patients with NLPHL is usually evidence of transformation

    • Extensive liver involvement is usually associated with transformation

  • Transformation of NLPHL to diffuse large B-cell lymphoma

    • Sheets of large neoplastic cells outside nodules of NLPHL



  • LP cells

    • CD20(+), CD22(+), CD79a(+), CD75(+)

    • pax-5(+), OCT2(+), BOB1(+), PU.1(+)

    • CD40(+), CD80(+), CD86(+)

    • Bcl-6(+), AID(+), SWAP-70(+)

    • CD45/LCA(+), Ki-67 (proliferation) high

    • EMA and MUM1(+) in ˜ 50% of cases

    • IgD(+) in ˜ 25% of cases

      • IgD correlates with younger patient age

    • Pan-T-cell antigens(-), Bcl-2(-)

    • CD15(-) and CD30(-)

      • CD30(+) LP cells reported in ˜ 10% of NLPHL cases

      • CD30(+) reactive immunoblasts are common in NLPHL

      • CD15(+) LP cells very rare; often at time of relapse

    • Epstein-Barr virus (EBV)-LMP1(-)

      • Rare (< 1%) cases of NLPHL with EBV(+) LP cells reported in developed countries

  • Background inflammatory infiltrate

    • Small lymphocytes are mixture of B and T cells

    • B cells

      • CD19(+), CD20(+), CD22(+), pax-5(+)

      • IgM(+), IgD(+)

      • CD10(-), Bcl-6(-)

    • T cells

      • CD2(+), CD3(+), CD5(+), CD7(+)

      • Form “rosettes” around LP cells

    • Minor population of CD3(+) cells is of follicular Thelper cell lineage

      • CD3(+), CD4(+), CD57(+)

      • CD10(+), Bcl-6(+) < PD-1(+)

      • Form “rosettes” around LP cells in ˜ 50% of cases

    • Follicular dendritic cell meshworks are present in nodular areas

      • CD21(+), CD23(+), &/or CD35(+)

    • Histiocytes

      • CD68(+)

  • Recurrent/relapsed NLPHL

    • Depletion of background small B cells

    • Decreased or absent follicular dendritic cells

    • Increased numbers of background T cells and histiocytes

    • LP cells may express CD30 or rarely CD15

Flow Cytometry

  • Polytypic B cells

  • Mature T cells

    • CD4(+), CD8(+) T cells in ˜ 50% of cases

  • Large neoplastic cells are lost or overlooked in routine flow cytometric analysis


  • Usually complex structural karyotypic aberrations

  • Chromosome 3q27 (BCL6 locus) involved in up to 60% of cases

In Situ Hybridization

  • EBER(-) in LP cells

    • < 1% of NLPHL cases are EBER(+) in Western countries

    • EBV may be more common in LP cells of NLPHL in developing countries


  • Monoclonal IgH or light chain gene rearrangements when using single-cell PCR analysis

  • Rearrangements often not detectable using standard PCR or Southern blot methods and whole biopsy specimens

Array CGH

  • 30-60% of cases may show gains or losses of chromosomes

    • Gains: Chromosomes 1, 2q, 3, 4q, 5q, 6, 8q, 11q, 12q, and X

    • Loss: Chromosome 17

Molecular Genetics

  • Frequent somatic mutations of IgH variable region

    • Evidence of ongoing mutations

  • BCL6 gene rearrangements in ˜ 50% of cases

    • IgH is most common partner

    • Other partners: Chromosome loci 2q23; 5q31, 6q22, 9q22, and 17p21


Lymphocyte-rich Classical Hodgkin Lymphoma, Nodular Variant

  • Form of classical Hodgkin lymphoma with prominent nodular pattern that can closely mimic NLPHL

  • Nodules composed of prominent mantle zones with atrophic or absent germinal centers

  • HRS cells in mantle zones of enlarged lymphoid follicles

  • Immunophenotype

    • HRS cells are CD15(+), CD30(+), EBV-LMP1(+/-), CD45/LCA(-)

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

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