B-cell Lymphoma, Unclassifiable, with Features Intermediate Between Diffuse Large B-cell Lymphoma and Classical Hodgkin Lymphoma

B-cell Lymphoma, Unclassifiable, with Features Intermediate Between Diffuse Large B-cell Lymphoma and Classical Hodgkin Lymphoma

Francisco Vega, MD, PhD

A case of DLBCL/CHL characterized by scattered large tumor cells with large eosinophilic nucleoli image in a background of numerous small lymphocytes. These histologic features suggest CHL.

A case of DLBCL/CHL strongly positive for CD20. The tumor cells were also positive for CD30 (variable) and EBV-LMP1, as well as negative for CD15, CD45/LCA, and CD79a (not shown).



  • B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma (DLBCL/CHL)


  • Gray zone lymphoma

  • Mediastinal gray zone lymphoma

  • Large B-cell lymphoma with Hodgkin features

  • Hodgkin-like anaplastic large cell lymphoma


  • Lymphoma with clinical, morphologic, &/or immunophenotypic features between diffuse large B-cell lymphoma (DLBCL) and classical Hodgkin lymphoma (CHL)



  • Age

    • Most common in patients 20-40 years or age (range: 13-70 years)

  • Gender

    • Male predominance

  • Ethnicity

    • Most common in Western countries

    • Less common in Asians and blacks


  • Most frequently patients present with anterior mediastinal mass

    • Often direct extension into lungs

    • Supraclavicular lymph nodes can be involved

  • Advanced clinical stage (III or IV)

  • Other peripheral lymph node groups are rarely involved


  • No consensus on optimum treatment protocol

  • Some patients treated with CHL protocols have failed to respond completely

  • Some groups have recommended treating DLBCL/CHL cases as aggressive DLBCL


  • Patients have aggressive clinical course and poorer outcome than patients with either CHL or primary mediastinal B-cell lymphoma


Histologic Features

  • Areas of confluent sheets of pleomorphic large tumor cells resembling DLBCL

  • Other areas can show scattered large cells, resembling Hodgkin and Reed-Sternberg (HRS) cells in CHL

  • Supraclavicular lymph nodes, if involved, can show morphologic features of either CHL or DLBCL or both

  • Variable inflammatory infiltrate in background

  • Mild stromal fibrosis and focal necrosis

    • Necrosis is usually not associated with neutrophils (unlike CHL)

  • Nonnecrotizing granulomas and histiocytes

Cytologic Features

  • Broad spectrum of cytologic appearance including

    • Centroblasts, immunoblasts, &/or HRS-like cells

  • Cells with cytoplasmic retraction, resembling lacunar cells, can be seen

  • Mummified cells (apoptotic large cells) are frequent



  • “Mixed immunophenotype” with

    • Expression of common markers of classical HL

      • CD30([+] all cases) &/or CD15([+] in most cases)

      • pax-5(+) and IRF-4/MUM-1(+)

    • And expression of markers usually absent in CHL

      • CD45/LCA(+), CD20 ([+]; uniformly strong), and CD79a(+)

      • OCT2(+), BOB1(+)

  • Cells with this “mixed immunophenotype” constitute predominant neoplastic cell population

  • Usually high proliferation rate, as measured by MIB-1 (Ki-67)

  • MAL(+) in ˜ 60% of cases

  • Bcl-6([+] variable), CD10 is usually (−)

  • Negative for T-cell markers, ALK(−)

  • Epstein-Barr virus (EBV) is usually (−)

    • Few cases reported were EBV(+); EBER &/or LMP1

  • Like CHL, lymphoid infiltrate in background is predominantly composed of T cells, CD3(+) and CD4(+)

  • These cases show immunohistochemical features supporting activation of NF-κB pathway

    • Nuclear location of c-REL/p65

    • Overexpression of phosphorylated IκBa

    • Overexpression of NF-κB targets, Bcl-XL, and c-FLIP

Molecular Genetics

  • Most cases have monoclonal IgH gene rearrangement

  • Few cases have rearrangements involving BCL6

  • Most cases lack t(14;18)(q32;q21)

  • In almost all cases assessed, P53 was in germline configuration

Gene Expression Profiling

  • Studies have shown similarity between CHL and primary mediastinal large B-cell lymphoma

    • This is theoretical support for category of DLBCL/CHL

    • However, few cases of DLBCL/CHL have been analyzed by gene expression profiling


Primary Mediastinal (Thymic) Large B-cell Lymphoma (PMLBCL)

  • Usually young women

  • Anterosuperior mediastinal mass (rapidly progressive)

  • Patients can have extrathoracic disease

    • Rare at time of diagnosis

    • More common at time of relapse

    • Usually extranodal: CNS, liver, adrenals, ovaries, and kidneys

    • Lymph nodes are often not involved at relapse

  • Histologic features

    • Diffuse growth pattern

    • Large cells with pale cytoplasm (often is retraction artifact)

    • Sclerosis

      • Often compartmentalizes tumor cells mimicking cohesive clusters

    • Reed-Sternberg-like or Hodgkin-like cells can be present

  • Immunophenotype

    • Positive for common pan B-cell markers

      • CD20(+), CD79a(+), pax-5(+)

    • CD45/LCA(+), IRF-4/MUM-1(+)

    • CD30([+] 80%), usually weak &/or focal

    • CD23([+] 70%), MAL([+] 70%)

    • Often surface immunoglobulin(−); best shown by flow cytometry

    • CD10(−), CD15(−)

    • EBV is usually (−)

    • T-cell antigens(−)

  • Molecular genetic features

    • Monoclonal Ig gene rearrangements are present

    • No evidence of monoclonal TCR gene rearrangements

    • Array CGH shows amplification at 9p24 (˜ 75%) and 2p15 (˜ 50%)

    • These neoplasms show a number of deletions

Nodular Sclerosis Classical Hodgkin Lymphoma

  • Usually young patients

  • Slight female predominance

  • Mediastinal involvement (˜ 80%)

  • Histologic features

    • Nodular growth pattern with fibrosis

      • Dense collagenous bands surround nodules

      • Collagenous bands are polarizable

    • Variable number of large HRS cells

  • Many histological variants of nodular sclerosis CHL have been described

    • Based on number of neoplastic cells, extent and nature of fibrosis, and inflammatory background

    • Of these, syncytial variant is particularly relevant in differential diagnosis

      • Sheets of large tumor cells that can mimic DLBCL

      • Often large areas of necrosis

      • Immunophenotype is typical of CHL

  • Immunophenotype

    • CD30(+), CD15(+) in most cases

    • pax-5(+) with characteristic weaker (dimmer) expression than reactive B-cells

    • CD20(−/+), CD79a(−/+)

      • Weakly &/or variably (+) in ˜ 20% of cases

    • Small subset (˜ 5%) of CHL can express T-cell antigens

      • These cases also express pax-5 or other B-cell antigens

    • CD45/LCA(−), EMA usually (−)

  • Molecular genetic features

    • Monoclonal IgH gene rearrangements usually only detected by single cell PCR

    • Usually no evidence of monoclonal Ig or TCR gene rearrangements by routine analysis

      • Standard PCR performed on whole tissue sections

      • Southern blot analysis

Diffuse Large B-cell Lymphoma

  • Older adults, but also occurs in children and young adults

  • Histologic features

    • Diffuse growth pattern

    • Large neoplastic cells (centroblasts &/or immunoblasts)

    • Large anaplastic cells can be present; known as anaplastic variant

      • These neoplasms may have intrasinusoidal growth pattern

      • CD30 often (+)

    • Large pleomorphic cells with features of HRS-like cells can be present

    • Sclerosis is frequent in extranodal sites

    • Areas of coagulative necrosis are common

  • Immunophenotype

    • CD20(+), CD22(+), CD79a(+)

    • pax-5(+), OCT2(+), BOB1(+)

    • CD10(+) and Bcl-6(+) in variable proportion of cases

    • CD30(−/+); if positive, often weak and focal except anaplastic variant

    • CD45/LCA(+), CD15(−)

    • Monotypic immunoglobulin(+)

      • Cytoplasmic; in cases with plasmacytoid differentiation

      • Surface; best shown by flow cytometry

  • Molecular genetic features

    • Monoclonal Ig gene rearrangements(+)

    • No evidence of monoclonal TCR gene rearrangements

    • t(14;18)(q32;q21)/IgH-BCL2 (+) in ˜ 20-30%

    • BCL6 rearrangements in ˜ 10-20%

  • Gene expression profiling has shown 2 subsets

    • Germinal center cell

    • Activated B cell

      • Poorer prognosis

ALK(+) Anaplastic Large Cell Lymphoma (ALCL)

Jul 8, 2016 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on B-cell Lymphoma, Unclassifiable, with Features Intermediate Between Diffuse Large B-cell Lymphoma and Classical Hodgkin Lymphoma
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