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





Key Facts


Terminology



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


Clinical Issues



  • Most frequently presents as mediastinal mass


  • More aggressive clinical course than either CHL and PMLBCL


Microscopic Pathology



  • Overlapping histologic features that make classification difficult



    • Can exhibit confluent sheets of large cells resembling DLBCL


    • Can have scattered HRS-like cells resembling CHL


Ancillary Tests



  • Immunophenotype



    • Strong and uniform expression of B-cell antigens


    • CD30(+), CD45/LCA(+)


    • CD15 usually (−), EBV usually (−)


Top Differential Diagnoses



  • PMLBCL


  • Nodular sclerosis CHL


Diagnostic Checklist



  • In cases that morphologically resemble CHL



    • Uniform and strong expression of B-cell markers and absence of CD15 suggest DLBCL/CHL


  • In cases that morphologically resemble DLBCL



    • CD15(+), EBV(+), &/or CD20(−) suggest DLBCL/CHL







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).


TERMINOLOGY


Abbreviations



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


Synonyms



  • Gray zone lymphoma


  • Mediastinal gray zone lymphoma


  • Large B-cell lymphoma with Hodgkin features


  • Hodgkin-like anaplastic large cell lymphoma


Definitions



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


CLINICAL ISSUES


Epidemiology



  • 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


Presentation



  • 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


Treatment



  • 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


Prognosis



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


MICROSCOPIC PATHOLOGY


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


ANCILLARY TESTS


Immunohistochemistry



  • “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


DIFFERENTIAL DIAGNOSIS


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)

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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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