Primary Mediastinal (Thymic) Large B-cell Lymphoma



Primary Mediastinal (Thymic) Large B-cell Lymphoma


Francisco Vega, MD, PhD





Key Facts


Terminology



  • Diffuse large B-cell lymphoma (DLBCL) arising in mediastinum of putative thymic B-cell origin


Clinical Issues



  • Most frequent from 20-35 years


  • M:F ratio = 1:2


  • Enlarging mass in anterior-superior mediastinum


  • Frequent infiltration of mediastinal structures and organs


  • Prognosis is similar to patients with other types of DLBCL



    • 60-70% chance of cure with appropriate therapy


Microscopic Pathology



  • Diffuse to vaguely nodular growth pattern usually associated with variable degrees of sclerosis


  • Interstitial sclerosis with compartmentalization of tumor cells


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


Ancillary Tests



  • CD20(+), CD45/LCA(+), IRF-4/MUM1(+/−)


  • CD30(+) ˜ 75%, usually weak &/or focal


  • CD10(−), CD15(−), Cyclin-E(−)


  • Monoclonal Ig gene rearrangements


Top Differential Diagnoses



  • Nodular sclerosis Hodgkin lymphoma


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


  • Diffuse large B-cell lymphoma


  • T-lymphoblastic leukemia/lymphoma







CT scan of a young woman who presented with a large anterior mediastinal mass image shows an example of primary mediastinal large B-cell lymphoma (PMLBCL).






PMLBCL. The neoplasm is composed of large cells with pale cytoplasm (retraction artifact) and fine sclerosis compartmentalizing the tumor cells. The neoplastic cells were CD20(+) (not shown).


TERMINOLOGY


Abbreviations



  • Primary mediastinal (thymic) large B-cell lymphoma (PMLBCL)


Synonyms



  • Mediastinal large B-cell lymphoma


  • Thymic large B-cell lymphoma


Definitions



  • Diffuse large B-cell lymphoma (DLBCL) arising in mediastinum of putative thymic B-cell origin


ETIOLOGY/PATHOGENESIS


Cell of Origin



  • Thymic B cell is presumed


CLINICAL ISSUES


Epidemiology



  • Incidence



    • 2% of all non-Hodgkin lymphomas


  • Age



    • Most frequent from 20-35 years


  • Gender



    • M:F ratio = 1:2


Presentation



  • Enlarging mass in anterior-superior mediastinum


  • Often manifests as bulky disease defined as > 10 cm in diameter



    • ˜ 75% of patients


  • B symptoms in 20-30%


  • PMLBCL patients have distinctive serum chemistry profile



    • Low serum β2 microglobulin and high lactate dehydrogenase (LDH) levels


  • Locally aggressive with compression of contiguous organs



    • Superior vena cava syndrome occurs in up to 30% of patients


  • Frequent infiltration of local structures and organs



    • Lung parenchyma, chest wall, pleura, and pericardium


  • Extrathoracic disease at diagnosis is rare


  • Bone marrow infiltration at presentation is also rare


  • Extrathoracic sites are often involved at relapse



    • Central nervous system, liver, adrenals, ovaries, and kidneys


Treatment



  • Drugs



    • Systemic chemotherapy is required; many regimens can be used



      • R-CHOP, rituximab, cyclophosphamide, hydroxydaunorubicin (doxorubicin), Oncovin (vincristine), prednisone


      • MACOPB, methotrexate, leucovorin, doxorubicin, cyclophosphamide, vincristine, prednisone, bleomycin


      • DA-EPOCH+R, etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin plus rituximab


      • HyperCVAD-R, high-dose cyclophosphamide, vincristine, doxorubicin, cytarabine, methotrexate, rituximab


    • If risk factors are present, central nervous system prophylaxis is recommended



      • High-dose methotrexate therapy


  • Radiation



    • Involved field therapy can be used for patients with bulky disease


Prognosis



  • 60-70% chance of cure with appropriate therapy




    • Outcome similar to that of patients with nodal DLBCL


  • Recurrences are almost always seen in 1st 2 years of follow-up


IMAGE FINDINGS


Radiographic Findings



  • Large mass in anterior-superior mediastinum


  • Often FDG-PET scan positive


MACROSCOPIC FEATURES


General Features



  • Unusual for mass to be resected based on size and location


  • In resection specimens, residual thymus gland may be identified


  • Currently, diagnosis is often established by needle biopsy


MICROSCOPIC PATHOLOGY


Histologic Features



  • Diffuse to vaguely nodular growth pattern usually associated with variable degrees of sclerosis


  • Interstitial sclerosis surrounds and compartmentalizes small groups of tumor cells


  • Broad collagenous bands divide tumor into large nodules


  • Intermediate to large lymphoid cells



    • Pale cytoplasm, often result of retraction artifact


    • HRS-like cells can be present


  • Reactive infiltrate of small T lymphocytes and histiocytes



    • ± plasma cells and eosinophils


  • Thymic components, such as Hassall corpuscles, may be identified



    • If present, supports thymic involvement and diagnosis of PMLBCL


Cytologic Features



  • Large lymphoma cells are present in fine needle aspiration smears



    • Not readily distinguishable from other types of large B-cell lymphoma


    • Extensive sclerosis can reduce yield of neoplastic cells aspirated


ANCILLARY TESTS


Immunohistochemistry



  • Positive for common pan-B-cell markers



    • CD19, CD20, CD22, CD79a


  • Positive for B-cell transcription factors



    • BOB1, OCT2, PU.1, pax-5


  • CD45/LCA(+), p63(+) in ˜ 95%


  • CD30(+/−), in ˜ 75% of cases



    • Expression is usually weak &/or focal


  • IRF-4/MUM-1(+) in ˜ 75%


  • CD23(+/−), MAL(+/−)


  • Bcl-2(+/−), Bcl-6(+/−); staining intensity can be variable


  • CD10(−), CD15(−)


  • T-cell antigens(−)


  • EBV LMP is usually negative


  • Cyclin-D1(−), Cyclin-E(−)


Flow Cytometry



  • B-cell immunophenotype


  • Discordance in B-cell receptor expression is common in PMLBCL



    • Surface Ig(−) and CD79a(+)


  • Variable loss of HLA class I and II (HLA-DR) molecules


Cytogenetics



  • Comparative genomic hybridization



    • Common regions of gain



      • Gains in 9p24 ˜ 75% and 2p15 ˜ 50%


      • Gains in chromosome X and in 12q31


      • JAK2 at 9p24 is not mutated


    • Common regions of loss



      • 1p, 3p, 13q, 15q, and 17p



  • Well-characterized chromosomal translocations are rare/absent in PMLBCL



    • CCND1, BCL2, BCL6, and MYC


In Situ Hybridization



  • EBER(−)


Molecular Genetics



  • Monoclonal Ig gene rearrangements


  • No monoclonal T-cell receptor gene rearrangements


  • High frequency of BCL6 gene mutations


  • SOCS1 mutations in subset of cases


  • High levels of expression of



    • IL-13 receptor


    • JAK2 and STAT1


Gene Expression Profiling



  • Studies have shown overlap in gene expression profile between PMLBCL and classical Hodgkin lymphoma



    • Signature is distinct from nodal DLBCLs



      • Either germinal center B-cell or activated B-cell types


Activation of NF-κB



  • Nuclear location of c-REL


  • Cytoplasmic expression of TRAF1


  • Combination of nuclear c-REL with expression of TRAF1 is highly specific for PMLBCL


DIFFERENTIAL DIAGNOSIS


Nodular Sclerosis (NS) Classical Hodgkin Lymphoma (CHL)

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Jul 8, 2016 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Primary Mediastinal (Thymic) Large B-cell Lymphoma

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