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4/11/2016 Spectrum of EBV+ B-Cell Lymphoproliferative Disorders ACCME/Disclosures Dr. Natkunam declares she has no conflict(s) of interest to disclose Yaso Natkunam, MD, PhD Professor of Pathology Stanford University School of Medicine http://www.bio‐rad.com/webroot/web/images/cdg/products/microbiology/product_detail/global/cmd_25183_pdp.jpg Outline • Pathologic spectrum of EBV+ B‐cell lymphoproliferative disorders • Nomenclature for immunodeficiency disorders • When to consider EBV testing and molecular clonality testing Epstein‐Barr Virus (HHV4) • Discovered in 1964 from cultured Burkitt lymphoma cells from an Ugandan child • EBV infected B‐cells persist within the memory B‐cell pool of most immunocompetent hosts • EBV‐encoded latent genes induce B‐cell transformation by altering gene transcription and activating signaling pathways • Immunosuppressed patients are at increased risk of developing EBV‐associated B‐cell lymphoproliferative disorders Epstein MA, Achong BG, Barr YM. Virus particles in cultured lymphoblasts from Burkitt's lymphoma. The Lancet, March 28, 1964, 1: 702–703 1 4/11/2016 Immunodeficiency Disorders Hyperplasia Hyperplasia EBV+ B‐Cell Spectrum Patterns of reactive B‐cell hyperplasia Lymphoma B‐LPD of varied malignant potential B‐cell lymphoproliferations EBV Indolent B‐cell lymphoma T & NK‐cell lymphoproliferations Aggressive B‐cell lymphoma HHV8 HHV8‐associated lymphoproliferations Lymphoma EBER Hyperplasias • Called early lesions in WHO 2008, renamed nondestructive lesions in WHO 2016 – Defined as mass forming lesions with preservation of overall tissue architecture (non‐destructive) • Three types 1. Follicular hyperplasia (formally recognized in WHO 2016) 2. Infectious mononucleosis‐like hyperplasia 3. Plasmacytic hyperplasia Follicular Hyperplasia • Presents with isolated or multifocal lymphadenopathy • No interfollicular expansion • Distribution of EBER+ cells variable, often confined to 1‐2 follicles • Occasional clonal IG or simple karyotypic abnormalities • Do not over‐react to clones! • Regress spontaneously in most cases • Rare concurrent or subsequent EBV+ B‐LPD, clonally related in some Images: Drs. Babu, Ewalt, Televantu Vakiani E et al, Hum Pathol 2007 Shapiro NL et al, J Pediatr Otorhinolaryn 2003 Williamson RA et al, Otolaryngol Head Neck Surg 2001 Sevilla DW et al, Hematol Oncol 2011;29‐90 2 4/11/2016 Dasatinib‐Related Hyperplasia Hyperplasias • Newer therapeutic agents expand spectrum of immunodeficiency–related hyperplasias Follicular • Scant interfollicular proliferation CD21 BCL2 IgD CD20 IM‐like • • • • CD20 Plasmacytic Numerous interfol immunoblasts Small to medium lymphoid cells Plasma cells ‐ polytypic FH usually present • • • • Numerous interfol plasma cells Few scattered immunoblasts Plasma cells ‐ polytypic FH usually present • Mass forming, non‐destructive lesions with overlapping patterns • Intact architecture helpful to differentiated from polymorphic B‐LPD • Clinical context important to separate from nonspecific causes • Difficult to recognize if EBV is negative • Small clones or abnormal karyotypes may be present • Majority regress spontaneously EBER Goodlad, SH Workshop 2015 Ozawa, Ewalt & Gratzinger, AJSP 2015 Full B‐cell spectrum FFH Genetic Complexity Polymorphic B‐LPD IM‐like • Morphologically polymorphous lesions that efface architecture or cause destructive masses, but do not fulfill criteria for diagnosis as lymphoma • Exhibit full range of B‐cell maturation – Variable number of B & T cells; T may predominate • Progressively increasing karyotypic abnormalities – Variable number of Hodgkin‐like cells P‐PTLD • CD45+ CD20/CD79A+ CD30+ CD15+/‐ PAX5+ OCT2+ – Light chain restriction +/‐ or focal or biclonal – Clonal IG gene rearrangements in almost all cases – Simple karyotypic abnormalities may be present M‐PTLD Vakiani et al, Hum Pathol 2007 Hodgkin‐like Immunoblasts • Some regress with withdrawal of immunosuppression; others need more active management such as Rituximab or RCHOP Vakiani et al, Hum Pathol 2007, 2008 Poirel ha et al, Transplantation 2005 Capello D et al, Hematol Oncol 2005 3 4/11/2016 Polymorphic B‐LPD in Iatrogenic/Autoimmune Setting • Iatrogenic LPDs usually arise in patients treated with immunosuppressive regimens for autoimmune disease *Important to obtain clinical history/ treatment regimens • Methotrexate commonly implicated Disorder Drug • Contribution of underlying autoimmune disease versus drug regimen is difficult to quantify; may depend on greater disease severity Rheumatoid Arthritis Methotrexate Steroids Hydroxychloroquine TNFα inhibitor Aplastic Anemia ATG Methyprednizone Cyclosporine • Longitudinal study of 10,815 RA patients on anti‐TNFα meta‐analyses of 14 published reports – Conclusion: no statistically significant difference in lymphoma rate Kamel OW et al, AJSP 1996; Semin Diagn Pathol 1997 Wolfe F, Michaud K, Arthritis Rheum. 2007 Hasserjian RP et al. Mod Pathol. 2009 Rizzi R, et al. Med Oncol 2009 Wong AK et al, Clin Rheumatol 2012 Ichikawa A et al., Eur J Haematol 2013 Polymorphic B‐LPD in Lung Polymorphic B‐LPD • 57M, HIV/AIDS • Abnormal LFT with multiple liver lesions • Architectural destruction, necrosis • Polymorphic background with RS‐like cells • IHC suggestive of Hodgkin lymphoma • Commenced HAART with resolution Images: Dr. Jonathan Said Polymorphic B‐LPD: Other Features • RS‐like cells and EBV+ cells associated with monocytoid clusters • Monocytoid B‐cell clusters should be a trigger to test for EBER Before HAART After HAART • 41F, HIV+ • Multiple lung nodules • HAART started after diagnosis with complete remission Images: Dr. John Goodlad Buxton J et al, Virch Arch 2012 Fujita H et al, Int J Haematol 2010 Images: Dr. Barath Nathwani May be associated with • Angiodestructive growth • Necrosis • Hemophagocytic lymphohistiocytosis Images: Dr. Jeannett Schiby 4 4/11/2016 “Large B‐Cell Proliferations associated with Chronic Inflammation” Mucocutaneous Ulcer • Isolated, sharply‐circumscribed ulcer in oropharyngeal mucosa, skin or GI tract Images: Dr. Alina Nicolae • Polymorphous infiltrate with RS‐like cells mimicking classical Hodgkin lymphoma – CD30+ EBER+ CD20+/‐ CD15+/‐ CD45+ – Prominent rim of CD8+ T‐cells at base of ulcer – Clonal IG in 39%, TCR in 38% • Rare EBV+ clonal large B‐cell proliferations arising in localized sites without mass lesions in immunocompetent patients • Overlap with Pyothorax‐associated lymphoma • Associated fibrin or amorphous material adjacent to cavities • Self‐limiting, indolent, IS withdrawal effective – Localized defect in immune surveillance? Dojcinov et al, Am J Surg Pathol 2010 Left atrial myxoma Images: Dr. Rogney • Clinically indolent; seldom disseminate – Resemble breast‐implant assoc. ALCL – Localized alteration in host immune surveillance? – Using “Large B‐cell lymphoma” name may cause overtreatment Aortic aneurysm thrombus EBER Images: Dr. Soumya Pandey Indolent EBV+ B‐Cell Lymphomas EBV+ DLBCL of the Elderly • Rarely reported in immunodeficiency settings EBER • Almost all plasmacytoid, most are MZL – EBV+ MZL designated as a PTLD in WHO 2016 – Very few FL and CLL/SLL – Difficult to designate EBV‐neg cases as immunodeficiency‐ related – IgA heavy chain predominant – CR with reduced IS +/‐ antiviral therapy, local excision, rituximab, or local radiation Gibson S et al, Am J Surg Pathol 2011 Images: Dr. Singhal • Aggressive EBV+ monoclonal B‐ cell proliferation arising in patients >50y with no known immunodeficiency • Provisional entity in WHO 2008 Kappa Lambda • Incidence increases with age • Immune senescence leading to defective immune surveillance? IgA CXCR3 • Broader range of morphologies than usual DLBCL Oyama et al, Am J Surg Pathol 2003; Clin Cancer Res 2007 Gibson et al, Hum Pathol 2009 Hoeller et al, Hum Pathol 2010 Hofscheier et al, Mod Pathol 2011 Kato et al Cancer Sci 2014 Ok et al, Blood 2013; Clin Cancer Res 2014 Gebauer et al, Leuk Lym 2015 5 4/11/2016 Immunophenotypic Spectrum EBV+ Large B‐Cell Proliferations • A spectrum of morphologies and immunophenotypes DLBCL TCRBCL/Hodgkin‐like DLBCL TCRBCL/Hodgkin‐like CHL CHL Centroblast/immunoblast‐like Intact B‐cell phenotype Hodgkin‐like Deficient B‐cell phenotype (CD20, CD79a, PAX5, OCT2, BOB1) Aberrant phenotype (CD15, granzyme B, perforin) Sparse infiltrate T‐cell rich histiocyte‐rich CD20 Few eosinophils Grey zone type diagnostic challenge PAX5 De Jong, SH Workshop 2015 De Jong, SH Workshop 2015 EBV+ DLBCL of the Elderly • Incidence 3‐14%; rare in West • DLBCL with non‐GC immunophenotype • GEP: constitutive activation of NF‐kB, enriched for JAK/STAT‐ signaling, immune/inflammatory, cell cycle, metabolism genes EBV+ DLBCL in the Young 46 DLBCL ≤ 45y Immunocompetent M:F = 3.6:1 Histologic spectrum PDL1 expression indicative of a tolerogenic immune microenvironment • Superior outcome of EBV+ DLBCL in the young compared to the elderly • • • • • TCRLBCL GZL DLBCL – CR 82%, AWD 10%, DOD 8% – 5 y OS of 89% vs 24.4% (p<.0001) • Term ‘elderly’ no longer in WHO 2016 Kato et al Cancer Sci 2014 Ok et al, Blood 2013; Clin Cancer Res 2014 Gebauer et al, Leuk Lym 2015 Nicolae et al, Blood 2015 6 4/11/2016 Nomenclature for Immunodeficiency Disorders EBV+ DLBCL: Is Age relevant? • Current classification is organized by immunodeficiency settings • 46 Caucasian EBV+ DLBCL Drugs Primary/ Congenital • Compared <50 vs >50 – No difference in clinicopathologic, IHC or genetic features – No difference in gene expression profiles or miRNA profiles Aging – No difference in clinical outcome Transplant Host immune status HIV • Need validation in larger cohorts of patients Autoimmunity EBV HHV8 Ok et al, Oncotarget 2015 Challenges… • Significant overlap of similar proliferations across different immunodeficiency settings – “Similar” lesions between immunodeficiency and immunocompetent patients and among different immunodeficiency states may not be biologically similar – Virus or immune status may not be causal (bystander) • Spectrum of lymphoid proliferations, diagnostic criteria and terminology are reasonably well established for post‐transplant setting, but not in other settings – Lack of unifying nomenclature • Increasing use of novel immunomodulatory agents and precision in immune monitoring, increases the complexity of treatment decisions related to whether or how early to treat Proposed Unifying Nomenclature for Immunodeficiency Disorders • 2015 SH Workshop Panel proposal • Aims to provide a common framework for discussion and further study and is not intended as a new classification at this time A name with 3 components • Lesion: hyperplasia, polymorphic LPD, DLBCL, etc • Virus: EBV, HHV8, other • Immunodeficiency setting: PTLD, HIV, primary, iatrogenic, etc Example • Polymorphic B‐lymphoproliferative disorder, EBV+, iatrogenic setting (methotrexate) 7 4/11/2016 When to Test for EBV and Molecular Clonality EBV testing • • • • • • • Known or suspected immunodeficiency Clinical history and drug regimen When morphology is polymorphous or discordant Necrosis Hemophagocytic lymphohistiocytosis Monocytoid B‐cell clusters EBV monitoring in PTLD setting Clonality testing • EBV can induce oligoclonal or clonal proliferations • Results should be interpreted with caution and in the context of clinical and histologic findings Clinical Cancer Research, May 14, 2013 Expressed in NSHL, MCHL PMBL TCRLBCL EBV+ DLBCL Plasmablastic lymphoma NK/T cell lymphoma HHV8+ PEL EBV+ DLBCL EBV‐ PTLD Lacking in DLBCL, NOS Burkitt Small B‐cell lymphoma DLBCL, NOS Role of EBV & PD1/PDL1 Pathway • EBV LMP1 & LMP2 enhance transcriptional activity of PDL1/PDL2 to create a tolerogenic microenvironment by inducing T‐cell anergy and immune evasion PD1/PD‐L1 blockade • Removes tumor cell resistance to cytotoxic T‐cell mediated lysis • Restores anti‐tumor activity of CD4+ T‐cells Thank you! • Offers a novel therapeutic option Chen et al, Clin Can Res 2013 Morscio et al, Am J Tanspl 2013 Hartman et al, BJH 2015 Yoon et al, Gene Chrom Can 2015 Nicolae et al, Blood 2015 http://www.bio‐rad.com/webroot/web/images/cdg/products/microbiology/product_detail/global/cmd_25183_pdp.jpg 8
