Infectious Disease Pathology Specialty Conference Case 1
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1 Infectious Disease Pathology Specialty Conference Case 1 Miguel Reyes Múgica, M.D. Department of Pathology Children s Hospital of Pittsburgh University of Pittsburgh Medical Center USCAP Annual Meeting. Washington, D.C. March 21 st, 2010
2 Case 1. Clinical History A 6 year-old girl with a large left neck mass. Past medical history: Biliary cirrhosis secondary to extra hepatic biliary obstruction (biliary atresia) Kasai procedure. At one year of age, she underwent an orthotopic liver transplant (OLTx). At hospital admission, five years after transplant, relevant laboratory results included: Hb= 12.2; Ht= 35.1 WBC= 7.6K/DL Plt.=296 K/dL Neut.= 49% Lymph.= 31% Mon.= 9% Eos.=10% Bas./Band= 1% SGTP/SGOT= 44/39 IU/L ALKP/GGTP= 157/22 IU/L Renal function tests, electrolytes, glucose= normal limits. Uric acid= 3 mg/dl. The mass was removed and sent to pathology. Representative photomicrographs are presented for discussion.
3
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5 Vincent van Gogh Starry Night Over the Rhone Arles, 1888 playhappy.wordpress.com/2009/03/30/ Starry Night Asylum at Saint-Remy in
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7 CD20 BCL6 CD10 Ki67
8 EBER
9 Immunophenotyping and ISH summary Positive CD10 +/++ CD λlight-chain ++ EBV-EZLF1 (multifocal) BCL6 +++ Ki67 100% EBER +++ Negative CD3 CD45O (UCHL1) Κ light-chain
10 Differential Diagnosis Relatively narrow Primary lymphoid neoplasm Post-transplant lymphoproliferative disorder (PTLD). Type?? Given the clinical history of OLTx, the second possibility is much more likely, and the documentation of EBV militates strongly in favor of this option.
11 Case 1. Diagnosis Post-Transplant Lymphoproliferative Disorder, Burkitt lymphoma type.
12 Post-Transplant Lymphoproliferative Disorder (PTLD) Entity with a wide spectrum: Atypical lymphoid (mononucleosis-type) or plasmacytoid proliferations malignant lymphomas Consequence of immunosuppression in patients transplanted with a solid organ, bone marrow, or stem cell allograft Pediatric transplant recipients are at increased risk due to their EBV-naïve status vulnerable to developing a primary EBV infection while on potent immunosuppressive medications Monomorphic PTLDs (M-PTLD): Transformed B-cells fitting criteria of non-hodgkin Lymphoma (NHL) Predominately diffuse large B-cell type (DLBCL) Rarely as a Burkitt lymphoma (BL). Histologically similar to their lymphoma counterparts arising in the immunocompetent patient New molecular evidence suggest that many B-cell M-PTLD are more closely related to other PTLDs rather than to B-cell NHL. Gene expression profiles related to memory or activated B-cells with a non-germinal center phenotype. Except BL, which retains a germinal center phenotype and does not cluster with the other PTLDs.
13 Burkitt Lymphoma Described clinically in 1957 by Denis P. Burkitt O Connor and Davis, first and then Dennis Howard Wright characterized it histologically Three types: Endemic equatorial Africa; strongly associated with EBV Sporadic children and young adults; less common EBV (30%) Immunodeficiency-associated primarily HIV infection; intermediate EBV expression (25-40%) PTLD-BLs seem to have an EBV expression profile intermediate between the endemic and immunodeficiency-associated types Histologically monomorphous, small to intermediate-sized, non-cleaved lymphoid elements High mitotic and proliferation rates Starry sky pattern, imparted from the scattered tingible body macrophages engulfing apoptotic debris of the tumor. A majority feature t(8;14), classic translocation of MYC, at 8q24, to 14q32 IG heavy chain region Other, less common sites MYCtranslocates to: λregion at 22q11, or the κregion at 2p12.
14 J. C. Farga
15 J. C. Farga
16 J. C. Farga
17 BL-PTLD BL-PTLD typically occurs later than other PTLDs (average 4.5 years) Presents at a higher stage than other M-PTLDs Must also be clinically treated more aggressively Decreased immunosuppression alone is inadequate therapy Immediate therapeutic regimens with alkylating chemotherapy agents must be used PTLD and BL are independently more commonly seen in children BL-PTLD is a rare entity within the pediatric transplant population: Only a handful of case reports Large transplant studies show a low incidence of BL-PTLD: 0.3 to 0.7% in heart and liver transplant patients BL-PTLD is emerging as a distinct form of PTLD that needs to be more fully characterized in the pediatric population.
18 BL-PTLD and EBV The role of EBV in the pathogenesis of BL is not well understood In the post-transplant immunosuppressed host, cytotoxic T-lymphocytes (CTL) are inhibited impairing their ability to kill EBV-infected B-lymphocytes EBV infected cells proliferate leading to polymorphous, or a monomorphous PTLD EBV may contribute to the dysfunction of the MYCgene altering specific breakpoint patterns Certain MYCbreakpoint locations (in which the c-mycregulatory region remains intact) are more common in EBV+ than in EBV(-) BL EBV proteins may influence regulatory regions of c-mycplay a specific pathogenic role in certain types of EBV+ BL, including BL-PTLD
19 BL-PTLD at Children s Hospital of Pittsburgh (1) Sex Age at Tx Tx organ Site BL-PTLD BL-1 M 7 mo heart BL-2 F 1 liver Neck lymph node Mandible, lymph node capsule, skull base, GI tract BL-3 M 5 mo heart Kidney-right; *Kidney-bilateral BL-4 F 3 heart Abdominal mass BL-5 M 10 small bowel Neck lymph node BL-6 M 16 liver/liver Small bowel BL-7 F 2 liver/liver Neck lymph node BL-8 M 8 kidney/kidney Small bowel, abdominal mass BL-9 M 9 mo heart Abdominal mass BL-10 M 10.5 liver Liver allograft, widespread metastasis
20 BL-PTLD at Children s Hospital of Pittsburgh (2) Summary of Pathology results BL-1 Histology Immunophenotype EBER Cytogenetics Previous PTLD CD20,10,79a, 43, bcl- 25.8% of cells c-myc - SNC-BL, vacuolated cytoplasm 6,cK; neg: TdT POS RA (BAP) BL-2 SNC-BL CD20,λ restricted, bcl6 POS NA yes; Mono-like BL-3 atypical cells with hi N/C ratio, apoptotic bodies *CD20,19,22,10,79a,bcl6, DR,cK; negtdt POS; POS t(8;14) yes;p-ptld BL-4 SNC-BL CD20,79a, CD10,bcl-6; neg:tdt POS NA NEG c-myc/igh; Medium-large atypical lymphoid CD20,19,10,bcl-6; 200/201 Neg (1- BL-5 cells, with GC-type BL phenotype neg:tdt NEG; rare+(x2) 8q24+) yes;p-ptld BL-6 Diffuse NHL B-cells NA NA NA BL-7 Monomorphic Large lymphoid cells; malignant lymphoma IgM,K,L, rare bcl6 POS t(8:14), complex karyotype yes;p-ptld BL-8 Monomorphous, BL-vacuoles, starry sky IgM kappa, bcl6 POS t(8:14) and +c-myc BL-9 Monomorphic, BL morphologyvacuoles, apoptosis, necrosis CD79a,10,bcl6,cK+; neg Tdt POS (50-80%) t(8;14) yes;monolike BL-10 intermediate non-cleaved-bl, TBM, apoptosis, mitosis *CD20,19,10,79a,bcl- 6,38,cK,DR+; neg: TdT NEG (rpt) t(8;14) and c-myc SNC=small noncleaved cell; *Immunophenotype from concurrent Bone Marrow. RA= rearrangement; BAP= break-apart probe. Index case is BL-2.
21 BL-PTLD at Children s Hospital of Pittsburgh (3) TX-PTLD PTLDoutcome EBV donor EBV Pretx PTLD Disease free (mo), Outcome BL POS NEG POS 127, Alive, no disease BL na na POS 168, Alive, no disease BL na NEG POS 60, Dead, complication of therapy, no disease at autopsy BL Equivocal NEG POS 14, Alive, no disease BL POS NEG POS 16, Alive, no disease BL na na na 134, Dead, infection BL na POS POS 199, Alive, no disease BL POS (LRD) NEG POS 178, Alive, no disease BL NEG NEG POS 86, Alive, no disease 3, Dead, graft failure and cardiac BL NEG NEG POS arrest
22 Conclusions BL-PTLD: emerging, aggressive subtype of M-PTLD It needs immediate therapy, not only decreased immunosuppression, but also administering alkylating agents. It shares with other PTLDs a high expression of EBV, which likely plays an additional role in the pathogenesis of MYCdysregulation. A more aggressive clinical presentation with higher stage, longer interval between transplant and presentation, and a GC-phenotype, segregate BL from other M-PTLDs. Awareness about BL-PTLD is necessary because a different clinical management is needed. Further work to understand the genetic expression profile of this PTLD subtype is needed to fully characterize its biology Only a handful of cases have been studied with current molecular methods, the minority in children.
23 When I eventually reached Africa, God, in his mercy, enabled me with my one eye to see things which my predecessors had missed with two. Denis Parsons Burkitt ( ), F.R.C.S. Illustration by Venita Jay.
24 Acknowledgments Jennifer Picarsic, PGY3, UPMC Ronald Jaffe, MBBCh George Mazariegos, Steve Weber, Michael Green, Demetrius Ellis
25 New Children s Hospital of Pittsburgh
26
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