Hepatic Lymphoma Diagnosis An Algorithmic Approach
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1 Hepatic Lymphoma Diagnosis An Algorithmic Approach Ryan M. Gill, M.D., Ph.D. University of California, San Francisco PLEASE TURN OFF YOUR CELL PHONES Disclosure of Relevant Financial Relationships USCAP requires that all planners (Education Committee) in a position to influence or control the content of CME disclose any relevant financial relationship WITH COMMERCIAL INTERESTS which they or their spouse/partner have, or have had, within the past 12 months, which relates to the content of this educational activity and creates a conflict of interest. Disclosure of Relevant Financial Relationships USCAP requires that all faculty in a position to influence or control the content of CME disclose any relevant financial relationship WITH COMMERCIAL INTERESTS which they or their spouse/partner have, or have had, within the past 12 months, which relates to the content of this educational activity and creates a conflict of interest. Dr. Ryan Gill declares he/she has no conflict(s) of interest to disclose. Why the Hepatopathologist? When to initiate work-up for a lymphoproliferative disorder Hepatic lymphoma may mimic a liver tumor Hepatic lymphoma may mimic medical liver disease Challenges for the Hepatopathologist Hematopathology is rapidly evolving and diagnosis integrates morphologic, immunophenotypic, and cytogenetic/molecular data. The classification scheme allows for significant immunophenotypic variability Limited tissue may be available in a liver biopsy once a lymphoproliferative disorder is detected 1
2 Outline Atypical Hepatic Lymphoid Infiltrate 1. What is an atypical lymphoid infiltrate in the liver? 2. How to diagnose EBV hepatitis. 3. Approach to the significant sinusoidal infiltrate. 4. Primary hepatic lymphoma. Normal Portal Effacing/Destructive Sinusoidal Effacing/Destructive CD20 Large Cells in the Sinusoids CD20 2
3 Which is lymphoma? Which is lymphoma? Primary Hepatic MALT lymphoma Atypical Cytologic Features Atypical Cytologic Features Large cells Piling up in sinusoids Increased mitotic figures Atypical mitotic figures Prominent nucleoli Hemophagocytosis Ductopenia Extramedullary hematopoiesis Geographic necrosis Granulomas Mitotic Activity Nuclear Atypia/ Nucleoli Hemophagocytosis Atypical Cytologic Features Extramedullary Hematopoiesis in Polycythemia Vera Megakaryocyte Erythroid Precursors Piling up in Sinusoids Fibrin Ring Granuloma 3
4 Geographic Necrosis EBV Hepatitis EBV typically infects B-cells Usually only a mild sinusoidal lymphohistiocytic infiltrate without necrosis or atypia Non-necrotizing granulomas (and rarely, fibrin ring granulomas) may be present Lineage markers important in establishing the diagnosis EBV Case #1 17 year old obese male with a persistent mild elevation in LFTs. Abdominal ultrasound demonstrates an enlarged liver, no lesions identified. HCV PCR is negative. ANA negative. SMA negative. IgG normal. Recent labs: AST 33 U/L ALT 49 U/L ALK 67 U/L T bili 1.4 mg/dl 4
5 EBER ISH PAX5 EBV Case #2 21 year old female with with splenomegaly, hepatomegaly, and thrombocytopenia and elevated liver enzymes. No history of immune suppression. Underwent liver biopsy and received a diagnosis of EBV hepatitis Treated with 4 cycles of rituximab, due to clinical concern for hemophagocytic syndrome, and returns with similar symptoms after 1 year (AST and ALT ~200 U/L with thrombocytopenia, but still a normal ferritin, hemoglobin, and neutrophil count), undergoes a second liver biopsy. Clonality testing negative. EBER ISH 5
6 EBER ISH PAX5 CD56 The Significant Sinusoidal Infiltrate Mature B-cell neoplasms Mature T- and NK-cell neoplasms Burkitt lymphoma* Adult T-cell leukemia/lymphoma B-cell lymphoma, unclassifiable, with features intermediate between Aggressive NK cell leukemia DLBCL and classical Hodgkin lymphoma B-cell prolymphocytic leukemia Anaplastic large cell lymphoma, ALK positive CLL/SLL Anaplastic large cell lymphoma, ALK negative Diffuse large B-cell lymphoma NOS (Germinal-center type or Angioimmunoblastic T-cell lymphoma Activated B-cell/non-germinalcenter type) EBV positive DLBCL, NOS Extranodal NK/T-cell lymphoma, nasal type Extranodal Marginal zone lymphoma of mucosa associated Hepatosplenic T-cell lymphoma lymphoid tissue (MALT lymphoma) Follicular lymphoma Other cytotoxic T-cell lymphomas* Hairy cell leukemia** Mycosis fungoides/sezary syndrome High grade B-cell lymphoma with MYC and BCL2 and/or BCL6 Peripheral T-cell lymphoma, NOS rearrangements High grade B-cell lymphoma, NOS PTLD Hodgkin's lymphoma (NLPHL and Systemic EBV+ T-cell lymphoma of childhood CHL) Intravascular large B-cell T-cell LGL leukemia lymphoma Lymphomatoid granulomatosis Lymphoplasmacytic lymphoma "Chronic active EBV infection" Mantle cell lymphoma Plasmablastic lymphoma Plasma cell myeloma PTLD T-cell histiocyte rich large B-cell lymphoma *e.g. Hydroa-vacciniforme-like lymphoproliferative disorder, enteropathy-associated T-cell *Note provisional entitiy "Burkitt lymphoma with 11q aberration." lymphoma, monomorphic epitheliotropic intestinal T-cell lymphoma, subcutaneous panniculitis-like ** Note provisional entity "Hairy cell leukemia variant." T-cell lymphoma in the appropriate clinical scenario 6
7 Blast Morphology What next? Caution in TdT Interpretation Pax5 TdT Sinusoidal: Large Cells Differential diagnosis DLBCL ALCL PTLD CD20, PAX5, CD3, CD30, and EBER, then stain for ALCL (e.g. CD4, EMA, ALK) or DLBCL (e.g. CD10, BCL6, MUM1) Sinusoidal: Small/Intermediate cells Differential diagnosis HCL PTLD ANK CAEBV HSTCL Other cytotoxic T cell lymphoma T-LGL CD20, PAX5, CD3, CD5, CD56, and EBER 7
8 What if it is not Sinusoidal? Broad differential diagnosis Assess for a predominant lineage EBER ISH Additional immunohistochemical stains may be needed Clonality testing (Kappa/lambda ISH, BCR PCR, TCR PCR) Consider bone marrow/peripheral blood evaluation Primary Hepatic Lymphoma Rare DLBCL and PTLD are most common diagnoses Older men, solitary mass, longer survival than systemic lymphoma with hepatic involvement May present as hepatomegaly and no discrete mass (predominant sinusoidal infiltrate) No clear association with viral infection Sinusoidal Predominant EBV Hepatitis? Blasts? Algorithm? Prominent Hepatic Lymphoid Infiltrate Atypical Infiltrate Portal Effacing/ Destructive Broad Differential Diagnosis Large cells: DLBCL ALCL PTLD Small/Intermediate cells: PTLD HCL CAEBV NK or T-cell Malignancies Important Information Regarding CME/SAMs The Online CME/Evaluations/SAMs claim process will only be available on the USCAP website until September 30, No claims can be processed after that date! After September 30, 2017 you will NOT be able to obtain any CME or SAMs credits for attending this meeting. 8
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