Disclosures. Diagnostic Issues. Sinusoidal Infiltrates in the Liver. Ryan M. Gill, M.D., Ph.D. Assistant Professor Department of Pathology.
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1 Disclosures I have nothing to disclose Sinusoidal Infiltrates in the Liver Ryan M. Gill, M.D., Ph.D. Assistant Professor Department of Pathology Diagnostic Issues Reactive infiltrates are common and may raise concern for lymphoma Lymphoid neoplasms with sinusoidal involvement are rare and are often confused with hepatitis or missed Liver biopsy may allow for primary diagnosis of an infection or myeloid lesion if the sinusoidal infiltrate is carefully evaluated u1
2 Atypical Sinusoidal Infiltrate CD20 Approach to Sinusoidal Infiltrates Sinusoidal infiltrate cell type? Sinusoidal Infiltrate Cell Type Granulocytes/ immature myeloid Out of proportion to primary liver disease? Macrophages Cytologic atypia? Blasts Immunophenotype? Mature lymphoid cells Molecular testing if still uncertain. u2
3 Sinusoidal Infiltrate Cell Type Myeloid Proliferation related to Down Syndrome Transient Abnormal Myelopoiesis Granulocytes/ immature myeloid MPN Leukemoid reaction Surgical effect Macrophages Blasts Mature lymphoid cells Extramedullary Hematopoiesis in Polycythemia Vera Extramedullary Hematopoiesis in Polycythemia Vera Megakaryocyte Erythroid Precursors u3
4 MPN/MDS Sinusoidal Infiltrate Cell Type Granulocytes/myeloid Macrophages Immunologic (HLH) Infectious (Histoplasmosis, Cryptococcus, visceral leishmaniasis) Storage disorders (Gaucher disease, Niemann- Pick disease, etc) Blasts Mature lymphoid cells CD163 Niemann-Pick Disease Gill RM et al. Macrophage Infiltrate, Ch 18 Liver Pathology, eds Linda Ferrell and Sanjay Kakar, Demos 2011 Gill RM et al. Macrophage Infiltrate, Ch 18 Liver Pathology, eds Linda Ferrell and Sanjay Kakar, Demos 2011 u4
5 Organisms Amastigotes of Visceral Leishmaniasis Gill RM et al. Macrophage Infiltrate, Ch 18 Liver Pathology, eds Linda Ferrell and Sanjay Kakar, Demos 2011 Gill RM et al. Macrophage Infiltrate, Ch 18 Liver Pathology, eds Linda Ferrell and Sanjay Kakar, Demos 2011 Sinusoidal Infiltrate Cell Type Granulocytes/myeloid Suspicious Sinusoidal Infiltrate Macrophages Blasts ALL AML CML blast crisis Mature lymphoid cells u5
6 Lymphoblasts CD34 Sinusoidal Infiltrate Cell Type Granulocytes/myeloid Reactive T cell Infiltrate Reactive infiltrates consist of small mature T-cells Macrophages PTCL may have piling up in sinusoids Blasts Mature lymphoid cells Reactive infiltrate B-cell neoplasms T-cells/NK cell neoplasms Viral hepatitis may cause hepatocellular damage (e.g. spotty necrosis (e.g. HCV) or neutrophil microabscesses (e.g. CMV)) A normal immunophenotype does not exclude T-cell lymphoma Gene rearrangement studies can be helpful in confirming a diagnosis of lymphoma u6
7 Sinusoidal Infiltrate Sinusoidal Infiltrate CD3 Hepatic Lymphomas Mature B-cell neoplasms Burkitt lymphoma B-cell prolymphocytic leukemia CLL/SLL Diffuse large B-cell lymphoma Follicular lymphoma Hairy cell leukemia Lymphomatoid granulomatosis Lymphoplasmacytic lymphoma Mantle cell lymphoma Marginal zone lymphoma (MALT) PTLD Mature T- and NK-cell neoplasms Adult T-cell leukemia/lymphoma Aggressive NK cell leukemia Anaplastic large cell lymphoma Angioimmunoblastic T-cell lymphoma EBV positive LPD of childhood Hepatosplenic T-cell lymphoma Other γ/δ T-cell lymphomas Mycosis fungoides/sezary syndrome Peripheral T-cell lymphoma, NOS PTLD T-cell LGL leukemia u7
8 Sinusoidal Involvement Primary Hepatic Lymphoma Mature B-cell neoplasms Burkitt lymphoma B-cell prolymphocytic leukemia CLL/SLL Diffuse large B-cell lymphoma Follicular lymphoma Hairy cell leukemia Lymphomatoid granulomatosis Lymphoplasmacytic lymphoma Mantle cell lymphoma Marginal zone lymphoma (MALT) PTLD Mature T- and NK-cell neoplasms Adult T-cell leukemia/lymphoma Aggressive NK cell leukemia Anaplastic large cell lymphoma Angioimmunoblastic T-cell lymphoma EBV positive LPD of childhood Hepatosplenic T-cell lymphoma Other γ/δ T-cell lymphomas Mycosis fungoides/sezary syndrome Peripheral T-cell lymphoma, NOS PTLD T-cell LGL leukemia Rare diagnosis (0.06% of NHL) Wide age range, M:F (2:1), B-symptoms, RUQ pain, or asymptomatic Hepatomegaly is common Mild transaminitis may be present, jaundice rare Immune dysfunction or chronic infection (e.g. HCV) Solitary mass, multinodular, or diffuse DLBCL, Burkitt lymphoma, MALT lymphoma, LPL, Follicular lymphoma, and PTCL most common CD20 Mature T and NK cell Neoplasms Hepatosplenic T-cell lymphoma Aggressive NK cell leukemia EBV positive T cell lymphoproliferative disorder of childhood Peripheral T cell lymphoma, NOS u8
9 Hepatosplenic T-cell lymphoma Portal and Sinusoidal Infiltrates Rare, <5% of PTCL, median age 35, male>female Medium sized lymphoid cells Marked sinusoidal infiltration/expansion of liver, spleen and bone marrow 20% arise in setting of chronic immune suppression or in patients treated with azathioprine and infliximab for Crohns disease Atypical Sinusoidal T-cells Hepatosplenic T-cell lymphoma CD3+, CD2+, TIA-1+, CD7+/-, CD56+/- CD4-/CD8- (or CD4-/CD8+) CD5-, TCRβF1-, granzyme B-, CD25-, CD30- Typically a large TCRγ clone by PCR and EBER is negative Recurrent cytogenetic abnormality (i7q) Aggressive disease with early relapse u9
10 Aggressive NK Cell Leukemia Aggressive NK cell Leukemia Similar presentation to HSTL and fulminant course NK cell neoplasm with a leukemic component CD2+, ccd3+, CD56+, TIA-1+. Granzyme B + T-cell markers negative (scd3, CD5, CD4, CD8, TCRβF1, CD7) EBER positive, TCR genes germline Hemophagocytosis Atypical Sinusoidal Infiltrate EBV positive T-cell LPD of childhood Clonal EBV infected T-cell proliferation, often in children and young adults Geographic predisposition (most prevalent in Asia and Latin America) Aggressive clinical course with hemophagocytic syndrome, multiple organ failure, and sepsis Liver and spleen usually involved Rare form presents in elderly with generalized lymphadenopathy and usually HBV or HCV infection u10
11 EBV positive T-cell LPD of childhood Sinusoidal and portal infiltration by medium sized cells Erythrophagocytosis, necrosis, steatosis, and cholestasis CD3+, CD2+, CD5+,TCRβF1+, TIA-1+, granzyme B+, CD8+/-, CD4-/+, CD56- EBER ISH is positive TCRγ clone can be demonstrated by PCR EBV+ T-cell Lymphoproliferative Disorder of Childhood EBV+ T-cell Lymphoproliferative Disorder of Childhood Peripheral T-cell lymphoma, NOS Monomorphous lymphocytes with dark smudgy chromatin and cleared out cytoplasm Portal based with focal extension into liver parenchyma along sinusoids Histiocytes and other inflammatory cells may be present. Usually CD3+, CD4+, TCRβF1+, CD8-, CD56-, CD30- Aberrant immunophenotype: CD7/CD5/ and/or CD2 loss Typically a large TCR clone by PCR and EBER is negative by ISH u11
12 Portal and Sinusoidal Infiltrate Large Atypical Lymphoid Cells Differential Diagnosis Pitfalls T and NK cell neoplasms Sinusoidal distention/cells pile up Cytologic atypia Aberrant T-cell antigen loss Hemophagocytosis EBER positive tumor cells Geographic necrosis Reactive infiltrate Single mature lymphoid cells Mixed acute and chronic inflammation Viral type injury EBER in rare B-cells Other liver disease findings TCR PCR negative Ductopenia due to lymphoma EBV hepatitis Atypical lymphoid infiltrates in a hepatocellular lesion u12
13 No Interlobular Bile Duct! Artery Artery Cholestasis & Atypical Sinusoidal Infiltrate CD3 u13
14 CD7 CK7 T-cell Lymphoma Associated Vanishing Bile Duct Syndrome Prolonged Transaminitis Following Acute Viral Illness CD3 u14
15 EBER ISH + Atypical Sinusoidal Infiltrate? EBV Hepatitis Hepatocellular Adenoma Inflammatory Variant Key Points Sinusoidal infiltrates are common, most are benign Correlate with background liver disease findings Cytologic atypia Immunohistochemical evaluation Molecular testing u15
16 References n Bowman SJ, Levison DA, Cotter FE, et al: Primary T cell lymphoma of the liver in a patient with Felty's syndrome. Br J Rheumatol 1994; 33: n Brugieres L, Deley MC, Pacquement H, et al: CD30+ anaplastic large-cell lymphoma in children: analysis of 82 patients enrolled in two consecutive studies of the French Society of Pediatric Oncology. Blood 1998; 92: n Bunn PA Jr et al. Clinical course of retrovirus-associated adult T-cell lymphoma in the United States. N Eng J Med. 1983;309: n Cai G. et al. Primary hepatic anaplastic large cell lymphoma diagnosed by fine needle aspiration biopsy. Diagn cytopathol. 2005;33: n Chang SE et al. Cutaneous dissemination of nasal NK/T-cell lymphoma with bone marrow, liver, and lung involvement. Clin Exp Dermatol. 2002;27: n Dogan A. et al. Angioimmunoblastic T-cell lymphoma. Br J Haematol. 2003;121: n Falchook GS et al. Hepatosplenic gamma-delta T cell lymphoma: clinicopathologic features and treatment. Ann Oncol. 2009;20: n Ferrell, LD, Kakar S. eds. Liver Pathology, Consultant Pathology Series. Demos Medical, New York, 2011 n Gentile TC, Uner AH, Hutchison RE, et al: CD3+, CD56+ aggressive variant of large granular lymphocyte leukemia. Blood 1994; 84: n Huang C-B, Eng H-L, Chuang J-H, et al: Primary Burkitt's lymphoma of the liver: report of a case with long-term survival after surgical resection and combination chemotherapy. J Pediatr Hematol Oncol 1997; 19: n Kikuma K et al. Etiological factors in primary hepatic B cell lymphoma. Virchows Arch 2012, 460: n Kim JH, Kim HY, Kang I, et al: A case of primary hepatic lymphoma with hepatitis C liver cirrhosis. Am J Gastroenterol 2000; 95: n Isaacson PG, Banks PM, Best PV, et al: Primary low-grade hepatic B-cell lymphoma of mucosa-associated lymphoid tissue (MALT)-type. Am J Surg Pathol 1995; 19: n Jaffe ES et al. Hematopathology. Expert Consult. Elsevier, St. Louis, 2011 n Jaffe ES. Malignant lymphomas, pathology or hepatic involvement. Semin Liv Dis, 1987, 7: References References n Le Deley MC, Reiter A, Williams D, et al: Prognostic factors in childhood anaplastic large cell lymphoma: results of a large European intergroup study. Blood 2008; 111: n Lukes RJ: Criteria for the involvement of lymph node, bone marrow, spleen and liver in Hodgkin's disease. Cancer Res 1971; 31: n Maes M, Depardieu J, Hermans M, et al: Primary low-grade B-cell lymphoma of MALT-type occurring in the liver. J Hepatol 1997; 27: n Memeo L, Pecorello I, Ciardi A, et al: Primary non-hodgkin's lymphoma of the liver. Acta Oncol 1999; 38: n Murakami J, Fukushima N, Ueno H, et al: Primary hepatic low-grade B-cell lymphoma of the mucosa-associated tissue type: a case report and review of the literature. Int J Hematol 2002; 75: n Osborne BM, Butler JJ, Guarda LA: Primary lymphoma of the liver. Ten cases and a review of the literature. Cancer 1985; 56: n Ohsawa M, Aozasa K, Horiuchi K, et al: Malignant lymphoma of the liver. Report of five cases and review of the literature. Dig Dis Sci 1992; 37: n Page R, Romaguera J, Osborne B, et al: Primary hepatic lymphoma favorable outcome after combination chemotherapy. Cancer 2001; 92: n Purtilo DR et al. EBV associated lymphoproliferative disorder. Lab invest 1992;67:5-23 n Quintanilla-Martinez L. et al. Fulminant EBV+ T-cell lymphoproliferative disorder following acute/chronic EBV infection: a distinct clinicopathologic syndrome. Blood. 2000; 96(2): n Rodriguez J, Rawls D, Speights V: Primary lymphoma of the liver mimicking metastatic liver disease. South Med J 1995; 88: n Scheimberg IB et al. Pathology of the liver in leukemia and lymphoma: A study of 110 autopsies: Histopathology. 1995;26: n Stein H, Foss HD, Durkop H, et al: CD30+ anaplastic large cell lymphoma: a review of its histopathologic, genetic, and clinical features. Blood 2000; 96: n Swerdlow SH, et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. IARC, Lyon 2008 n Walz-mattmuller R. et al. Incidence and pattern of liver involvement in haematological malignancies. Pathol Res Pract. 1998;194: n Ye M, Suriawinata A, Black C, et al: Primary hepatic marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue type in a patient with primary biliary cirrhosis. Arch Pathol Lab Med 2000; 124: u16
17 Differential Diagnosis CD8 T-cell Large Granular Lymphocytic Leukemia Indolent/assymptomatic, cytopenia, autoimmune disease LGL increased in peripheral blood CD2+, CD3+, CD5w+, CD7+, CD8+CD4-, CD56+/- TCRβF1+, granzyme B+ TCRγ rearranged CD4 CD8 u17
18 Portal Involvement Large Atypical Lymphoid Cells u18
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