Case 5 -

Hepatosplenic Lymphoma Marsha C. Kinney and Steven H. Swerdlow

Clinical History 52 year old male initially presenting with anemia, thrombocytopenia and normal leukocyte number/differential and splenomegaly. Splenectomy revealed a "hematopoietic/lymphoid neoplasm, unclassified". Marrow examination was negative except for a mild lymphocytosis. The patient was followed and at one year developed hepatomegaly. An open liver biopsy was performed. Diagnosis: Hepatosplenic Lymphoma Case 5 - Figure 1 - Hepatosplenic T-cell lymphoma, liver. Liver sinuses are expanded by a monomorphic population of lymphocytes. There is little involvement of portal triads (Upper right). Case 5 - Figure 2 - Hepatosplenic T-cell lymphoma, liver. The lymphocytes are medium to large and have partially dispersed chromatin and indistinct, pale cytoplasm. Case 5 - Figure 3 - Hepatosplenic T-cell lymphoma, liver, paraffin immunoperoxidase, antibody polyclonal-anti CDS. The lymphocytes are CD3+. Case 5 - Figure 4 - Hepatosplenic T-cell lymphoma, spleen. The red pulp is expanded by a homogeneous population of medium-sized lymphocytes with preferential localization to the sinuses. Immunophenotype: CD3+, CD45RO+, CD43+, CD4-, CD8-, bF-1+, CD56+, TIA-1+, EBER- An uncommon (less than 5% of peripheral T-cell lymphomas) but distinct T-cell lymphoma with a characteristic growth pattern involving hepatic sinusoids and splenic red pulp. Discussion of Case 5 Diagnosis of hepatosplenic lymphoma: clinical and pathologic features Recognition of subtle marrow involvement in T-cell neoplasms Immunophenotype of hepatosplenic lymphoma Definition and biology of gd -T cells Phenotypic diversity in T-cell populations giving rise to extranodal T-cell neoplasms T-cell posttransplant lymphoproliferative disorders Differential diagnosis of hepatosplenic lymphoma Clinical features of hepatosplenic lymphoma: [12, 13, 14, 15, 16, 17, 18, 19] Most patients are young adults (median 29-34 yrs, however, the range is wide: 5- 68 yrs); approximately 20% are in children and adolescents [13a, 18, 19, 20] Marked male predominance (approximately 5:1) Splenomegaly (98%); hepatomegaly (80%) in the absence of lymphadenopathy Fever, abdominal pain, and weakness Thrombocytopenia (85%); anemia (84%); rarely autoimmune hemolytic anemia is present; white blood count is variable; leukopenia (45%) [18, 21, 22] ; circulating tumor cells present in 25%-50% or more of patients during the course of disease; elevated liver function tests (43%) Poor prognosis; CR is uncommon (14%); frequent relapse despite initial response; median survival 8-16 mos (range 0-42 mos); curative treatment not available, some BMT have been performed but followup is short [13a, 15, 16, 18] Can be misdiagnosed clinically as:   ITP, as thrombocytopenia can disappear temporarily with splenectomy   ALL, circulating abnormal cells can appear blast-like   Viral infection, due to hepatosplenomegaly, fever, and jaundice with elevated liver function tests Histologic features of hepatosplenic lymphoma: Tumor cells in most cases are homogeneous, medium-sized lymphocytes with partially dispersed chromatin, somewhat inconspicuous nucleoli, eosinophilic cytoplasm and little cytologic atypia; smaller numbers of cases have pleomorphic mixed medium and large cell or large cell histology [16] Infiltration of hepatic sinuses with relative sparing of the portal tracts Splenic red pulp with involvement of sinuses rather than cords; if involvement is not extensive and fixation is not optimal, may be missed because of lack of cytologic dysplasia and preservation of white pulp On Wright's stain, the tumor cells are medium in size with partially condensed chromatin and pale blue cytoplasm; the presence of granules is variable, many report tumor cells are agranular Marrow involvement is present in ~ two-thirds and is usually subtle involving the sinuses; immunoperoxidase staining for T-cell antigens should be performed [15, 18, 18a] Hemophagocytosis by macrophages or tumor cells is rarely reported [16, 18, 23, 24, 25] Blastic or "prolymphocytic" transformation has been described in rare cases, particularly in a terminal leukemic phase [16, 26, 27] Marrow involvement by peripheral T cell neoplasms: Marrow involvement is present in up to 73% of peripheral T-cell lymphomas as reported by Gaulard et al, 1991 (60% of these cases were nodal in origin). [28] Marrow involvement by extranodal T-cell lymphoma is often subtle as large lymphoid aggregates or consolidated lesions may absent. Careful morphologic examination, aided by immunostaining, is particularly useful in hepatosplenic lymphoma [13a, 15] , mycosis fungoides [29], and anaplastic large cell lymphoma [30, 31] Recognition is important for staging and evaluation of marrow for transplantation Immunophenotype of hepatosplenic lymphoma: [13a, 18] Most have a gd phenotype, but ab forms are present and are clinically and pathologically similar (case 5, presented here, had an ab phenotype) [22, 32, 33] CD4-, CD8-; approximately 15% are CD4-CD8+ CD2+, CD3+, CD7+/-, CD5-/+ CD56+ in >60%-70%, and to a lesser extent CD16+ (~50%). TIA-1+ in virtually all; many (~50%) lack granzyme B and/or perforin, indicating a non-activated cytolytic T-cell phenotype [15, 16, 18, 34] ~15% express CD30 but few cases have been tested [18] Criteria for defining ab and gd T-cells: Based on TCR protein expression rather than genotype   TCR g or d genes are rearranged in most T-cells expressing ab TCR protein   50%-60% of gd hepatosplenic T-cell lymphomas have non-productive TCR ab [14, 16, 18] Biology of gd T-cells: [35, 36, 37] Fewer in number and more limited diversity than abT-cells; important in early immune response to infections, autoimmune disorders, and cancer immune surveillance Tissue restricted repertoire; largest number of gd T-cells are in the splenic red pulp (10-12%) and smaller numbers are present in the thymus (1-3%), tonsils (<1%), lymph nodes (1-2%), skin, and intestinal epithelium; approximately 1%-16% of peripheral blood T-cells are gd T-cells First line of defense at epidermal and epithelial surfaces in the immune response against pathogens (viruses, bacteria, and parasites) Less dependent on MHC to recognize their targets (heat shock proteins produced by damaged or infected cells, bacterial antigens, etc.) Normally function as cytotoxic lymphocytes (CTLs) with NK-like or lymphokine-activated killer activity Cytolysis occurs via apoptosis through the Fas/Fas-L pathway or through release of cytolytic granule effector proteins including perforin, granzyme B, TIA-1 [38] Activated gd T-cells produce cytokines particularly IFN g, tumor necrosis factor, GM-CSF, IL-2, IL-4, IL-5, and IL-10; cytokines can stimulate B cells to produce immunoglobulin, cause marrow suppression (IFNg ), or promote the hemophagocytic syndrome (IFNg , IL-10) . gd T-cells can be subdivided according to the type of V (variable) gene usage into V d1 cells present predominantly in the thymus and spleen and having a naiveT-cell phenotype (CD45RO-) and Vd 2 cells which are present in the peripheral blood, lymph nodes and tonsils and have a memory phenotype (CD45RO+). Note: Reactive populations of CD4-CD8- CD5- gd T-cells expressing cytotoxic T-cell/NK cell antigens can be significantly increased in patients with lymphoid neoplasms and in infections (eg, Ehrlichia) and can be confused with neoplastic proliferations. [39] Non-hepatosplenic lymphomas with a gd T-cell phenotype: [17, 40, 41, 41a] gd T-cell lymphomas have been described at other extranodal sites including: skin and subcutaneous tissue and mucosal sites (nasal, gastrointestinal tract), thyroid, lung, larynx [42] Older patients More frequent association with EBV Activated cytotoxic T-cell phenotype Most are similar to their counterparts with different immunophenotypes (ie, ab T-cell or NK cell) arising at the same site. [17] Cutaneous tumors are characterized by epidermotropism (pagetoid reticulosis-like) or have a subcutaneous panniculitis-like T-cell lymphoma histology; [40, 41, 44, 45, 46] SCPTCL with gd T-cell phenotype appears to have a more aggressive course with hemophagocytosis and cytopenias [45, 46] Gastrointestinal tumors have multifocal involvement of the the gut with an aggressive course that is resistant to chemotherapy; tumor cells are variable in size and shape; not strictly associated with gluten sensitive enteropathy; CD5- Nasal tumors have pleomorphic histology and arise from V d2 subsets and are CD56+, EBV+ with no clearcut difference from the true NK tumors arising in that area Nodal tumors can be monomorphic with a sinusal pattern similar to hepatosplenic T-cell lymphoma or pleomorphic with more diffuse growth resembling other T-cell lymphomas with an ab phenotype [47] Phenotypic diversity in extranodal T/NK -cell lymphomas: Most extranodal T-cell lymphomas are ab T-cells. Table 5 illustrates the phenotypic diversity in T-cell populations giving rise to extranodal T-cell neoplasms. As mentioned above, no matter what the phenotype, T or NK-cell lymphoproliferations arising in the same site are similar to one another with a few exceptions (eg., subcutaneous panniculitis-like T-cell lymphoma with agd phenotype may be more aggressive than those with an ab phenotype.) Table 5. T-cell Receptor (TCR) Protein Expression in Extranodal T-cell Neoplasms Subtype TCR Protein Hepatosplenic gd>>ab T-large granular lymphocyte leukemia ab>>gd Subcutaneous panniculitis-like lymphoma ab>>gd Primary cutaneous ALCL ab>>gd Mycosis fungoides ab>>gd Nasal/nasal type NK/T gd>>ab * Intestinal ab>>gd * Most of these tumors are NK-cells and lack TCR protein expression Isochromosome 7 and hepatosplenic lymphoma: Appears to be the primary genetic event in hepatosplenic lymphoma, although commonly seen as a secondary event in hematologic malignancies (AML, ALL, PLL) and Wilm's tumor [13a, 16, 18, 48, 49] Pathogenesis of hepatosplenic lymphoma: Cell of origin: splenic red pulp gd T-cell as the tissue distribution of hepatosplenic lymphoma reflects the normal homing pattern of gd T-cells that go to the splenic sinuses Likely results from chronic antigen stimulation possibly in an altered immune status:   ~20%-30% have been reported in immunosuppressed, predominantly post transplant patients; clinical and pathologic are features similar to other T-cell PTLD (see below) [13a, 50, 51, 52, 53, 54, 55, 56]   In HIV infection, autoimmune disease, and hereditary immunodeficiency, expansion of gd T-cells is observed.   Although most cases are EBV negative some EBV+ cases are reported and have an activated cytotoxic phenotype (granzyme B+, perforin +/-); histologically they are mixed medium and large cells [57]   Rarely reported in association with chronic hepatitis B virus infection suggesting proliferation of gd T-cells in response to HBV [58] T-cell posttransplant lymphoproliferative disorders: [55, 59] May represent up to 14% of PTLD Extranodal sites Usually a late complication More frequent in renal transplants rather than heart and heart-lung and liver Often not associated with EBV, HTLV-1, HTLV-2, or HHV-8 Often do not respond to decreased immunosuppression Often aggressive, median survival less than a year in some series Hepatosplenic T-cell lymphoma, appears over-represented, and may result from the allograft acting as a long term autoimmune stimulant of cytotoxic lymphocytes, including gd T-cells that are increased in allografts at various stages of rejection. Table 6. Neoplasms in the Differential Diagnosis of Hepatosplenic T-cell Lymphoma Large Granular Lymphocyte (LGL) Leukemia Older patients; frequent association with rheumatologic disease; cytopenias; indolent course; prominent intrasinus infiltrate of mononuclear cells; portal areas are involved if there is marked infiltration; spleen shows variable involvement of the cords and sinuses [60, 61] ; the phenotype is typically CD3+, CD8+, TCR ab+, CD16+, CD57+ (hepatosplenic lymphoma is CD57-) Aggressive NK cell Leukemia Disseminated disease with lymphadenopathy; azurophilic granules; more cytologic dysplasia and variability from cell to cell; lack TCR protein expression and TCR gene rearrangement; EBV+/-; CD56+,TIA-1+, granzyme B+, perforin + T-ALL/LBL More blastic appearance, TdT+, CD10+/-, CD34+/-, can be CD56+ [62] CD8+ T-CLL/PLL [63, 64] Rare; patients have cytopenias and hepatosplenomegaly without adenopathy; normal WBC with lymphocytosis; irregular or notched nuclear profiles with a central prominent nucleolus and moderately condensed chromatin; moderate agranular cytoplasm; diffuse infiltration in the marrow; liver shows involvement of portal tracts and sinuses; spleen has white and red pulp involvement; CD8+ ab phenotype; TIA-1- and granzyme B- Note: - The aggressive NK-like T-cell lymphomas described by Gentile et al 65 likely represent the leukemic phase of hepatosplenic lymphoma; - S-100+ T-cell lymphoma has conspicuous blood involvement, CD8+, CD56+, and ab phenotype and may represent a hepatosplenic lymphoma 22,66 - A rare case of hepatosplenic B-cell lymphoma with hemophagocytosis has been described in a Korean patient 67 Table 7. Differential Diagnosis of Hepatosplenic Lymphoma: Clinical, Morphologic and Immunophenotypic Features Tumor Type Clinical Adeno-pathy Morphology Marrow Cell Type NK Antigens Cytolytic Protein EBV Hepato-splenicLymphoma Young male - Medium lymphocyte +/- granules Subtle T CD56+ TIA-1+>>GrB, perforin - LGL Leukemia Older patient/indolent course - LGL Subtle T>>NK CD 57+ (T); CD56+ or CD16+/-(NK) NT - Aggressive NK Leukemia Young or old; very aggressive + More blastic Variable NK CD56+ TIA-1+, GrB+, perforin+ +/- T-ALL/LBL Young >older +/- Blastic Variable Immature T Rare cases CD56+ - - CD8+ CLL Olderpatient -/+ Small to medium lymphocyte, irregular nuclei with central prominent nucleolus Diffuse T CD56-CD57- TIA-1-, GrB- - LGL = large granular lymphocyte GrB = granzyme B References 12. Gaulard P, Zafrani ES, Mavier P, Rocha FD, Farcet J-P, Divine M, Haioun C, Pinaudeau Y. Peripheral T-cell lymphoma presenting as predominant liver disease: a report of three cases. 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