T-Cell Large Granular Lymphocytic Leukemia and Coexisting B-Cell Lymphomas: A Study From the Bone Marrow Pathology Group

T-Cell Large Granular Lymphocytic Leukemia and Coexisting B-Cell Lymphomas: A Study From the Bone... Abstract Objective T-cell large granular lymphocytic (T-LGL) leukemia is associated with B-cell lymphomas (BCLs), especially small BCLs. We aimed to explore and expand upon its association with BCLs. Methods We retrospectively studied clinicopathologic features of T-LGL leukemia patients with coexisting BCL from January 2001 to December 2016. Results Among 432 patients with T-LGL leukemia, 22 (5.1%) had an associated B-cell non-Hodgkin lymphoma. Thirteen (59%) patients had large and nine (41%) had small BCL. T-LGL leukemia occurred synchronously with BCL in five, preceded BCL in three, and followed BCL in 14 patients. Anemia was the most common cytopenia (68%). Only one patient had a history of rheumatoid arthritis. Conclusion To our knowledge, this is the first multicenter study looking at the spectrum and incidence of BCLs in patients with T-LGL leukemia and highlights its association with large BCLs (3% of T-LGL leukemias). T-LGL leukemia, B-cell lymphoma, Diffuse large B-cell lymphoma T-cell large granular lymphocytic (T-LGL) leukemia is a chronic lymphoproliferative disorder characterized by a clonal expansion of T-LGLs expressing cytotoxic proteins, CD3, CD8, and CD57.1 It is a rare disease with an incidence of 0.2 cases per 1 million individuals per year and represents 2% to 5% of chronic lymphoproliferative diseases in the US.2 The median age at diagnosis is 66.5 years.2 While there is no absolute large granular lymphocytic (LGL) count required for diagnosis of T-LGL leukemia, a T-LGL value of greater than 2 × 109/L is frequently associated with a clonal proliferation. In the appropriate clinical context (autoimmune disease, cytopenia, splenomegaly), patients with a peripheral blood expansion of the T-LGL population more than 0.5 × 109/L in association with a CD3+/CD8+ phenotype and evidence of clonality can be considered to have T-LGL leukemia.2,3 The pathogenesis is incompletely understood, but chronic activation of T cells with autoantigen or viral antigen has been suggested as an initial stimulus leading to an expansion of LGLs. Leukemic LGLs have dysregulation in apoptosis. They escape Fas-mediated, activation-induced cell death. Increased numbers of circulating leukemic T-LGLs result from activation of multiple survival pathways.4 T-LGL leukemia is an indolent disease. The majority of patients are asymptomatic initially, but more than one half of the patients require treatment for cytopenias in the course of disease.1 Neutropenia is the most common cytopenia, leading to recurrent bacterial infections, followed by anemia and thrombocytopenia.5 A substantial proportion of patients with T-LGL leukemia have immunologic abnormalities, including seropositivity for rheumatoid factor and antinuclear antibodies, polyclonal hypergammaglobulinemia, circulating immune complexes, high β2 microglobulin, and antineutrophil antibodies.6,7 The most common autoimmune disorder associated with T-LGL leukemia is rheumatoid arthritis, which manifests in about 25% to 33% of patients.6 The association of T-LGL leukemia with B-cell lymphoproliferative disorders is well-recognized.6,8 There are a number of isolated case reports and case series looking at the association of B-cell neoplasms in the setting of T-LGL leukemia. The spectrum of clonal B-cell neoplasms in T-LGL leukemia includes hairy cell leukemia (HCL),8,9 monoclonal B-cell lymphocytosis,10 monoclonal gammopathy of unknown significance (MGUS),11 chronic lymphocytic leukemia (CLL),8 Hodgkin lymphoma (HL),8 plasma cell myeloma,12,13 mantle cell lymphoma,14 lymphoplasmacytic lymphoma (LPL),11 marginal zone lymphoma (MZL),15 and follicular lymphoma (FL).8 Interestingly, a PubMed search revealed only two cases of diffuse large B-cell lymphoma (DLBCL) in association with T-LGL leukemia. One is a case report by Anoop et al.16 Another case of DLBCL is included in a study that looked at the frequency of T-LGL leukemia in association with hematopoietic stem cell transplant, which might select for diseases such as DLBCL.17 In addition, Viny et al8 reported one case of DLBCL transformed from FL in their series of T-LGL leukemia associated with B-cell dyscrasias. In this study, we intend to further explore the spectrum of B-cell lymphomas (BCLs) in patients with T-LGL leukemia. Materials and Methods This study was undertaken to explore the association of BCLs with T-LGL leukemia. The study protocol was approved by the institutional review boards of all institutions involved. Data were requested from the institutions participating in the Bone Marrow Pathology Group. Five institutions (Cleveland Clinic Foundation, MD Anderson Cancer Center, Mayo Clinic, Hospital of the University of Pennsylvania, and University of New Mexico) contributed data for the study. Patients with T-LGL leukemia diagnosed from January 2001 to December 2016 were identified retrospectively. One institution contributed cases diagnosed from 2005 to 2016. A total of 432 patients of T-LGL leukemia were identified, with 22 patients having BCLs at some point in their care. B-cell proliferations with only leukemic presentation such as HCL and CLL were excluded, since their occurrence with T-LGL leukemia is previously well-described.8 A total of 22 patients with BCLs and clonal T-LGL proliferations were included in the study. We separated these patients into synchronous and metachronous based on the diagnosis of the T-LGL leukemia and BCL. Patients with two diagnoses made within 3 months were considered synchronous because this interval could represent the time difference between peripheral blood flow cytometry and tissue biopsy. Patients with a large BCL anytime during the disease course were grouped together. Laboratory values for hemoglobin, leukocyte count, platelet count, absolute lymphocyte count, absolute neutrophil count, T-LGL count, rheumatoid factor, antinuclear antibodies, serum protein electrophoresis, and gammaglobulin levels were collected for each patient. Medical records, clinical history, presence of autoimmune conditions, transplant, and treatment history were reviewed. Bone marrow findings were locally reviewed for each case. Surgical pathology slides and medical records were reviewed for the coexisting BCLs. Data related to classification, histological features, immunophenotype, and treatment were recorded. Immunophenotype was determined by flow cytometric analysis using monoclonal antibodies per individual institution practice. Despite interlaboratory technical variation, all laboratories identified T-LGLs by expression of CD3, CD4, CD8, and aberrant expression of natural killer cell markers (CD16, CD56, and CD57) using primary CD45 and/or light-scatter lymphocyte gating. Blood counts were compared using Mann-Whitney U test performed at a significance level of P < .05, using statistical analysis software (StatSoft, Tulsa, OK). Results We identified 432 patients with T-LGL leukemia. Of these, there were 22 (5.1%) patients with associated BCL Table 1, which formed the population for this study. Thirteen (59%) patients had a large B-cell non-Hodgkin lymphoma (B-NHL) in the course of their disease and nine (41%) had a small B-NHL. We did not identify any case of only tissue-based small cell lymphoma. Six patients had multiple BCLs in their disease course. Since molecular studies were not performed on all BCL cases and given the dissimilar histology and wide time interval in some of the cases, we considered them separate events. Among those patients with multiple BCLs, the spectrum included two large B-NHLs (one patient), small and large B-NHLs (one patient), Hodgkin and non-Hodgkin lymphomas (two patients), and transformation from a low-grade lymphoma (two patients). Table 1 Summary of B-NHLs in T-LGL Leukemia Type of Lymphoma  No. of Cases  DLBCL, NOS  11  MALT lymphoma  3a  THRLBCL  2  LGBCL-PD  2  Low-grade lymphoma, unclassified  2  LPL  2  MCL  1  FL  1  PTLPD-DLBCL  1  Splenic MZL  1b  Type of Lymphoma  No. of Cases  DLBCL, NOS  11  MALT lymphoma  3a  THRLBCL  2  LGBCL-PD  2  Low-grade lymphoma, unclassified  2  LPL  2  MCL  1  FL  1  PTLPD-DLBCL  1  Splenic MZL  1b  B-NHL, B-cell non-Hodgkin lymphoma; DLBCL, diffuse large B-cell lymphoma; FL, follicular lymphoma; LGBCL-PD, low-grade B-cell lymphoma with plasmacytic differentiation; LPL, lymphoplasmacytic lymphoma; MALT, extranodal marginal zone lymphoma of mucosa associated lymphoid tissue; MCL, mantle cell lymphoma; MZL, marginal zone lymphoma; NOS, not otherwise specified; PTLPD, posttransplant lymphoproliferative disorder; THRLBCL, T-cell/histiocyte rich large B-cell lymphoma; T-LGL, T-cell large granular lymphocytic. aOne patient had history of Hodgkin lymphoma. bPatient later developed Hodgkin lymphoma with T-LGL leukemia. View Large T-LGL Leukemia With Large BCLs Large BCLs were identified in 13 patients with T-LGL leukemia, including seven males and six females. The median age at the time of T-LGL leukemia diagnosis was 68 years. The spectrum of large BCLs in T-LGL in our series is shown in Table 2. Table 2 Clinicopathologic Features of Large B-NHLs Occurring in Patients With T-Large Granular Lymphocytic Leukemia Patient No.  Age (y)/Sex  Order of Presentation and Interval  AI  Splenomegaly  Tx  HB (g/dL)  WBC (×109/L)  L Count (×109/L)  LGL Count (×109/L)  ANC (×109/L)  Platelet (×109/L)  Immunophenotype ( CD8/CD16/ CD56/ CD57)  Rx for T-LGL  Clonality (PCR)  BCL  COO  Site  EBER  1  60/F  Syn  −  +  Liver  7.6  14.08  3.57  2.5  8.59  155  +/+/+/+  +  +  PTLPD-DLBCL  GC  EN Ttnsil  −  2  68/M  Syn  −  +  −  11.3  6.01  7.7  4.62  1.21  315  +/−/−/NA  −  +  DLBCL, NOS  NGC  EN spleen  NA  3  74/F  Syn  AIHA  −  −  NA  NA  NA  NA  NA  NA  +/NA/NA/+  NA  +  DLBCL, NOS  GC  EN  −  4  74/M  T>B, 6 y  −  Splenectomy  −  8.8  2.37  1.12  1.06  0.94  109  +/+/+/+  +  +  DLBCL, NOS  GC  EN mediastinum  −  5  53/M  B>T, 19 y  −  −  BM (Auto)  12.4  5.5  3.08  1.2  1.6  41  +/−/−/+  −  +  DLBCL, NOS THRLBCL  NA  N  −  6  45/M  B>T, 1 y  −  Splenectomy  BM (Auto)  9.1  35  29.1  NA  3.2  71  +/−/+/+  −  +  THRLBCL  −  EN  NA  7  75/M  B>T, 3.7 y  NA  −  −  14.2  4.3  2.58  1.3  1.2  143  +/NA/+/+  −  +  DLBCL, NOS  NA  EN  −  8  48/M  B>T, 11 mo  −  Splenectomy  −  14  4.3  3.05  1.2  0.516  314  +/NA/NA/+  −  +  DLBCL, NOS  GC  EN spleen  NA  9  73/M  B>T, 3 y  −  −  −  13.3  4.3  2.8  NA  0.7  172  +/+/−/+  +  +  DLBCL, NOS  GC  N and EN lung, muscle  NA  10  66/F  B>T, 3.5 y  −  −  BM (Auto)  7.6  4.3  2.09  NA  1.3  99  +/−/+/+  +  +  DLBCL, NOS  NGC  EN liver  NA  11  72/F  B>T, 18 y  MCTD  Splenectomy  −  9.7  8.4  4.49  3.1  3.01  359  +/+/−/+  +  +  LGBCL-U and later DLBCL, NOS  N/A  BM  NA  12  68/F  B>T, 25 y  −  −  −  10.7  16.44  11.84  4.49  2.96  299  +/+/+/NA  −  +  LGBCL-PD and later DLBCL, NOS  NGC  LGBCL spleen, DLBCL, NOS N  −  13  69/F  B>T, 1 y  −  −  BM (Auto)  12.1  2.9  1.4  NA  1.2  146  +/NA/+/+  −  +  DLBCL, NOS and later LGBCL-U   NGC  N  NA  Patient No.  Age (y)/Sex  Order of Presentation and Interval  AI  Splenomegaly  Tx  HB (g/dL)  WBC (×109/L)  L Count (×109/L)  LGL Count (×109/L)  ANC (×109/L)  Platelet (×109/L)  Immunophenotype ( CD8/CD16/ CD56/ CD57)  Rx for T-LGL  Clonality (PCR)  BCL  COO  Site  EBER  1  60/F  Syn  −  +  Liver  7.6  14.08  3.57  2.5  8.59  155  +/+/+/+  +  +  PTLPD-DLBCL  GC  EN Ttnsil  −  2  68/M  Syn  −  +  −  11.3  6.01  7.7  4.62  1.21  315  +/−/−/NA  −  +  DLBCL, NOS  NGC  EN spleen  NA  3  74/F  Syn  AIHA  −  −  NA  NA  NA  NA  NA  NA  +/NA/NA/+  NA  +  DLBCL, NOS  GC  EN  −  4  74/M  T>B, 6 y  −  Splenectomy  −  8.8  2.37  1.12  1.06  0.94  109  +/+/+/+  +  +  DLBCL, NOS  GC  EN mediastinum  −  5  53/M  B>T, 19 y  −  −  BM (Auto)  12.4  5.5  3.08  1.2  1.6  41  +/−/−/+  −  +  DLBCL, NOS THRLBCL  NA  N  −  6  45/M  B>T, 1 y  −  Splenectomy  BM (Auto)  9.1  35  29.1  NA  3.2  71  +/−/+/+  −  +  THRLBCL  −  EN  NA  7  75/M  B>T, 3.7 y  NA  −  −  14.2  4.3  2.58  1.3  1.2  143  +/NA/+/+  −  +  DLBCL, NOS  NA  EN  −  8  48/M  B>T, 11 mo  −  Splenectomy  −  14  4.3  3.05  1.2  0.516  314  +/NA/NA/+  −  +  DLBCL, NOS  GC  EN spleen  NA  9  73/M  B>T, 3 y  −  −  −  13.3  4.3  2.8  NA  0.7  172  +/+/−/+  +  +  DLBCL, NOS  GC  N and EN lung, muscle  NA  10  66/F  B>T, 3.5 y  −  −  BM (Auto)  7.6  4.3  2.09  NA  1.3  99  +/−/+/+  +  +  DLBCL, NOS  NGC  EN liver  NA  11  72/F  B>T, 18 y  MCTD  Splenectomy  −  9.7  8.4  4.49  3.1  3.01  359  +/+/−/+  +  +  LGBCL-U and later DLBCL, NOS  N/A  BM  NA  12  68/F  B>T, 25 y  −  −  −  10.7  16.44  11.84  4.49  2.96  299  +/+/+/NA  −  +  LGBCL-PD and later DLBCL, NOS  NGC  LGBCL spleen, DLBCL, NOS N  −  13  69/F  B>T, 1 y  −  −  BM (Auto)  12.1  2.9  1.4  NA  1.2  146  +/NA/+/+  −  +  DLBCL, NOS and later LGBCL-U   NGC  N  NA  –, negative; +, positive; >, precede; AI, autoimmune disease; AIHA, autoimmune hemolytic anemia; ANC, absolute neutrophil count; Auto, autologous; B, B-cell lymphoma; BCL, B-cell lymphoma; BM, bone marrow; B-NHL, B-cell non-Hodgkin lymphoma; COO, cell of origin (Han’algorithm); DLBCL, diffuse large B-cell lymphoma; EN, extranodal; GC, germinal center; HB, hemoglobin; L, lymphocyte; LGBCL, low-grade B-cell lymphoma; LGBCL-PD, low-grade B-cell lymphoma with plasmacytic differentiation; LGBCL-U, low-grade B-cell lymphoma, unclassifiable; MCTD, mixed connective tissue disease; N, nodal; NA, not available; NGC, nongerminal center; PTLPD, posttransplant lymphoproliferative disorder; Rx, treatment; Syn, synchronous; T, T-cell large granular lymphocytic leukemia; THRLBCL, T-cell/histiocyte rich large B-cell lymphoma; Tx, transplant. View Large Splenomegaly was found in two patients. Four patients had a history of splenectomy. Patients 3 and 11 had a history of autoimmune disease. Patient 1 had a history of solid organ transplant. Four patients (patients 5, 6, 10, and 13) received autologous stem cell transplant for the preceding BCL before developing T-LGL leukemia. Four patients had coexisting dysgammaglobulinemia. Patient 4 had a coexisting hypergammaglobulinemia, and patients 5 and 6 had coexisting hypogammaglobulinemia. Patient 1 had hypogammaglobulinemia and later developed hypergammaglobulinemia. None of the patients had coexisting MGUS. Nine (69.2%) patients had anemia, six (46%) patients with an absolute neutrophil count less than 1.5 × 109/L, four (30.7%) had thrombocytopenia, and two (15.3%) had leukopenia. None of the patients had lymphopenia. In one patient, peripheral blood counts were not available. T-LGL counts were available in eight patients and varied from 1.06 to 4.49 × 109/L. Bone marrow biopsies showed an interstitial/sinusoidal infiltrate of T-LGLs in all the patients. T-LGL infiltrates involved 7.5% to 50% of the marrow cellularity in eight patients with available data. In the remaining patients, quantification data were not available. Based on the flow cytometry performed on the peripheral blood/bone marrow or bone marrow immunohistochemistry studies, seven patients expressed CD56 and four patients were negative for CD56. In two patients, the status of CD56 expression was not known. Patient 13 expressed both CD4 and CD8. None of the cases had a CD4+/CD8− immunophenotype. Data regarding αβ/γδ types were not collected. Polymerase chain reaction (PCR)-based gene rearrangement studies were performed on all the patients. A monoclonal T-cell rearrangement was identified in all 13 patients. Three out of 13 patients (patients 1-3) had T-LGL leukemia and BCL synchronously, and the remaining 10 patients had a metachronous occurrence. With regards to the synchronous patients, patient 1 had a liver transplant for primary sclerosing cholangitis who later developed synchronous T-LGL leukemia and monomorphic posttransplant lymphoproliferative disorder (lymphoma) consistent with an extranodal DLBCL of germinal center origin (PTLPD-DLBCL). This patient also had hypogammaglobulinemia and later had hypergammaglobulinemia. Patients 2 and 3 had synchronous T-LGL leukemia and an extranodal DLBCL, not otherwise specified (NOS). Patient 3 also had a long-standing history of autoimmune hemolytic anemia. For the 10 patients with a metachronous occurrence, the time interval between the two lymphoid neoplasms ranged from 11 months to 25 years. Among these, in only patient 4 the T-LGL leukemia preceded the de novo DLBCL, NOS (DLBCL of a germinal center phenotype in the mediastinum occurring 6 years later). He manifested with pancytopenia at presentation and was observed but not treated for T-LGL leukemia. A large BCL preceded T-LGL leukemia in the other nine patients. Patient 5 initially had nodal DLBCL and later developed nodal T-cell/histiocyte rich large B-cell lymphoma (THRLBCL). This patient received an autologous bone marrow transplant for THRLBCL, and T-LGL was diagnosed 8 years after the transplant. Patient 6 had an extranodal THRLBCL preceding T-LGL leukemia. This patient also received an autologous stem cell transplant for the BCL. Both of these patients (patients 5 and 6) had hypogammaglobulinemia. Four patients (patients 7-10) had DLBCL, NOS. Patient 11, with a history of low-grade BCL, developed DLBCL 12 years later and then after 6 years developed T-LGL leukemia. This patient also had a history of mixed connective tissue disease. Another similar patient (patient 12), who initially had a low-grade BCL with plasmacytic differentiation (LGBCL-PD), developed DLBCL 25 years later and subsequently developed T-LGL leukemia after 6 months. Another patient (patient 13) with DLBCL, NOS, was diagnosed with T-LGL leukemia a year later. Three years from her first diagnosis, she had a low-grade BCL. She received an autologous bone marrow transplant and 2 years later again relapsed with a low-grade BCL. Out of 12 patients with DLBCL, NOS, at some point during the course of disease process, eight patients were extranodal, three were nodal, and one was both nodal and extranodal. Five patients had DLBCL of a germinal center phenotype, four with a nongerminal center phenotype, and in three sufficient data were not available to classify cell of origin. Epstein–Barr encoding region (EBER) in situ hybridization was negative in all 6 patients with available data. Patients with de novo DLBCL, transplant-related DLBCL, or DLBCL that transformed from low-grade lymphoma received cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP)/CHOP with rituximab (R-CHOP)/cyclophosphamide, vincristine, doxorubicin, and dexamethasone with rituximab (R-CVAD) therapy. In one patient, the treatment history was not available. Mean follow-up time from the first diagnosis is 103 months (range, 24-329 months). Five patients were treated for T-LGL leukemia for cytopenias. Eight patients were alive at the time of last review of medical records, with a median follow-up time of 62 months (range, 24-329 months). Three were lost to follow-up. Two patients died at 54 and 74 months after diagnosis of DLBCL. T-LGL Leukemia With Small BCLs Nine patients of T-LGL leukemia associated with small BCL were identified; the lymphomas spanned a broad spectrum of types Table 3. Five patients were men and four were women. The median age at the time of T-LGL leukemia diagnosis was 58 years. Table 3 Clinicopathologic Features of Small B-NHLs Occurring in Patients With T-Large Granular Lymphocytic Leukemia Patient No.  Age (y)/Sex  Order of Presentation and Interval  AI  Splenomegaly  Tx  HB (g/dL)  WBC (×109/L)  L Count (×109/L)  LGL Count (×109/L)  ANC (×109/L)  Platelet (×109/L)  Immunopheno- type ( CD8/CD16/ CD56/ CD57)  Rx for T-LGL  Clonality (PCR)  BCL  Site  EBER  14  58/F  B>T, 3 y  −  −  BM (Allo)  10.1  8.9  7.3  NA  0.9  11  +/−/−/+  +  +  FL  EN    15  53/M  B>T, 5.5 y  −  Splenectomy  BM (Allo)  10.7  16.5  10.9  NA  3.8  187  +/−/−/+  +  +  MCL  N  10  16  63/M  B>T, 3 y  −  Splenectomy  −  11.8  8.2  3.0  1.9  3.0  217  +/+/+/+  −  +  Splenic MZL, and later HL nodular sclerosis type  Spleen, HL-N  −  17  61/F  HL>B>T, 21 y, 2 y  −  −  −  11.4  2.8  1.99  NA  0.53  147  +/−/−/+  +  +  HL, MALT  NA EN    18  47/F  B>T, 10 y  RA  −  −  12.3  2.4  0.69  NA  1.3  211  +/NA/−/+  +  +  MALT  EN    19  49/F  T>B, 5 mo  −  −  −  12.1  2.9  2.23  1.6  0.26  207  +/+/−/+  −  +  LGBCL-PD  N  −  20  79/M  T>B, 5 mo  −  −  −  9.7  3.2  2.1  1.8  0.96  140  +/+/−/+  +  +  MALT  Colon  NA  21  63/M  T>B, 2 mo Considered syn  −  −  −  11.8  5.8  3.19  1.3  1.9  236  +/+/+/+  −  +  LPL (MyD88+)  BM  −  22  45/M  Syn  −  −  −  8  14.2  12.9  10.4  1.27  313  +/+/−/+  +  +  LPL (MyD88+)  BM  NA  Patient No.  Age (y)/Sex  Order of Presentation and Interval  AI  Splenomegaly  Tx  HB (g/dL)  WBC (×109/L)  L Count (×109/L)  LGL Count (×109/L)  ANC (×109/L)  Platelet (×109/L)  Immunopheno- type ( CD8/CD16/ CD56/ CD57)  Rx for T-LGL  Clonality (PCR)  BCL  Site  EBER  14  58/F  B>T, 3 y  −  −  BM (Allo)  10.1  8.9  7.3  NA  0.9  11  +/−/−/+  +  +  FL  EN    15  53/M  B>T, 5.5 y  −  Splenectomy  BM (Allo)  10.7  16.5  10.9  NA  3.8  187  +/−/−/+  +  +  MCL  N  10  16  63/M  B>T, 3 y  −  Splenectomy  −  11.8  8.2  3.0  1.9  3.0  217  +/+/+/+  −  +  Splenic MZL, and later HL nodular sclerosis type  Spleen, HL-N  −  17  61/F  HL>B>T, 21 y, 2 y  −  −  −  11.4  2.8  1.99  NA  0.53  147  +/−/−/+  +  +  HL, MALT  NA EN    18  47/F  B>T, 10 y  RA  −  −  12.3  2.4  0.69  NA  1.3  211  +/NA/−/+  +  +  MALT  EN    19  49/F  T>B, 5 mo  −  −  −  12.1  2.9  2.23  1.6  0.26  207  +/+/−/+  −  +  LGBCL-PD  N  −  20  79/M  T>B, 5 mo  −  −  −  9.7  3.2  2.1  1.8  0.96  140  +/+/−/+  +  +  MALT  Colon  NA  21  63/M  T>B, 2 mo Considered syn  −  −  −  11.8  5.8  3.19  1.3  1.9  236  +/+/+/+  −  +  LPL (MyD88+)  BM  −  22  45/M  Syn  −  −  −  8  14.2  12.9  10.4  1.27  313  +/+/−/+  +  +  LPL (MyD88+)  BM  NA  −, negative; +, positive; >, precede; AI, autoimmune disease; Allo, allogeneic; ANC, absolute neutrophil count; B, B-cell lymphoma; BCL, B-cell lymphoma; BM, bone marrow; B-NHL, B-cell non-Hodgkin lymphoma; EN, extranodal; FL, follicular lymphoma; HB, hemoglobin; HL, Hodgkin lymphoma; L, lymphocyte; LGBCL-PCD, low-grade B-cell lymphoma with plasmacytic differentiation; LPL, lymphoplasmacytic lymphoma; MALT, extranodal marginal zone lymphoma of mucosa associated lymphoid tissue; MCL, mantle cell lymphoma; MZL, marginal zone lymphoma; N, nodal; NA, not available; RA, rheumatoid arthritis; Rx, treatment; Syn, synchronous; T, T-cell large granular lymphocytic leukemia; Tx, transplant. View Large Splenomegaly was found in one patient. Patients 15 and 16 had a history of splenectomy. In one patient (patient 15), splenectomy was done as part of the treatment for lymphoma. In another patient (patient 16), splenic MZL was diagnosed on splenectomy performed for possible immune thrombocytopenic purpura. Patient 18 had a history of rheumatoid arthritis. No patient had a history of solid organ transplant. Two patients (patients 14 and 15) received allogeneic bone marrow transplant for a preceding BCL. Three patients had dysgammaglobulinemia. Two patients (patients 17 and 21) had coexisting MGUS and one patient (patient 21) had hypergammaglobulinemia. No patient had hypogammaglobulinemia. Six patients (66%) had anemia and neutropenia. Four (44.4%) patients had leukopenia, one (11.1%) had thrombocytopenia, and one (11.1%) had lymphopenia. T-LGL counts were available in five patients and varied from 1.3 to 10.4 × 109/L. Bone marrow biopsy showed an interstitial/sinusoidal infiltrate of T-LGLs in all the patients involving 10% to 50% of the marrow cellularity in eight patients. In one case, the quantification data were not available. Based on the immunophenotypic data, two patients expressed CD56 and seven patients were negative for CD56. None of the patients had CD4+/CD8+ or CD4+/CD8− immunophenotype. PCR-based gene rearrangement studies were performed on all the patients. Monoclonal T-cell gene rearrangements were identified in all nine patients. Seven patients had a metachronous occurrence. The time interval between the two lymphoid neoplasms ranged from 5 months to 10 years. Five patients had a small BCL preceding T-LGL leukemia. The spectrum of small BCLs included FL (patient 14), mantle cell lymphoma (patient 15), splenic MZL (patient 16), and extranodal marginal zone BCL of mucosa-associated lymphoid tissue (MALT) (patients 17 and 18). The patient (patient 16) with splenic MZL later developed synchronous T-LGL leukemia and classical HL of nodular sclerosis type. Patient 17, who had a remote history of HL, developed a λ-restricted pulmonary MALT lymphoma 19 years later. This patient also had an associated IgG lambda MGUS. The clonal relation between the MALT lymphoma and MGUS was not known. Patient 18, with a thymic MALT lymphoma, had rheumatoid arthritis. T-LGL leukemia preceded BCL in two patients. Patient 19 developed a nodal LGBCL-PD, and patient 20 was diagnosed with an MALT lymphoma of the descending colon 5 months after the T-LGL leukemia diagnosis. Another patient with T-LGL leukemia (patient 21) was diagnosed with LPL in the bone marrow after 2 months of initial diagnosis, which was considered synchronous. This patient had a coexisting IgM λ paraproteinemia. One patient (patient 22) was diagnosed synchronously with LPL and T-LGL leukemia. All the patients received therapy for their BCL and HL. Six patients received treatment for T-LGL leukemia. The mean follow-up time was 72 months (range, 48-132 months) from the first diagnosis. Six patients were alive at the time of last review of medical records, with median follow-up of 68.5 months (range, 60-132 months). Three patients died at 48, 75, and 90 months after the diagnosis of BCL. Comparing the features of patients with large BCLs to those with small BCLs, we noticed some differences. In patients with large BCLs, the T-LGL leukemias appeared to occur more frequently in the setting of bone marrow transplantation compared to small BCLs. This may relate to the propensity to treat relapsed DLBCL with stem cell transplantation and the known occurrence of T-LGL in the setting of hematopoietic stem cell transplantation.17 Even though the degree of cytopenias in the two groups were not statistically significant (P > .05), more patients in the small BCL group (6/9) received treatment for T-LGL leukemia, as compared to the large BCL group (5/13). Discussion The most notable finding of this study is the identification of 13 patients with large BCLs in association with T-LGL leukemia, in addition to nine small B-NHLs with this association. While a number of small BCLs are described previously in case reports and case series, only two patients with de novo DLBCL and one case of transformed low-grade lymphoma in association with T-LGL leukemia are reported in the literature, to the best of our knowledge. The most common B-cell lymphoproliferative disorders reported are MGUS, CLL, and HCL. When limited to patients with B-NHL, we identified more patients with large BCLs than small BCLs likely due to the exclusion of CLL and HCL patients, which are reported as the most common small BCLs in association with T-LGL leukemia. In the case report by Anoop et al,16 a 74-year-old man had incidental lymphocytosis and neutropenia. He was treated with methotrexate for neutropenia. Two years later he developed an Epstein-Barr virus (EBV) negative DLBCL of germinal center in the inguinal lymph node. There could be a possible contribution of methotrexate-related immunosuppression in the development of this large-cell lymphoma in the setting of T-LGL. In our series, we had only one case in which an EBV-negative extranodal DLBCL, NOS, developed after T-LGL leukemia. This patient never received treatment for T-LGL leukemia. The majority of large BCLs in our series either preceded or occurred synchronously with T-LGL leukemia. To the best of our knowledge, there is only one similar case reported in the literature.17 In the case described by Viny et al,8 the patient had a DLBCL transformed from a preexisting FL. We identified two similar patients with preexisting, low-grade small BCLs who subsequently developed DLBCL. The occurrence of T-LGL leukemia in the setting of synchronous or prior DLBCL suggests that the DLBCL may set up an immune environment conducive to the T-LGL proliferation, which might include an antigenic stimulus for the proliferation. T-LGL leukemia can precede, follow, or present synchronously with BCLs. T-LGL leukemias preceding BCLs appear to be rare. There is only one case report in the literature, and we identified three such patients in this multicenter study. This co-occurrence could be a coincidence. Underlying infection, generalized immune and B-cell dysregulation, or possibly T-LGLs acting as an antigenic trigger are other possible explanations. T-LGL leukemia commonly follows or occurs synchronously with BCLs. In 19 out of 22 patients, BCL either preceded (14 patients) or was diagnosed synchronously (5 patients) with T-LGL in our series. Various possible mechanisms might link these two processes. One possible hypothesis is a clonal expansion of T-LGLs in response to the BCL as an antigenic trigger. This expansion might have a role in tumor surveillance. In the series reported by Viny et al,8 none of the T-LGL leukemia patients with MGUS progressed to plasma cell myeloma and one patient even had spontaneous remission of both T-LGL leukemia and MGUS. How this immune surveillance might impact the course of BCL requires further investigation. Another possibility is a common antigenic drive for concomitant T- and B-cell proliferations in the setting of autoimmune disease, viral infections, or organ transplants. This is supported by the synchronous presence of these two processes in five patients. Coexisting BCLs and T-LGL leukemia are likely to be clonally unrelated. However, formal clonal relatedness studies were not performed and are beyond the scope of this study. As expected, patients with T-LGL leukemia in our series commonly manifested with cytopenias. Neutropenia is the most common cytopenia reported in T-LGL leukemia patients. In contrast, patients with BCLs in our series had a slightly higher incidence of anemia (68%) as compared to neutropenia (63%). This could be due to underlying lymphomas and related therapy. A similar high incidence of anemia was reported in a T-LGL leukemia developing in post kidney transplant patients18 who might also be expected to manifest with anemia due to the underlying condition. Rheumatoid arthritis does not appear to have a strong association in the subset of T-LGL leukemia patients with BCLs because we identified only one patient with rheumatoid arthritis as compared to the reported incidence of 25% to 33% in T-LGL leukemia patients.1 CD56 expression is a marker of aggressive clinical course in T-LGL leukemia.19 CD56 was expressed in nine (41%) of the patients in our series, but only three of those patients received treatment for T-LGL leukemia. The other eight patients who received therapy for the T-LGL leukemia were CD56 negative. Thus, we cannot confirm CD56 as a reliable marker of aggressive disease requiring active therapy. Our study is the first multicenter retrospective study looking at the frequency of BCLs occurring in T-LGL leukemia. Since this is a retrospective study, it was difficult to obtain complete information on some patients, and this is an acknowledged limitation. We were also unable to study the known mutations in T-LGL leukemias, such as those affecting STAT3 and STAT5B. However, this study helps define the incidence of B-NHL (5%) in patients with T-LGL leukemia and, in particular, large BCLs (3%). Given the relative rarity of B-NHL in the general population (70,000 new cases/year in the United States with a population of over 300 million)20 and our finding of 5.3% B-NHL in this cohort of patients, the association between T-LGL and B-NHL may not be coincidental. Further studies about the possible immunogenic role of clonal B cells in the pathogenesis of clonal T-LGL expansions are required to delineate the underlying pathophysiology. References 1. Sokol L, Loughran TPJr. Large granular lymphocyte leukemia. Oncologist . 2006; 11: 263 -273. Google Scholar CrossRef Search ADS PubMed  2. Shah MV, Hook CC, Call TGet al.   A population-based study of large granular lymphocyte leukemia. Blood Cancer J . 2016; 6: e455. Google Scholar CrossRef Search ADS PubMed  3. Singleton TP, Yin B, Teferra Aet al.   Spectrum of clonal large granular lymphocytes (LGLs) of αβ T cells: T-cell clones of undetermined significance, T-cell LGL leukemias, and T-cell immunoclones. Am J Clin Pathol . 2015; 144: 137- 144. Google Scholar CrossRef Search ADS PubMed  4. Lamy T, Moignet A, Loughran TPJr. LGL leukemia: from pathogenesis to treatment. Blood . 2017; 129: 1082 -1094. Google Scholar CrossRef Search ADS PubMed  5. Lamy T, Loughran TPJr. Clinical features of large granular lymphocyte leukemia. Semin Hematol . 2003; 40: 185 -195. Google Scholar CrossRef Search ADS PubMed  6. Zhang R, Shah MV, Loughran TPJr. The root of many evils: indolent large granular lymphocyte leukemia and associated disorders. Hematol Oncol . 2010; 28: 105 -117. Google Scholar PubMed  7. Bockorny B, Codreanu I, Dasanu CA. Prevalence of autoimmune hematologic and nonhematologic conditions in large granular lymphocytic leukemia: exploratory analysis of a series of consecutive patients. Leuk Lymphoma . 2014; 55: 1399 -1401. Google Scholar CrossRef Search ADS PubMed  8. Viny AD, Lichtin A, Pohlman Bet al.   Chronic B-cell dyscrasias are an important clinical feature of T-LGL leukemia. Leuk Lymphoma . 2008; 49: 932 -938. Google Scholar CrossRef Search ADS PubMed  9. Xie XY, Sorbara L, Kreitman RJet al.   Development of lymphoproliferative disorder of granular lymphocytes in association with hairy cell leukemia. Leuk Lymphoma . 2000; 37: 97 -104. Google Scholar CrossRef Search ADS PubMed  10. Howard MT, Bejanyan N, Maciejewski JPet al.   T/NK large granular lymphocyte leukemia and coexisting monoclonal B-cell lymphocytosis-like proliferations: an unrecognized and frequent association. Am J Clin Pathol . 2010; 133: 936 -941. Google Scholar CrossRef Search ADS PubMed  11. Papadaki T, Stamatopoulos K, Kosmas Cet al.   Clonal T-large granular lymphocyte proliferations associated with clonal B-cell lymphoproliferative disorders: report of 8 cases. Leukemia . 2002; 16: 2167 -2169. Google Scholar CrossRef Search ADS PubMed  12. Broome HE, Wang HY. A case of concomitant T-cell large granular lymphocytic leukemia and plasma cell myeloma. Clin Adv Hematol Oncol . 2011; 9: 958 -959. Google Scholar PubMed  13. Nawaz U, Baidas S, Jones E. A case of concomitant T-cell large granular lymphocyte leukemia and plasma cell myeloma. Clin Adv Hematol Oncol . 2011; 9: 956 -957. Google Scholar PubMed  14. Papadaki T, Stamatopoulos K, Stavroyianni Net al.   Evidence for T-large granular lymphocyte-mediated neutropenia in Rituximab-treated lymphoma patients: report of 2 cases. Leuk Res . 2002; 26: 597- 600. Google Scholar CrossRef Search ADS PubMed  15. Papadaki T, Stamatopoulos K, Kosmas Cet al.   A unique case of splenic marginal zone-cell lymphoma with synchronous clonal T-cell large granular lymphocyte proliferation: an immunologic, immunohistochemical, and genotypic study. Leuk Res . 2003; 27: 85 -87. Google Scholar CrossRef Search ADS PubMed  16. Anoop P, Ravindranathan G, Osuji Net al.   Epstein-Barr virus negative large B-cell lymphoma during long-term immunomodulatory therapy for T-cell large granular lymphocytic leukemia. Br J Haematol . 2010; 148: 337 -339. Google Scholar CrossRef Search ADS PubMed  17. Gill H, Ip AH, Leung Ret al.   Indolent T-cell large granular lymphocyte leukemia after hematopoietic SCT: a clinicopathologic and molecular analysis. Bone Marrow Transplant . 2012; 47: 952- 956. Google Scholar CrossRef Search ADS PubMed  18. Alfano G, Fontana F, Colaci Eet al.   T-cell large granular lymphocytes leukemia (T-LGL) in kidney transplant and review of the literature. Nephrol Dial Transplant . 2017; 32: 730 -731. Google Scholar CrossRef Search ADS PubMed  19. Gentile TC, Uner AH, Hutchison REet al.   CD 3+, CD56+ aggressive variant of large granular lymphocyte leukemia. Blood . 1994; 84: 2315 -2321. Google Scholar PubMed  20. National Cancer Institute: Surveillance, Epidemiology, and End Results program. Available at https://seer.cancer.gov/statfacts/html/nhl.html. © American Society for Clinical Pathology, 2018. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png American Journal of Clinical Pathology Oxford University Press

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Abstract

Abstract Objective T-cell large granular lymphocytic (T-LGL) leukemia is associated with B-cell lymphomas (BCLs), especially small BCLs. We aimed to explore and expand upon its association with BCLs. Methods We retrospectively studied clinicopathologic features of T-LGL leukemia patients with coexisting BCL from January 2001 to December 2016. Results Among 432 patients with T-LGL leukemia, 22 (5.1%) had an associated B-cell non-Hodgkin lymphoma. Thirteen (59%) patients had large and nine (41%) had small BCL. T-LGL leukemia occurred synchronously with BCL in five, preceded BCL in three, and followed BCL in 14 patients. Anemia was the most common cytopenia (68%). Only one patient had a history of rheumatoid arthritis. Conclusion To our knowledge, this is the first multicenter study looking at the spectrum and incidence of BCLs in patients with T-LGL leukemia and highlights its association with large BCLs (3% of T-LGL leukemias). T-LGL leukemia, B-cell lymphoma, Diffuse large B-cell lymphoma T-cell large granular lymphocytic (T-LGL) leukemia is a chronic lymphoproliferative disorder characterized by a clonal expansion of T-LGLs expressing cytotoxic proteins, CD3, CD8, and CD57.1 It is a rare disease with an incidence of 0.2 cases per 1 million individuals per year and represents 2% to 5% of chronic lymphoproliferative diseases in the US.2 The median age at diagnosis is 66.5 years.2 While there is no absolute large granular lymphocytic (LGL) count required for diagnosis of T-LGL leukemia, a T-LGL value of greater than 2 × 109/L is frequently associated with a clonal proliferation. In the appropriate clinical context (autoimmune disease, cytopenia, splenomegaly), patients with a peripheral blood expansion of the T-LGL population more than 0.5 × 109/L in association with a CD3+/CD8+ phenotype and evidence of clonality can be considered to have T-LGL leukemia.2,3 The pathogenesis is incompletely understood, but chronic activation of T cells with autoantigen or viral antigen has been suggested as an initial stimulus leading to an expansion of LGLs. Leukemic LGLs have dysregulation in apoptosis. They escape Fas-mediated, activation-induced cell death. Increased numbers of circulating leukemic T-LGLs result from activation of multiple survival pathways.4 T-LGL leukemia is an indolent disease. The majority of patients are asymptomatic initially, but more than one half of the patients require treatment for cytopenias in the course of disease.1 Neutropenia is the most common cytopenia, leading to recurrent bacterial infections, followed by anemia and thrombocytopenia.5 A substantial proportion of patients with T-LGL leukemia have immunologic abnormalities, including seropositivity for rheumatoid factor and antinuclear antibodies, polyclonal hypergammaglobulinemia, circulating immune complexes, high β2 microglobulin, and antineutrophil antibodies.6,7 The most common autoimmune disorder associated with T-LGL leukemia is rheumatoid arthritis, which manifests in about 25% to 33% of patients.6 The association of T-LGL leukemia with B-cell lymphoproliferative disorders is well-recognized.6,8 There are a number of isolated case reports and case series looking at the association of B-cell neoplasms in the setting of T-LGL leukemia. The spectrum of clonal B-cell neoplasms in T-LGL leukemia includes hairy cell leukemia (HCL),8,9 monoclonal B-cell lymphocytosis,10 monoclonal gammopathy of unknown significance (MGUS),11 chronic lymphocytic leukemia (CLL),8 Hodgkin lymphoma (HL),8 plasma cell myeloma,12,13 mantle cell lymphoma,14 lymphoplasmacytic lymphoma (LPL),11 marginal zone lymphoma (MZL),15 and follicular lymphoma (FL).8 Interestingly, a PubMed search revealed only two cases of diffuse large B-cell lymphoma (DLBCL) in association with T-LGL leukemia. One is a case report by Anoop et al.16 Another case of DLBCL is included in a study that looked at the frequency of T-LGL leukemia in association with hematopoietic stem cell transplant, which might select for diseases such as DLBCL.17 In addition, Viny et al8 reported one case of DLBCL transformed from FL in their series of T-LGL leukemia associated with B-cell dyscrasias. In this study, we intend to further explore the spectrum of B-cell lymphomas (BCLs) in patients with T-LGL leukemia. Materials and Methods This study was undertaken to explore the association of BCLs with T-LGL leukemia. The study protocol was approved by the institutional review boards of all institutions involved. Data were requested from the institutions participating in the Bone Marrow Pathology Group. Five institutions (Cleveland Clinic Foundation, MD Anderson Cancer Center, Mayo Clinic, Hospital of the University of Pennsylvania, and University of New Mexico) contributed data for the study. Patients with T-LGL leukemia diagnosed from January 2001 to December 2016 were identified retrospectively. One institution contributed cases diagnosed from 2005 to 2016. A total of 432 patients of T-LGL leukemia were identified, with 22 patients having BCLs at some point in their care. B-cell proliferations with only leukemic presentation such as HCL and CLL were excluded, since their occurrence with T-LGL leukemia is previously well-described.8 A total of 22 patients with BCLs and clonal T-LGL proliferations were included in the study. We separated these patients into synchronous and metachronous based on the diagnosis of the T-LGL leukemia and BCL. Patients with two diagnoses made within 3 months were considered synchronous because this interval could represent the time difference between peripheral blood flow cytometry and tissue biopsy. Patients with a large BCL anytime during the disease course were grouped together. Laboratory values for hemoglobin, leukocyte count, platelet count, absolute lymphocyte count, absolute neutrophil count, T-LGL count, rheumatoid factor, antinuclear antibodies, serum protein electrophoresis, and gammaglobulin levels were collected for each patient. Medical records, clinical history, presence of autoimmune conditions, transplant, and treatment history were reviewed. Bone marrow findings were locally reviewed for each case. Surgical pathology slides and medical records were reviewed for the coexisting BCLs. Data related to classification, histological features, immunophenotype, and treatment were recorded. Immunophenotype was determined by flow cytometric analysis using monoclonal antibodies per individual institution practice. Despite interlaboratory technical variation, all laboratories identified T-LGLs by expression of CD3, CD4, CD8, and aberrant expression of natural killer cell markers (CD16, CD56, and CD57) using primary CD45 and/or light-scatter lymphocyte gating. Blood counts were compared using Mann-Whitney U test performed at a significance level of P < .05, using statistical analysis software (StatSoft, Tulsa, OK). Results We identified 432 patients with T-LGL leukemia. Of these, there were 22 (5.1%) patients with associated BCL Table 1, which formed the population for this study. Thirteen (59%) patients had a large B-cell non-Hodgkin lymphoma (B-NHL) in the course of their disease and nine (41%) had a small B-NHL. We did not identify any case of only tissue-based small cell lymphoma. Six patients had multiple BCLs in their disease course. Since molecular studies were not performed on all BCL cases and given the dissimilar histology and wide time interval in some of the cases, we considered them separate events. Among those patients with multiple BCLs, the spectrum included two large B-NHLs (one patient), small and large B-NHLs (one patient), Hodgkin and non-Hodgkin lymphomas (two patients), and transformation from a low-grade lymphoma (two patients). Table 1 Summary of B-NHLs in T-LGL Leukemia Type of Lymphoma  No. of Cases  DLBCL, NOS  11  MALT lymphoma  3a  THRLBCL  2  LGBCL-PD  2  Low-grade lymphoma, unclassified  2  LPL  2  MCL  1  FL  1  PTLPD-DLBCL  1  Splenic MZL  1b  Type of Lymphoma  No. of Cases  DLBCL, NOS  11  MALT lymphoma  3a  THRLBCL  2  LGBCL-PD  2  Low-grade lymphoma, unclassified  2  LPL  2  MCL  1  FL  1  PTLPD-DLBCL  1  Splenic MZL  1b  B-NHL, B-cell non-Hodgkin lymphoma; DLBCL, diffuse large B-cell lymphoma; FL, follicular lymphoma; LGBCL-PD, low-grade B-cell lymphoma with plasmacytic differentiation; LPL, lymphoplasmacytic lymphoma; MALT, extranodal marginal zone lymphoma of mucosa associated lymphoid tissue; MCL, mantle cell lymphoma; MZL, marginal zone lymphoma; NOS, not otherwise specified; PTLPD, posttransplant lymphoproliferative disorder; THRLBCL, T-cell/histiocyte rich large B-cell lymphoma; T-LGL, T-cell large granular lymphocytic. aOne patient had history of Hodgkin lymphoma. bPatient later developed Hodgkin lymphoma with T-LGL leukemia. View Large T-LGL Leukemia With Large BCLs Large BCLs were identified in 13 patients with T-LGL leukemia, including seven males and six females. The median age at the time of T-LGL leukemia diagnosis was 68 years. The spectrum of large BCLs in T-LGL in our series is shown in Table 2. Table 2 Clinicopathologic Features of Large B-NHLs Occurring in Patients With T-Large Granular Lymphocytic Leukemia Patient No.  Age (y)/Sex  Order of Presentation and Interval  AI  Splenomegaly  Tx  HB (g/dL)  WBC (×109/L)  L Count (×109/L)  LGL Count (×109/L)  ANC (×109/L)  Platelet (×109/L)  Immunophenotype ( CD8/CD16/ CD56/ CD57)  Rx for T-LGL  Clonality (PCR)  BCL  COO  Site  EBER  1  60/F  Syn  −  +  Liver  7.6  14.08  3.57  2.5  8.59  155  +/+/+/+  +  +  PTLPD-DLBCL  GC  EN Ttnsil  −  2  68/M  Syn  −  +  −  11.3  6.01  7.7  4.62  1.21  315  +/−/−/NA  −  +  DLBCL, NOS  NGC  EN spleen  NA  3  74/F  Syn  AIHA  −  −  NA  NA  NA  NA  NA  NA  +/NA/NA/+  NA  +  DLBCL, NOS  GC  EN  −  4  74/M  T>B, 6 y  −  Splenectomy  −  8.8  2.37  1.12  1.06  0.94  109  +/+/+/+  +  +  DLBCL, NOS  GC  EN mediastinum  −  5  53/M  B>T, 19 y  −  −  BM (Auto)  12.4  5.5  3.08  1.2  1.6  41  +/−/−/+  −  +  DLBCL, NOS THRLBCL  NA  N  −  6  45/M  B>T, 1 y  −  Splenectomy  BM (Auto)  9.1  35  29.1  NA  3.2  71  +/−/+/+  −  +  THRLBCL  −  EN  NA  7  75/M  B>T, 3.7 y  NA  −  −  14.2  4.3  2.58  1.3  1.2  143  +/NA/+/+  −  +  DLBCL, NOS  NA  EN  −  8  48/M  B>T, 11 mo  −  Splenectomy  −  14  4.3  3.05  1.2  0.516  314  +/NA/NA/+  −  +  DLBCL, NOS  GC  EN spleen  NA  9  73/M  B>T, 3 y  −  −  −  13.3  4.3  2.8  NA  0.7  172  +/+/−/+  +  +  DLBCL, NOS  GC  N and EN lung, muscle  NA  10  66/F  B>T, 3.5 y  −  −  BM (Auto)  7.6  4.3  2.09  NA  1.3  99  +/−/+/+  +  +  DLBCL, NOS  NGC  EN liver  NA  11  72/F  B>T, 18 y  MCTD  Splenectomy  −  9.7  8.4  4.49  3.1  3.01  359  +/+/−/+  +  +  LGBCL-U and later DLBCL, NOS  N/A  BM  NA  12  68/F  B>T, 25 y  −  −  −  10.7  16.44  11.84  4.49  2.96  299  +/+/+/NA  −  +  LGBCL-PD and later DLBCL, NOS  NGC  LGBCL spleen, DLBCL, NOS N  −  13  69/F  B>T, 1 y  −  −  BM (Auto)  12.1  2.9  1.4  NA  1.2  146  +/NA/+/+  −  +  DLBCL, NOS and later LGBCL-U   NGC  N  NA  Patient No.  Age (y)/Sex  Order of Presentation and Interval  AI  Splenomegaly  Tx  HB (g/dL)  WBC (×109/L)  L Count (×109/L)  LGL Count (×109/L)  ANC (×109/L)  Platelet (×109/L)  Immunophenotype ( CD8/CD16/ CD56/ CD57)  Rx for T-LGL  Clonality (PCR)  BCL  COO  Site  EBER  1  60/F  Syn  −  +  Liver  7.6  14.08  3.57  2.5  8.59  155  +/+/+/+  +  +  PTLPD-DLBCL  GC  EN Ttnsil  −  2  68/M  Syn  −  +  −  11.3  6.01  7.7  4.62  1.21  315  +/−/−/NA  −  +  DLBCL, NOS  NGC  EN spleen  NA  3  74/F  Syn  AIHA  −  −  NA  NA  NA  NA  NA  NA  +/NA/NA/+  NA  +  DLBCL, NOS  GC  EN  −  4  74/M  T>B, 6 y  −  Splenectomy  −  8.8  2.37  1.12  1.06  0.94  109  +/+/+/+  +  +  DLBCL, NOS  GC  EN mediastinum  −  5  53/M  B>T, 19 y  −  −  BM (Auto)  12.4  5.5  3.08  1.2  1.6  41  +/−/−/+  −  +  DLBCL, NOS THRLBCL  NA  N  −  6  45/M  B>T, 1 y  −  Splenectomy  BM (Auto)  9.1  35  29.1  NA  3.2  71  +/−/+/+  −  +  THRLBCL  −  EN  NA  7  75/M  B>T, 3.7 y  NA  −  −  14.2  4.3  2.58  1.3  1.2  143  +/NA/+/+  −  +  DLBCL, NOS  NA  EN  −  8  48/M  B>T, 11 mo  −  Splenectomy  −  14  4.3  3.05  1.2  0.516  314  +/NA/NA/+  −  +  DLBCL, NOS  GC  EN spleen  NA  9  73/M  B>T, 3 y  −  −  −  13.3  4.3  2.8  NA  0.7  172  +/+/−/+  +  +  DLBCL, NOS  GC  N and EN lung, muscle  NA  10  66/F  B>T, 3.5 y  −  −  BM (Auto)  7.6  4.3  2.09  NA  1.3  99  +/−/+/+  +  +  DLBCL, NOS  NGC  EN liver  NA  11  72/F  B>T, 18 y  MCTD  Splenectomy  −  9.7  8.4  4.49  3.1  3.01  359  +/+/−/+  +  +  LGBCL-U and later DLBCL, NOS  N/A  BM  NA  12  68/F  B>T, 25 y  −  −  −  10.7  16.44  11.84  4.49  2.96  299  +/+/+/NA  −  +  LGBCL-PD and later DLBCL, NOS  NGC  LGBCL spleen, DLBCL, NOS N  −  13  69/F  B>T, 1 y  −  −  BM (Auto)  12.1  2.9  1.4  NA  1.2  146  +/NA/+/+  −  +  DLBCL, NOS and later LGBCL-U   NGC  N  NA  –, negative; +, positive; >, precede; AI, autoimmune disease; AIHA, autoimmune hemolytic anemia; ANC, absolute neutrophil count; Auto, autologous; B, B-cell lymphoma; BCL, B-cell lymphoma; BM, bone marrow; B-NHL, B-cell non-Hodgkin lymphoma; COO, cell of origin (Han’algorithm); DLBCL, diffuse large B-cell lymphoma; EN, extranodal; GC, germinal center; HB, hemoglobin; L, lymphocyte; LGBCL, low-grade B-cell lymphoma; LGBCL-PD, low-grade B-cell lymphoma with plasmacytic differentiation; LGBCL-U, low-grade B-cell lymphoma, unclassifiable; MCTD, mixed connective tissue disease; N, nodal; NA, not available; NGC, nongerminal center; PTLPD, posttransplant lymphoproliferative disorder; Rx, treatment; Syn, synchronous; T, T-cell large granular lymphocytic leukemia; THRLBCL, T-cell/histiocyte rich large B-cell lymphoma; Tx, transplant. View Large Splenomegaly was found in two patients. Four patients had a history of splenectomy. Patients 3 and 11 had a history of autoimmune disease. Patient 1 had a history of solid organ transplant. Four patients (patients 5, 6, 10, and 13) received autologous stem cell transplant for the preceding BCL before developing T-LGL leukemia. Four patients had coexisting dysgammaglobulinemia. Patient 4 had a coexisting hypergammaglobulinemia, and patients 5 and 6 had coexisting hypogammaglobulinemia. Patient 1 had hypogammaglobulinemia and later developed hypergammaglobulinemia. None of the patients had coexisting MGUS. Nine (69.2%) patients had anemia, six (46%) patients with an absolute neutrophil count less than 1.5 × 109/L, four (30.7%) had thrombocytopenia, and two (15.3%) had leukopenia. None of the patients had lymphopenia. In one patient, peripheral blood counts were not available. T-LGL counts were available in eight patients and varied from 1.06 to 4.49 × 109/L. Bone marrow biopsies showed an interstitial/sinusoidal infiltrate of T-LGLs in all the patients. T-LGL infiltrates involved 7.5% to 50% of the marrow cellularity in eight patients with available data. In the remaining patients, quantification data were not available. Based on the flow cytometry performed on the peripheral blood/bone marrow or bone marrow immunohistochemistry studies, seven patients expressed CD56 and four patients were negative for CD56. In two patients, the status of CD56 expression was not known. Patient 13 expressed both CD4 and CD8. None of the cases had a CD4+/CD8− immunophenotype. Data regarding αβ/γδ types were not collected. Polymerase chain reaction (PCR)-based gene rearrangement studies were performed on all the patients. A monoclonal T-cell rearrangement was identified in all 13 patients. Three out of 13 patients (patients 1-3) had T-LGL leukemia and BCL synchronously, and the remaining 10 patients had a metachronous occurrence. With regards to the synchronous patients, patient 1 had a liver transplant for primary sclerosing cholangitis who later developed synchronous T-LGL leukemia and monomorphic posttransplant lymphoproliferative disorder (lymphoma) consistent with an extranodal DLBCL of germinal center origin (PTLPD-DLBCL). This patient also had hypogammaglobulinemia and later had hypergammaglobulinemia. Patients 2 and 3 had synchronous T-LGL leukemia and an extranodal DLBCL, not otherwise specified (NOS). Patient 3 also had a long-standing history of autoimmune hemolytic anemia. For the 10 patients with a metachronous occurrence, the time interval between the two lymphoid neoplasms ranged from 11 months to 25 years. Among these, in only patient 4 the T-LGL leukemia preceded the de novo DLBCL, NOS (DLBCL of a germinal center phenotype in the mediastinum occurring 6 years later). He manifested with pancytopenia at presentation and was observed but not treated for T-LGL leukemia. A large BCL preceded T-LGL leukemia in the other nine patients. Patient 5 initially had nodal DLBCL and later developed nodal T-cell/histiocyte rich large B-cell lymphoma (THRLBCL). This patient received an autologous bone marrow transplant for THRLBCL, and T-LGL was diagnosed 8 years after the transplant. Patient 6 had an extranodal THRLBCL preceding T-LGL leukemia. This patient also received an autologous stem cell transplant for the BCL. Both of these patients (patients 5 and 6) had hypogammaglobulinemia. Four patients (patients 7-10) had DLBCL, NOS. Patient 11, with a history of low-grade BCL, developed DLBCL 12 years later and then after 6 years developed T-LGL leukemia. This patient also had a history of mixed connective tissue disease. Another similar patient (patient 12), who initially had a low-grade BCL with plasmacytic differentiation (LGBCL-PD), developed DLBCL 25 years later and subsequently developed T-LGL leukemia after 6 months. Another patient (patient 13) with DLBCL, NOS, was diagnosed with T-LGL leukemia a year later. Three years from her first diagnosis, she had a low-grade BCL. She received an autologous bone marrow transplant and 2 years later again relapsed with a low-grade BCL. Out of 12 patients with DLBCL, NOS, at some point during the course of disease process, eight patients were extranodal, three were nodal, and one was both nodal and extranodal. Five patients had DLBCL of a germinal center phenotype, four with a nongerminal center phenotype, and in three sufficient data were not available to classify cell of origin. Epstein–Barr encoding region (EBER) in situ hybridization was negative in all 6 patients with available data. Patients with de novo DLBCL, transplant-related DLBCL, or DLBCL that transformed from low-grade lymphoma received cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP)/CHOP with rituximab (R-CHOP)/cyclophosphamide, vincristine, doxorubicin, and dexamethasone with rituximab (R-CVAD) therapy. In one patient, the treatment history was not available. Mean follow-up time from the first diagnosis is 103 months (range, 24-329 months). Five patients were treated for T-LGL leukemia for cytopenias. Eight patients were alive at the time of last review of medical records, with a median follow-up time of 62 months (range, 24-329 months). Three were lost to follow-up. Two patients died at 54 and 74 months after diagnosis of DLBCL. T-LGL Leukemia With Small BCLs Nine patients of T-LGL leukemia associated with small BCL were identified; the lymphomas spanned a broad spectrum of types Table 3. Five patients were men and four were women. The median age at the time of T-LGL leukemia diagnosis was 58 years. Table 3 Clinicopathologic Features of Small B-NHLs Occurring in Patients With T-Large Granular Lymphocytic Leukemia Patient No.  Age (y)/Sex  Order of Presentation and Interval  AI  Splenomegaly  Tx  HB (g/dL)  WBC (×109/L)  L Count (×109/L)  LGL Count (×109/L)  ANC (×109/L)  Platelet (×109/L)  Immunopheno- type ( CD8/CD16/ CD56/ CD57)  Rx for T-LGL  Clonality (PCR)  BCL  Site  EBER  14  58/F  B>T, 3 y  −  −  BM (Allo)  10.1  8.9  7.3  NA  0.9  11  +/−/−/+  +  +  FL  EN    15  53/M  B>T, 5.5 y  −  Splenectomy  BM (Allo)  10.7  16.5  10.9  NA  3.8  187  +/−/−/+  +  +  MCL  N  10  16  63/M  B>T, 3 y  −  Splenectomy  −  11.8  8.2  3.0  1.9  3.0  217  +/+/+/+  −  +  Splenic MZL, and later HL nodular sclerosis type  Spleen, HL-N  −  17  61/F  HL>B>T, 21 y, 2 y  −  −  −  11.4  2.8  1.99  NA  0.53  147  +/−/−/+  +  +  HL, MALT  NA EN    18  47/F  B>T, 10 y  RA  −  −  12.3  2.4  0.69  NA  1.3  211  +/NA/−/+  +  +  MALT  EN    19  49/F  T>B, 5 mo  −  −  −  12.1  2.9  2.23  1.6  0.26  207  +/+/−/+  −  +  LGBCL-PD  N  −  20  79/M  T>B, 5 mo  −  −  −  9.7  3.2  2.1  1.8  0.96  140  +/+/−/+  +  +  MALT  Colon  NA  21  63/M  T>B, 2 mo Considered syn  −  −  −  11.8  5.8  3.19  1.3  1.9  236  +/+/+/+  −  +  LPL (MyD88+)  BM  −  22  45/M  Syn  −  −  −  8  14.2  12.9  10.4  1.27  313  +/+/−/+  +  +  LPL (MyD88+)  BM  NA  Patient No.  Age (y)/Sex  Order of Presentation and Interval  AI  Splenomegaly  Tx  HB (g/dL)  WBC (×109/L)  L Count (×109/L)  LGL Count (×109/L)  ANC (×109/L)  Platelet (×109/L)  Immunopheno- type ( CD8/CD16/ CD56/ CD57)  Rx for T-LGL  Clonality (PCR)  BCL  Site  EBER  14  58/F  B>T, 3 y  −  −  BM (Allo)  10.1  8.9  7.3  NA  0.9  11  +/−/−/+  +  +  FL  EN    15  53/M  B>T, 5.5 y  −  Splenectomy  BM (Allo)  10.7  16.5  10.9  NA  3.8  187  +/−/−/+  +  +  MCL  N  10  16  63/M  B>T, 3 y  −  Splenectomy  −  11.8  8.2  3.0  1.9  3.0  217  +/+/+/+  −  +  Splenic MZL, and later HL nodular sclerosis type  Spleen, HL-N  −  17  61/F  HL>B>T, 21 y, 2 y  −  −  −  11.4  2.8  1.99  NA  0.53  147  +/−/−/+  +  +  HL, MALT  NA EN    18  47/F  B>T, 10 y  RA  −  −  12.3  2.4  0.69  NA  1.3  211  +/NA/−/+  +  +  MALT  EN    19  49/F  T>B, 5 mo  −  −  −  12.1  2.9  2.23  1.6  0.26  207  +/+/−/+  −  +  LGBCL-PD  N  −  20  79/M  T>B, 5 mo  −  −  −  9.7  3.2  2.1  1.8  0.96  140  +/+/−/+  +  +  MALT  Colon  NA  21  63/M  T>B, 2 mo Considered syn  −  −  −  11.8  5.8  3.19  1.3  1.9  236  +/+/+/+  −  +  LPL (MyD88+)  BM  −  22  45/M  Syn  −  −  −  8  14.2  12.9  10.4  1.27  313  +/+/−/+  +  +  LPL (MyD88+)  BM  NA  −, negative; +, positive; >, precede; AI, autoimmune disease; Allo, allogeneic; ANC, absolute neutrophil count; B, B-cell lymphoma; BCL, B-cell lymphoma; BM, bone marrow; B-NHL, B-cell non-Hodgkin lymphoma; EN, extranodal; FL, follicular lymphoma; HB, hemoglobin; HL, Hodgkin lymphoma; L, lymphocyte; LGBCL-PCD, low-grade B-cell lymphoma with plasmacytic differentiation; LPL, lymphoplasmacytic lymphoma; MALT, extranodal marginal zone lymphoma of mucosa associated lymphoid tissue; MCL, mantle cell lymphoma; MZL, marginal zone lymphoma; N, nodal; NA, not available; RA, rheumatoid arthritis; Rx, treatment; Syn, synchronous; T, T-cell large granular lymphocytic leukemia; Tx, transplant. View Large Splenomegaly was found in one patient. Patients 15 and 16 had a history of splenectomy. In one patient (patient 15), splenectomy was done as part of the treatment for lymphoma. In another patient (patient 16), splenic MZL was diagnosed on splenectomy performed for possible immune thrombocytopenic purpura. Patient 18 had a history of rheumatoid arthritis. No patient had a history of solid organ transplant. Two patients (patients 14 and 15) received allogeneic bone marrow transplant for a preceding BCL. Three patients had dysgammaglobulinemia. Two patients (patients 17 and 21) had coexisting MGUS and one patient (patient 21) had hypergammaglobulinemia. No patient had hypogammaglobulinemia. Six patients (66%) had anemia and neutropenia. Four (44.4%) patients had leukopenia, one (11.1%) had thrombocytopenia, and one (11.1%) had lymphopenia. T-LGL counts were available in five patients and varied from 1.3 to 10.4 × 109/L. Bone marrow biopsy showed an interstitial/sinusoidal infiltrate of T-LGLs in all the patients involving 10% to 50% of the marrow cellularity in eight patients. In one case, the quantification data were not available. Based on the immunophenotypic data, two patients expressed CD56 and seven patients were negative for CD56. None of the patients had CD4+/CD8+ or CD4+/CD8− immunophenotype. PCR-based gene rearrangement studies were performed on all the patients. Monoclonal T-cell gene rearrangements were identified in all nine patients. Seven patients had a metachronous occurrence. The time interval between the two lymphoid neoplasms ranged from 5 months to 10 years. Five patients had a small BCL preceding T-LGL leukemia. The spectrum of small BCLs included FL (patient 14), mantle cell lymphoma (patient 15), splenic MZL (patient 16), and extranodal marginal zone BCL of mucosa-associated lymphoid tissue (MALT) (patients 17 and 18). The patient (patient 16) with splenic MZL later developed synchronous T-LGL leukemia and classical HL of nodular sclerosis type. Patient 17, who had a remote history of HL, developed a λ-restricted pulmonary MALT lymphoma 19 years later. This patient also had an associated IgG lambda MGUS. The clonal relation between the MALT lymphoma and MGUS was not known. Patient 18, with a thymic MALT lymphoma, had rheumatoid arthritis. T-LGL leukemia preceded BCL in two patients. Patient 19 developed a nodal LGBCL-PD, and patient 20 was diagnosed with an MALT lymphoma of the descending colon 5 months after the T-LGL leukemia diagnosis. Another patient with T-LGL leukemia (patient 21) was diagnosed with LPL in the bone marrow after 2 months of initial diagnosis, which was considered synchronous. This patient had a coexisting IgM λ paraproteinemia. One patient (patient 22) was diagnosed synchronously with LPL and T-LGL leukemia. All the patients received therapy for their BCL and HL. Six patients received treatment for T-LGL leukemia. The mean follow-up time was 72 months (range, 48-132 months) from the first diagnosis. Six patients were alive at the time of last review of medical records, with median follow-up of 68.5 months (range, 60-132 months). Three patients died at 48, 75, and 90 months after the diagnosis of BCL. Comparing the features of patients with large BCLs to those with small BCLs, we noticed some differences. In patients with large BCLs, the T-LGL leukemias appeared to occur more frequently in the setting of bone marrow transplantation compared to small BCLs. This may relate to the propensity to treat relapsed DLBCL with stem cell transplantation and the known occurrence of T-LGL in the setting of hematopoietic stem cell transplantation.17 Even though the degree of cytopenias in the two groups were not statistically significant (P > .05), more patients in the small BCL group (6/9) received treatment for T-LGL leukemia, as compared to the large BCL group (5/13). Discussion The most notable finding of this study is the identification of 13 patients with large BCLs in association with T-LGL leukemia, in addition to nine small B-NHLs with this association. While a number of small BCLs are described previously in case reports and case series, only two patients with de novo DLBCL and one case of transformed low-grade lymphoma in association with T-LGL leukemia are reported in the literature, to the best of our knowledge. The most common B-cell lymphoproliferative disorders reported are MGUS, CLL, and HCL. When limited to patients with B-NHL, we identified more patients with large BCLs than small BCLs likely due to the exclusion of CLL and HCL patients, which are reported as the most common small BCLs in association with T-LGL leukemia. In the case report by Anoop et al,16 a 74-year-old man had incidental lymphocytosis and neutropenia. He was treated with methotrexate for neutropenia. Two years later he developed an Epstein-Barr virus (EBV) negative DLBCL of germinal center in the inguinal lymph node. There could be a possible contribution of methotrexate-related immunosuppression in the development of this large-cell lymphoma in the setting of T-LGL. In our series, we had only one case in which an EBV-negative extranodal DLBCL, NOS, developed after T-LGL leukemia. This patient never received treatment for T-LGL leukemia. The majority of large BCLs in our series either preceded or occurred synchronously with T-LGL leukemia. To the best of our knowledge, there is only one similar case reported in the literature.17 In the case described by Viny et al,8 the patient had a DLBCL transformed from a preexisting FL. We identified two similar patients with preexisting, low-grade small BCLs who subsequently developed DLBCL. The occurrence of T-LGL leukemia in the setting of synchronous or prior DLBCL suggests that the DLBCL may set up an immune environment conducive to the T-LGL proliferation, which might include an antigenic stimulus for the proliferation. T-LGL leukemia can precede, follow, or present synchronously with BCLs. T-LGL leukemias preceding BCLs appear to be rare. There is only one case report in the literature, and we identified three such patients in this multicenter study. This co-occurrence could be a coincidence. Underlying infection, generalized immune and B-cell dysregulation, or possibly T-LGLs acting as an antigenic trigger are other possible explanations. T-LGL leukemia commonly follows or occurs synchronously with BCLs. In 19 out of 22 patients, BCL either preceded (14 patients) or was diagnosed synchronously (5 patients) with T-LGL in our series. Various possible mechanisms might link these two processes. One possible hypothesis is a clonal expansion of T-LGLs in response to the BCL as an antigenic trigger. This expansion might have a role in tumor surveillance. In the series reported by Viny et al,8 none of the T-LGL leukemia patients with MGUS progressed to plasma cell myeloma and one patient even had spontaneous remission of both T-LGL leukemia and MGUS. How this immune surveillance might impact the course of BCL requires further investigation. Another possibility is a common antigenic drive for concomitant T- and B-cell proliferations in the setting of autoimmune disease, viral infections, or organ transplants. This is supported by the synchronous presence of these two processes in five patients. Coexisting BCLs and T-LGL leukemia are likely to be clonally unrelated. However, formal clonal relatedness studies were not performed and are beyond the scope of this study. As expected, patients with T-LGL leukemia in our series commonly manifested with cytopenias. Neutropenia is the most common cytopenia reported in T-LGL leukemia patients. In contrast, patients with BCLs in our series had a slightly higher incidence of anemia (68%) as compared to neutropenia (63%). This could be due to underlying lymphomas and related therapy. A similar high incidence of anemia was reported in a T-LGL leukemia developing in post kidney transplant patients18 who might also be expected to manifest with anemia due to the underlying condition. Rheumatoid arthritis does not appear to have a strong association in the subset of T-LGL leukemia patients with BCLs because we identified only one patient with rheumatoid arthritis as compared to the reported incidence of 25% to 33% in T-LGL leukemia patients.1 CD56 expression is a marker of aggressive clinical course in T-LGL leukemia.19 CD56 was expressed in nine (41%) of the patients in our series, but only three of those patients received treatment for T-LGL leukemia. The other eight patients who received therapy for the T-LGL leukemia were CD56 negative. Thus, we cannot confirm CD56 as a reliable marker of aggressive disease requiring active therapy. Our study is the first multicenter retrospective study looking at the frequency of BCLs occurring in T-LGL leukemia. Since this is a retrospective study, it was difficult to obtain complete information on some patients, and this is an acknowledged limitation. 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Journal

American Journal of Clinical PathologyOxford University Press

Published: Feb 1, 2018

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