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The presence of expanded proliferation centers (PCs) in lymph nodes involved by chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma has been associated with adverse clinical outcomes, but the frequency and significance of PCs in bone marrow (BM) remain unclear. The study group included 36 patients with BM involvement by CLL in which PCs were present. We compared this group with 110 randomly selected BM samples involved by CLL without morphologically discernable PCs. Patients with PCs in BM were younger (median age, 53 years [range,18-71 years] versus 58 years [range, 31-82 years]; P = .007), more frequently experienced B symptoms (27.8% versus 8.2%, P = .0076), more often had Rai stage IV disease (30.6% versus 17.3%, P = .02) and higher serum lactate dehydrogenase (P = .0037) and β 2 -microglobulin (P = .0001) levels, and lower hemoglobin (P = .026) and platelet counts (P = .0422). TP53 alterations were more common in patients with PCs in BM (45.4% versus 18.7%; P = .0049), as was a complex karyotype (26.4% versus 9%; P = .019). There were no significant differences in the frequency of ZAP70 or CD38 positivity or IGHV mutation status. The median time to first treatment was shorter in patients with PCs in BM (7 months versus 19 months, P = .047), and the frequency of Richter syndrome was higher (14% versus 4%, P = .041). Patients with PCs in BM had significantly shorter overall survival compared with the control group (median, 249.3 months versus undefined; P = .0241). These data suggest that identification of PCs in BM samples involved by CLL is associated with adverse prognostic features., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Reactive germinal centers (GCs) in the bone marrow (BM) have been described in patients with autoimmune disorders, infections, malignancies, and following certain drug therapies, or as an isolated finding without obvious underlying disease. In this study, we describe the clinical conditions in which reactive GCs occur in BM samples, and their topography and accompanying laboratory and ancillary findings in the setting of a cancer center. We identified 32 BM specimens with reactive GCs with an estimated frequency less than 0.02% over a 12-year period. Fifteen (46.9%) BM specimens had concurrent hematolymphoid neoplasms: most often a variety of small B-cell lymphomas, but also myelodysplastic syndromes. One (3.1%) case was involved by metastatic melanoma. Isolated reactive GCs were observed in 16 (50%) patients. Most BM specimens (n = 25; 78.1%) showed only one reactive GC with a size ranging from 20 to 500 μm, and most GCs (29/32) were nonparatrabecular. GCs were positive for CD10 and BCL6, and were negative for BCL2. CD3 and CD5 demonstrated T cells surrounding the GC and CD21, and CD23 highlighted follicular dendritic cells. Reactive GCs are uncommon and can be seen in association with hematolymphoid and other types of neoplasms or as an isolated finding. Reactive GCs are usually located in a nonparatrabecular distribution. A panel of immunohistochemical stains is useful to confirm the nonneoplastic nature of these GCs to avoid misdiagnosis as lymphoma or as histologic evidence of transformation in a patient with small B-cell lymphoma in the bone marrow., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Rearrangements of FGFR1 result in the 8p11 myeloproliferative syndrome, a group of rare diseases that features a myeloproliferative neoplasm (MPN) that commonly progresses to lymphoblastic leukemia/lymphoma or acute myeloid leukemia. The most common partner of FGFR1 is ZMYM2, and patients with the ZMYM2-FGFR1 fusion often present with MPN and T-lymphoblastic lymphoma. There are 14 other partners that can fuse with FGFR1, and of interest is the BCR-FGFR1 fusion that results from t(8;22)(p11.2;q11.2). Patients with t(8;22) often show leukocytosis and present with an MPN resembling chronic myeloid leukemia or very rarely, with B-lymphoblastic leukemia (B-ALL). In this study, we analyzed the clinicopathological, cytogenetic, and molecular features of 2 new patients with the t(8;22)(p11.2;q11.2)/BCR-FGFR1 who presented with B-ALL. An underlying MPN became apparent when a morphologic remission of B-ALL was achieved after chemotherapy. We subsequently reviewed the literature and identified 18 additional cases reported with B-ALL in a background MPN or with the MPN as a chronic phase. Our data suggest that the t(8;22)(p11.2;q11.2)/BCR-FGFR1 may arise from a myeloid/B progenitor cell. It is important to recognize that neoplasms carrying the t(8;22)/BCR-FGFR1, although rare, can commonly with B lymphoblastic leukemia at the initial diagnosis, which could distract one from recognizing a possible underlying 8p11 myeloproliferative syndrome., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Hepatosplenic T-cell lymphoma (HSTCL) is a rare T-cell lymphoma commonly associated with cytopenias. The pathogenesis of cytopenias in patients with HSTCL is not well defined, although the presence of dyspoietic hematopoietic cells and the common association with trisomy 8 raise the possibility of an associated myelodysplastic syndrome (MDS). In 25 bone marrow specimens involved by HSTCL, we systematically assessed for morphologic features of dyspoiesis and correlated the findings with peripheral cytopenia(s), cytogenetic findings, and detection of chromosome 8 by fluorescence in situ hybridization. The median patient age was 33 years. One patient had a history of MDS diagnosed 1 year prior to the diagnosis of HSTCL. Thirteen (54%) patients had anemia less than 100 g/L, 10 (53%) of 19 had neutropenia less than 1.8 × 10(9)/L, and 15 (60%) had thrombocytopenia less than 100 × 10(9)/L. Dyspoietic features were identified in 1 to 3 hematopoietic cell lineages in 20 (80%) of 25 patients. Cytogenetic analysis identified trisomy 8 in 7 cases. Patients with trisomy 8 had a lower platelet count, but trisomy 8 was not associated with cytopenias, dyspoietic features, or cytogenetic abnormalities. Combined morphologic and fluorescence in situ hybridization analysis showed that trisomy 8 was restricted to the lymphoma cells, except in the 1 patient with a history of MDS. In conclusion, dyspoietic changes are common in the bone marrow of patients with HSTCL. These changes are not associated with cytopenias or chromosomal abnormalities, suggesting that dyspoiesis in patients with HSTCL is not a manifestation of a MDS., (Copyright © 2015 Elsevier Inc. All rights reserved.)

MLL gene rearrangements are well-recognized aberrations in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). In contrast, MLL gene amplification in AML/MDS remains poorly characterized. Here, we report a series of 21 patients with myeloid neoplasms associated with MLL gene amplification from 1 institution. This series included 13 men and 8 women, with a median age of 64 years. Eleven patients presented as AML with myelodysplasia-related changes, 6 as therapy-related AML, and 4 as therapy-related MDS. All patients had a highly complex karyotype, including frequent -5/del(5q), -18, and -17/del(17p) abnormalities; 16 patients were hypodiploid. TP53 mutations were detected in all 12 patients tested, and 3 patients showed TP53 mutation before MLL amplification. Morphologically, the leukemic cells frequently showed cytoplasmic vacuoles, bilobed nuclei, and were associated with background dyspoiesis. Immunophenotypically, 15 patients had a myeloid and 4 had myelomonocytic immunophenotype. Laboratory coagulopathies were common; 7 patients developed disseminated intravascular coagulopathy, and 3 died of intracranial bleeding. All patients were refractory to therapy; the median overall survival was 1 month, after MLL gene amplification was detected. We concluded that AML/MDS with MLL gene amplification is likely a subset of therapy-related AML/MDS or AML with myelodysplasia-related changes, associated with distinct clinicopathological features, frequent disseminated intravascular coagulopathy, a highly complex karyotype, TP53 deletion/mutation, and an aggressive clinical course., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Mantle cell lymphoma (MCL) and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) share many features and both arise from CD5+ B-cells; their distinction is critical as MCL is a more aggressive neoplasm. Rarely, cases of composite MCL and CLL/SLL have been reported. Little is known about the nature of these cases and, in particular, the clonal relationship of the 2 lymphomas. Eleven composite MCL and CLL/SLL cases were identified. The clinical, morphologic and immunophenotypic features of the MCL and CLL/SLL were characterized. IGH (immunoglobulin heavy chain) gene analysis was performed on microdissected MCL and CLL/SLL components to assess their clonal relationship. Ten patients had lymphadenopathy, and 7 patients had bone marrow involvement. The MCL component had the following growth patterns: in situ (n = 1), mantle zone (n = 3), nodular and diffuse (n = 3), diffuse (n = 3), and interstitial in the bone marrow (the only patient without lymphadenopathy) (n = 1); 6 MCLs had blastoid or pleomorphic and 5 small lymphocytic features. The CLL/SLL component was nodular (n = 9) or diffuse (n = 2). All MCL were CD5(+) and cyclin D1(+) with t(11;14) translocation. All CLL/SLL were CD5(+), CD23(+) and negative for cyclin D1 or t(11;14). IGH gene analysis showed that the MCL and CLL/SLL components displayed different sized fragments, indicating that the MCL and CLL/SLL are likely derived from different neoplastic B-cell clones. The lack of a clonal relationship between the MCL and CLL/SLL components suggests that MCL and CLL/SLL components represent distinct disease processes and do not share a common progenitor B-cell., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Skeletal integrity is sustained by osteoblast-osteoclast interactions, controlled by several signaling pathways that include tyrosine kinases. Imatinib is a tyrosine kinase inhibitor with an extended therapeutic range based on its ability to differentially bind to receptor and nonreceptor tyrosine kinases. In this study, we used digital image analysis to assess changes in trabecular bone surface area within bone marrow biopsy specimens of 34 patients with chronic phase chronic myelogenous leukemia treated with single-agent imatinib. These patients were 25 men and 9 women with a median age of 59 years. We selected representative areas of paired bone marrow biopsy specimens obtained at baseline and within the subsequent 48 months. Computer-assisted analysis was performed to calculate trabecular bone area (TBA) within the sample by using the equation TBA% = sum of trabecular area/total biopsy specimen area. Percentage changes were defined as ΔTBA% and were arbitrarily subdivided into marked (>50%), moderate (10%-50%), and mild (<10%). During the study interval, TBA% increased in 24 patients (71%) and decreased in 10 patients (29%). Overall, there was a significant increase in TBA% (P = .02). No correlation was found between changes in trabecular bone area and either clinical or cytogenetic response (P = .25). The results show that imatinib therapy can alter trabecular bone in bone marrow biopsy specimens of chronic myelogenous leukemia patients, most often resulting in an increase in TBA%., (Copyright © 2012 Elsevier Inc. All rights reserved.)

B-lymphoblastic leukemia/lymphoma, also known as B-acute lymphoblastic leukemia, is derived from B-cell progenitors. B-acute lymphoblastic leukemia occurs predominantly in children, but can occur at any age. Risk-adapted intensive chemotherapy is effective in treating most children with B-acute lymphoblastic leukemia, but this approach is less successful in adults. Recent developments in genome-wide genetic analysis in B-acute lymphoblastic leukemia have provided insights into disease pathogenesis and prognosis. B-acute lymphoblastic leukemia cases usually carry a primary genetic event, often a chromosome translocation, and a constellation of secondary genetic alterations that are acquired and selected dynamically in a nonlinear fashion. These genetic changes commonly affect cellular mechanisms that control B-cell differentiation and proliferation. The cooperative interaction between inactivation of hematopoietic transcription factors involved in differentiation (class II mutation) and activating mutations involved in cell proliferation (class I mutation) is reminiscent of the pathogenic model of acute myeloid leukemia. The resulting improved molecular understanding of B-acute lymphoblastic leukemia is helping to refine disease risk stratification and discover new therapeutic approaches for patients with refractory disease. In this review, we first summarize the clinicopathologic and immunophenotypic features of B-acute lymphoblastic leukemia and introduce current understanding of B-cell development and B-acute lymphoblastic leukemia leukemogenesis. We then focus on recent advances in genetic analysis and gene expression profiling of B-acute lymphoblastic leukemia and discuss the implications of these findings for disease evolution, risk prediction, and possible novel therapeutic approaches., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Composite lymphoma is a rare circumstance in which 2 or more distinct types of lymphoma occur in a single anatomical location. Although composite lymphoma has been increasingly identified with the advent of molecular genetic techniques, this topic has only rarely been a specific focus of the medical scientific literature. In this review, we focus on mantle cell lymphoma occurring as a major pathologic component of composite lymphoma and emphasize the clinicopathologic features of these tumors and associated biologic implications. To date, 26 cases of composite lymphoma including a component of mantle cell lymphoma have been previously published. Issues of clonal relatedness between the individual lymphoma components and emerging biologic implications as well as potential diagnostic pitfalls are evaluated., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Angioimmunoblastic T-cell lymphoma is known to frequently involve bone marrow. However, the histologic and immunophenotypic features of angioimmunoblastic T-cell lymphoma at this site are poorly defined. We assessed 27 bone marrow specimens involved by angioimmunoblastic T-cell lymphoma from 20 patients. Histologically, bone marrow involvement was predominantly multifocal (74%) and exhibited a nodular pattern (78%), often associated with other patterns. Using immunohistochemistry, programed death-1 and CD10 were expressed by atypical lymphocytes in 17 (85%) of 20 and 5 (18.5%) of 27 specimens, respectively. CXCL13 was not expressed by atypical lymphocytes in all cases but did stain stromal cells consistent with follicular dendritic cells in 1 case. BCL-6 as a single antibody was difficult to interpret because many normal bone marrow cells are dimly positive, but BCL-6/CD3 dual staining highlighted BCL-6+ T-cells in all cases assessed. Antibodies specific for CD21 and CD35 did not highlight follicular dendritic cells in any biopsy specimens. Flow cytometry immunophenotyping revealed a CD3+CD10+ T-cell population in 2 (25%) of 8 cases assessed. We conclude that the recognition and classification of angioimmunoblastic T-cell lymphoma in bone marrow are made difficult by the uncommon expression of CD10 (25%), rarity of follicular dendritic cells, and lack of CXCL13 expression at this site. This is most likely attributable to the very different microenvironment of the bone marrow relative to lymph nodes and, in particular, the absence of follicles in bone marrow. By contrast, programed death-1 immunohistochemical staining and double labeling using antibodies specific for BCL-6 and CD3 were helpful in appreciating the follicular T-helper cell immunophenotype of angioimmunoblastic T-cell lymphoma.

The nuclear transcription factor NF-kappa B regulates cell survival, proliferation, and differentiation. Little is known about NF-kappa B in myeloid malignancies. In this report, we assessed NF-kappa B in a group of myeloid neoplasms by using an electrophoretic mobility shift assay (EMSA) and immunofluorescence methods in freshly isolated leukemia cells. We analyzed 30 cases of acute myeloid leukemia (AML), 5 cases of myelodysplastic syndrome (MDS), 3 cases of chronic myelomonocytic leukemia (CMML), 15 cases of chronic myeloid leukemia in chronic phase (CML-CP), and 2 cases of chronic myeloid leukemia in blast crisis (CML-BC). Unstimulated cells (bone marrow and peripheral blood) from 17 normal donors and apheresis samples from 6 peripheral blood stem cell donors treated with granulocyte colony-stimulating factor (G-CSF) were used as controls. When EMSA was used, NF-kappa B was elevated in 14 of 30 (47%) cases of AML, in both cases of CML-BC, and in all reference donors treated with G-CSF, but it was at basal levels in all cases of MDS and CML-CP and in normal donors (P = <.01). Immunofluorescence analysis confirmed strong nuclear RelA/NF-kappa B immunoreactivity in AML blasts but not in normal bone marrow. Bcl-2, a downstream molecule, was expressed in cases with elevated NF-kappa B, but not in cases with basal levels of NF-kappa B, suggesting that NF-kappa B is active and provides the cells with survival advantages in vivo. These results suggest that suppression of NF-kappa B may be a useful therapeutic strategy for a subset of patients with AML.