Histone deacetylase 1, 2, 6 and acetylated histone H4 in B- and T-cell lymphomas

Aims:  Histone deacetylase (HDAC) inhibitors are novel therapeutics in the treatment of peripheral T-cell lymphoma, unspecified (PTCL) and diffuse large B-cell lymphoma (DLBCL), where, for unknown reasons, T-cell malignancies appear to be more sensitive than B-cell malignancies. The aim was to determine HDAC expression in DLBCL and PTCL which has not previously been investigated.
Methods and results:  The expression of HDAC1, HDAC2, HDAC6 and acetylated histone H4 was examined immunohistochemically in 31 DLBCL and 45 PTCL. All four markers showed high expression in both DLBCL and PTCL compared with normal lymphoid tissue. HDAC1 was more abundantly expressed in PTCL than in DLBCL ( P  = 0.0046), whereas acetylated H4 was more frequent in DLBCL ( P  < 0.0001), the latter suggesting a mechanism for T-cell lymphoma sensitivity to HDAC inhibitors. Moderate to strong HDAC6 expression was significantly correlated with favourable outcome ( P  = 0.016) in DLBCL patients, whereas the opposite effect was observed in PTCL patients ( P  < 0.0001). The other markers did not correlate with survival ( P  > 0.05).
Conclusions:  HDAC1, HDAC2, HDAC6 and acetylated H4 are overexpressed in DLBCL and PTCL relative to normal lymphoid tissue. Furthermore, HDAC6 may be an important prognostic marker associated with favourable outcome in DLBCL and a more aggressive course in PTCL.     

Concurrent classical Hodgkin lymphoma and plasmablastic lymphoma in a patient with chronic lymphocytic leukemia/small lymphocytic lymphoma treated with fludarabine: a dimorphic presentation of iatrogenic immunodeficiency-associated lymphoproliferative disorder with evidence suggestive of multiclonal transformability of B cells by Epstein-Barr virus

A small fraction of patients with chronic lymphocytic leukemia/small lymphocytic lymphoma develop Epstein-Barr virus–positive B-cell lymphoproliferative disorders. These Epstein-Barr virus–B-cell lymphoproliferative disorders are thought to be related to immune suppression induced by fludarabine/other chemotherapeutic regimens. As in other immunodeficiency-associated lymphoproliferative disorders, these disorders demonstrate a heterogeneous histological spectrum that ranges from polymorphic to monomorphic to classical Hodgkin lymphoma–like lesions. We report a case of concurrent classical Hodgkin lymphoma and plasmablastic lymphoma in a patient with chronic lymphocytic leukemia/small lymphocytic lymphoma treated with fludarabine. Both classical Hodgkin lymphoma and plasmablastic lymphoma were positive for Epstein-Barr virus-encoded RNA, whereas classical Hodgkin lymphoma was also positive for Epstein-Barr virus- latent membrane protein 1, suggesting a different viral latency. Immunoglobulin gene rearrangement studies demonstrated distinct clones in the plasmablastic lymphoma and chronic lymphocytic leukemia/small lymphocytic lymphoma. These findings suggest biclonal secondary lymphomas associated with iatrogenic immunodeficiency. Epstein-Barr virus–B-cell lymphoproliferative disorders in the setting of chronic lymphocytic leukemia/small lymphocytic lymphoma, in particular those arising after chemotherapy, should be separated from true Richter's transformation, and be categorized as (iatrogenic) immunodeficiency-associated lymphoproliferative disorder.     

T-cell/histiocyte-rich large B-cell lymphoma is a disseminated aggressive neoplasm: differential diagnosis from Hodgkin's lymphoma

AIMS: An accurate diagnosis of T-cell/histiocyte-rich large B-cell lymphoma needs to take into consideration those forms of Hodgkin's lymphoma also characterized by a predominance of small lymphocytes and histiocytes, i.e. nodular lymphocyte predominance Hodgkin's lymphoma and lymphocyte-rich classical Hodgkin's lymphoma. We have studied the clinical, phenotypic and genetic features of a series of 12 cases of T-cell/histiocyte-rich large B-cell lymphoma along with 18 cases of Hodgkin's lymphoma for comparative purposes. METHODS AND RESULTS: Of the Hodgkin's lymphoma cases, there were 11 lymphocyte predominance type and seven classic type. T-cell/histiocyte-rich large B-cell lymphomas presented usually in advanced stages (III or IV in 11/12 cases), frequently with 'B' symptoms (6/9 cases), and followed a more aggressive course than Hodgkin's lymphoma (4/8 patients died due to the tumour in T-cell/histiocyte-rich large B-cell lymphoma versus 0/15 in Hodgkin's lymphoma). T-cell/histiocyte-rich large B-cell lymphoma cases showed diffuse effacement of the nodal architecture by a proliferation of scattered large atypical B-cells obscured by a background of small T-lymphocytes (more CD8+, TIA1+ than CD57+). Five cases showed also a prominent histiocytic component. The large B-cells expressed CD45 and often EMA (6/10 cases). On the other hand, CD 30, CD15 and latent infection by Epstein-Barr virus (EBV) were generally lacking. bc l6 and CD10 were, respectively, detected in 6/6 and 1/5 cases. Conventional polymerase chain reaction (PCR) showed monoclonal immunoglobulin heavy chain (IgH) gene rearrangements in all T-cell/histiocyte-rich large B-cell lymphomas studied (5/5), but did not detect any case with t(14;18) involving the major breakpoint region (0/4). CONCLUSIONS: The differential diagnosis of T-cell/histiocyte-rich large B-cell lymphoma from Hodgkin's lymphoma is facilitated by the integration of different immunophenotypic, molecular and clinical findings. T-cell/histiocyte-rich large B-cell lymphoma is a monoclonal neoplasm of bc l6+ B-cells with a phenotypic profile similar to lymphocyte predominance Hodgkin's lymphoma, suggesting a germinal centre origin and a possible relation to this disease. Therefore, in order to distinguish it from lymphocyte predominance Hodgkin's lymphoma, characterization of the reactive background, IgH gene rearrangement studies by conventional PCR and clinical features are more useful. In contrast, T-cell/histiocyte-rich large B-cell lymphoma can be distinguished from classical Hodgkin's lymphoma thanks to the presence of monoclonal IgH rearrangement and the CD 30-CD15-CD45+EMA+ immunophenotypic profile of the neoplastic cells in T-cell/histiocyte-rich large B-cell lymphoma.     

Programmed death 1 is a marker of angioimmunoblastic T-cell lymphoma and B-cell small lymphocytic lymphoma/chronic lymphocytic leukemia

Programmed death 1 (PD-1) is a lymphoid receptor that negatively regulates immune responses. PD-1 expression was recently reported in some T-cell non-Hodgkin lymphoma (NHL) subtypes, but the expression profile of PD-1 and its ligands (PD-L1 and PD-L2) in B-NHLs remains largely to be characterized. To investigate this issue, monoclonal antibodies against PD-1, PD-L1, and PD-L2 were generated by immunization of balb-c mice. A series of 161 lymphoma tissue and 11 blood samples was analyzed using either immunohistochemistry or flow cytometry. In reactive lymph nodes, PD-1 was mainly expressed in follicular T cells. In B-NHLs, PD-1 was mainly expressed in reactive T cells; but expression was also noted in neoplastic B cells from small lymphocytic lymphoma (SLL, 12/13), grade III follicular lymphoma (3/3), and diffuse large cell lymphoma (2/25). In contrast, neoplastic B cells from mantle cell lymphoma (0/11), marginal zone lymphoma (0/12), Burkitt lymphoma (0/3), and grade 1 to 2 follicular lymphoma (0/40) were PD-1 negative. PD-L1 and PD-L2 were negative in small B-cell lymphomas, including B-SLL. Flow cytometry showed that blood cells from chronic lymphocytic leukemia (B-CLL) also displayed PD-1 expression, which could be increased by CD40 stimulation. PD-1 expression in T-NHLs was restricted to the angioimmunoblastic subtype (8/8). These results show that PD-1 expression among B-NHLs is mainly associated with SLL/CLL and is influenced by activation of the CD40/CD40L pathway. Because the anti-PD-1.6.4 antibody works on paraffin sections, it represents a useful tool to differentiate SLL/CLL from other small B-cell lymphomas.     

T-cell-rich B-cell lymphoma presenting as liver disease

We describe a series of eight cases of T-cell-rich B-cell lymphoma diagnosed on liver biopsy and collected over a period of 15 years. Of seven cases that were referred from elsewhere, in only one was the correct diagnosis of B-cell lymphoma suggested. Common errors included misdiagnosis as inflammatory disease on histology, and misinterpretation as T-cell lymphoma on immunohistochemistry. However, the cases had a distinct morphological appearance and immunohistochemical profile. They showed a lymphohistiocytic or granulomatous infiltrate, usually centred on portal tracts and containing abundant small T-cells and scanty B-cell blasts. All patients had an atypical clinical presentation which favoured non-neoplastic liver disease. In seven cases liver involvement represented Stage IV disease and in one case disease was confined to the liver consistent with a primary hepatic lymphoma. Despite combination chemotherapy, the prognosis was poor with no patients surviving beyond 15 months from diagnosis. We believe T-cell-rich B-cell lymphoma to be an under-recognized subset of non-Hodgkin's lymphoma that may mimic primary liver disease.     

T-cell rich B-cell non-Hodgkin's lymphoma: a progressed form of follicle centre cell lymphoma and lymphocyte predominance Hodgkin's disease

T-cell rich B-cell non-Hodgkin's lymphoma (T-cell rich B-cell lymphoma) is a morphological variant of diffuse large B-cell lymphoma. It is important to recognize this variant in the differential diagnosis of T-cell non-Hodgkin's lymphoma. The main differential diagnosis of T-cell rich B-cell lymphoma, nodular and diffuse lymphocyte predominance Hodgkin's disease (lymphocyte predominance Hodgkin's disease), is, however, even more difficult and differentiating criteria are still not satisfactorily defined. Moreover, T-cell rich B-cell lymphoma may not represent a clinicopathological entity. Twelve cases of T-cell rich B-cell lymphoma, selected on the basis of morphology and limited immunohistochemistry without previous knowledge of clinical data, were studied by immunohistochemistry and polymerase chain reaction for bcl-2 rearrangements to investigate the histogenetic background. In three of 12 cases, bcl-2 rearrangements were found, strongly suggesting a follicle centre cell origin. In three other cases, a documented history of definite nodular lymphocyte predominance Hodgkin's disease 29 months to 20 years prior to the diagnosis of the lymphoma was present. No differences in growth pattern, residual nodularity, tumour cell distribution, cellular morphology and composition, or immunophenotypical differences were noted in these six cases as compared to the remaining cases. These data underscore the histogenetic diversity in T-cell rich B-cell lymphoma and identify it as a progressed form of lymphoma derived from entities as diverse as follicle centre cell lymphoma and nodular lymphocyte predominance Hodgkin's disease. Moreover, it shows a complete morphological overlap with the diffuse form of lymphocyte predominance Hodgkin's disease and may actually encompass this disease entity.     

Primary non-Hodgkin's lymphoma of the intestine: a morphological, immunohistochemical and clinical study of 31 Chinese cases

Thirty-one cases of primary non-Hodgkin's lymphoma of the intestine were investigated. Twenty-one were of B-cell and 10 of T-cell origin. The B-cell lymphomas comprised two cases of low-grade B-cell lymphoma of mucosaassociated lymphoid tissue (MALT), one of centroblastic/centrocytic type, three of high-grade B-cell lymphoma coexisting with a low-grade B-cell lymphoma of MALT, nine of centroblastic, three of immunoblastic and three of Burkitt type. Of the T-cell lymphomas, eight were of pleomorphic medium-to large-sized cell type and two of large cell anaplastic type. All the B-cell lymphomas expressed CD20 (L26) and/or Ki-B5; in six there was monotypic immunoglobulin light chain restriction. Membrane positivity for CD45RO (UCHL1) was observed in the 10 cases of T-cell lymphoma, but the tumour cells did not express monocyte-macrophage markers. Clinically, the patients with T-cell lymphomas were usually young males with constitutional symptoms and their prognosis was significantly worse than those of patients with intestinal B-cell lymphoma.     

Expression of Grb2 distinguishes classical Hodgkin lymphomas from primary mediastinal B-cell lymphomas and other diffuse large B-cell lymphomas

Growth factor receptor-bound protein 2 is an adaptor molecule that mediates B-cell receptor (BCR) signaling pathways, but the expression of growth factor receptor-bound protein 2 in lymphoma tissues has not been reported. We sought to characterize growth factor receptor-bound protein 2 protein expression in reactive tonsillar tissues and lymphoma tissues obtained from diagnostic biopsies of classical Hodgkin lymphoma, primary mediastinal large B-cell lymphoma, diffuse large B-cell lymphoma, nodular lymphocyte predominant Hodgkin lymphoma, and 20 low-grade B-cell lymphomas. Growth factor receptor-bound protein 2 expression was assessed in tissues by immunohistochemistry and in lymphoma cell lines by immunoblotting. In reactive lymphoid tissues, growth factor receptor-bound protein 2 was expressed in the cytoplasm of B-cells and histiocytes but not T-cells. Strong, cytoplasmic growth factor receptor-bound protein 2 expression was seen in the neoplastic cells of follicular lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma, splenic marginal zone lymphoma, primary mediastinal large B-cell lymphoma, diffuse large B-cell lymphoma, and nodular lymphocyte predominant Hodgkin lymphoma. In contrast, only 10% of the classical Hodgkin lymphomas showed growth factor receptor-bound protein 2 expression in the neoplastic cells. Growth factor receptor-bound protein 2 protein expression was detected by Western blotting in all lymphoma cell lines tested with higher levels in primary mediastinal large B-cell lymphoma compared with classical Hodgkin lymphoma cell lines. These findings support a role for growth factor receptor-bound protein 2 in the diagnostically challenging workup of classical Hodgkin lymphoma versus primary mediastinal large B-cell lymphoma and warrant further studies to evaluate the biologic significance of growth factor receptor-bound protein 2 in the pathogenesis of classical Hodgkin lymphoma.     

Small lymphocytic lymphoma/chronic lymphocytic leukemia in a pelvic myelolipoma

Myelolipoma is a rare benign tumor composed of mature adipose tissue and normal hematopoietic elements. Extra-adrenal myelolipomas are extremely rare, with approximately 50% of cases occurring in the presacral region. We report a case of an 85 year old woman who presented with small bowel obstruction relating to a pelvic mass detected on computed tomography (CT) scan. At laparotomy, a 12-cm. pre-sacral mass was resected. Histologic examination showed a myelolipoma with dense lymphoid aggregates. On immunostains, the lymphoid aggregates showed positivity for CD20, CD5, and CD23, consistent with small lymphocytic lymphoma/chronic lymphocytic leukemia (SLL/CLL). Molecular evaluation confirmed the presence of a clonal B-cell lymphocytic proliferation that did not harbor BCL-2 or BCL-1 gene rearrangements. This case represents the first report of a myelolipoma involved by a non-Hodgkin lymphoma. The unique combination of these findings raises questions about the relationship between the two observed entities. The likeliest scenario is that an unusual benign tumor (myelolipoma) was colonized by a relatively common systemic hematopoietic neoplasm SLL/CLL, producing a collision tumor.     

The world health organization classification of malignant lymphomas in japan: incidence of recently recognized entities. Lymphoma Study Group of Japanese Pathologists

New insights into the immunology and genetics of malignant lymphomas have allowed the recognition of new entities and the refinement of previously recognized disease categories. The relative incidence of these subtypes of malignant lymphoma is also known to differ according to geographic location. In order to clarify the current status of malignant lymphomas in Japan and the relative incidences of their subtypes, 3194 patients were classified according to the new World Health Organization (WHO) classification. Among these were 3025 cases (94.71%) of non-Hodgkin's lymphoma (2189 cases (68.53%) of B-cell lymphoma, 796 cases (24.92%) of T-cell lymphoma) and 141 cases (4.41%) of Hodgkin's lymphoma. The incidences of the major subtypes of non-Hodgkin's lymphoma were 33.34% for diffuse large B-cell lymphoma, 8.45% for marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) type, 8.05% for plasma cell myeloma, 7.45% for adult T-cell leukemia/lymphoma (ATLL), 6.7% for follicular lymphoma, 6.67% for peripheral T-cell lymphoma of unspecified type, 2.79% for mantle cell lymphoma, 2.6% for nasal and nasal-type T/NK cell lymphoma, 2.35% for angioimmunoblastic T-cell lymphoma, and 2.35% for precursor B-cell lymphoblastic leukemia/lymphoma, in decreasing order. The other subtypes comprised less than 2%, mainly precursor T-cell lymphoblastic lymphoma/leukemia (1.72%), anaplastic large-cell lymphoma of T- and null-cell types (1.53%), and B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma (1.31%). The incidence of ATLL was influenced by its high percentage (19.20%) in the south-western Japanese island, Kyushu, an endemic area of human T-cell leukemia virus type 1 (HTLV-1), but which appeared to be lower than that in a previous study. The nodular sclerosis and mixed cellularity types of Hodgkin's disease occupied 1.78% and 1.63%, respectively. These data are distinct from those in Western countries and similar in several ways to those in the East, although the relatively high rate of ATLL was attributed to the geographical difference in the etiologic factor, HTLV-1.     

Peripheral T-cell lymphoma mimicking marginal zone B-cell lymphoma.

Peripheral T-cell lymphoma (PTCL) may assume a variety of histologic and cytologic appearances. We describe eight cases of PTCL morphologically simulating marginal zone B-cell lymphoma. We reviewed PTCL cases diagnosed in our institution between 1990 and 2000 and selected eight cases for study based on the following criteria: small-cell morphology with abundant, clear cytoplasm and either marginal zone involvement by the neoplastic infiltrate in lymph node biopsies or lymphoepithelial lesions in extranodal biopsies. Histologic features and ancillary studies were reviewed. Patients included six women and two men with a median age of 53 years (range, 35 to 74 years). Six patients were diagnosed with primary nodal PTCL, and two presented with primary extranodal disease. The original diagnosis was PTCL in only four cases; three cases were diagnosed as atypical lymphoid infiltrate, and one case as benign lymphoepithelial lesion. Lymph node biopsies revealed partial effacement of the architecture with residual follicles surrounded by the neoplastic small cells. Extranodal sites included hard palate, tongue, tonsil, and submandibular glands; all but one case demonstrated lymphoepithelial lesions. Monoclonality was demonstrated in six of eight cases (rearrangement of T-cell receptor gene), and three of eight had an aberrant T-cell population by flow cytometry. The differential diagnosis of atypical lymphoid infiltrates with morphologic features of marginal zone B-cell lymphoma should include PTCL. This uncommon morphological mimicry should be recognized, because PTCL is an aggressive disease regardless of morphology and should be treated accordingly.     

Epstein-Barr virus-associated B-cell lymphoproliferative disorders in angloimmunoblastic T-cell lymphoma and peripheral T-cell lymphoma, unspecified

Various patterns of Epstein-Barr virus (EBV)-associated B-cell lymphoproliferation occur in patients with immunodeficiency. We studied 17 cases of T-cell lymphoma displaying extensive EBV-driven B-cell lymphoproliferation or simultaneous/subsequent EBV-associated B-cell lymphoma. In 10 cases of angioimmunoblastic T-cell lymphoma, an uncommonly prominent population of EBV+ atypical, activated, focally confluent large transformed B cells was found in the background of T-cell lymphoma. In 4 cases, an EBV-associated B-cell neoplasm (3 diffuse large B-cell lymphomas, 1 plasmacytoma) occurred in patients with T-cell lymphoma. Three cases were composite lymphomas of a peripheral T-cell lymphoma, unspecified, combined with EBV-associated diffuse large B-cell lymphoma. The transformed B-cell population displayed EBV latency types 2 and 3. Monoclonal and oligoclonal B-cell populations were detected in 5 and 6 cases, respectively. Similar to other states of immunodeficiency, disease-related and therapy-induced immunosuppression in T-cell lymphoma may lead to a prominent EBV-associated B-cell lymphoproliferation and to EBV+ B-cell neoplasms.     

Primary cutaneous B-cell lymphoma with abundant reactive gamma/delta T-cells within the skin lesion and peripheral blood

T-cell/histiocyte-rich diffuse large B-cell lymphoma is characterized by abundant reactive T-cell and histiocyte infiltration within nodal diffuse large B-cell lymphoma, and only limited cases of primary cutaneous T-cell-rich B-cell lymphoma have been documented. These reactive T-cells usually show a T-helper phenotype. Gamma/delta T-cell is a functionally distinct T-cell lineage, which constitutes on average 5% of all T-cells in the peripheral blood. Herein, we report the first documented case of primary cutaneous malignant B-cell lymphoma with abundant reactive gamma/delta⁺ T-cells within the skin lesion and peripheral blood. An 80-year-old Japanese male presented with a gradually enlarged knee nodule. Histopathological study revealed diffuse infiltration of lymphoid cells in the dermis and subcutis. Proliferation of large-sized atypical lymphoid cells was observed among medium-sized lymphocytes with convoluted nuclei. Immunohistochemically, these large-sized atypical lymphocytes were CD20⁺, and relatively many gamma/delta⁺ cell infiltration was also noted. Flowcytometric analysis revealed deviation of lambda+ cells (lambda/kappa 58) and increase of CD3⁺ gamma/delta⁺ cells (6%). Peripheral blood had CD3⁺ gamma/delta⁺ cells (28.8%). Rearrangement of immunoglobulin heavy chain, but not of T-cell receptor beta and gamma chains, was observed. Accordingly, an ultimate diagnosis of cutaneous B-cell lymphoma with abundant reactive gamma/delta⁺ cells was made. Recent studies have shown reactive gamma/delta⁺ T-cell infiltration and/or elevation in the peripheral blood in patients with various types of carcinoma, and that they play a role in the pathogenesis of some carcinomas. Therefore, additional analysis is needed to clarify the role of reactive gamma/delta⁺ T-cells in malignant lymphoma.     

Peripheral T-cell lymphoma of Lennert type complicated by monoclonal proliferation of large B-cells

A 69-year-old man presented with lymph node swelling in the right inguinal region. A biopsy was made (LN1) and diagnosed as peripheral T-cell lymphoma. The lesion remitted completely over a period of about 51 months after combination chemotherapy, but erythematous papules, systemic lymphadenopathy, and fever of 38° appeared. Skin (S1) and lymph nodes (LN2) were biopsied. Erythematous papules once disappeared spontaneously, but appeared again and were biopsied (S2). LN1 displayed the typical histologic and immunohistochemical features of Lennert lymphoma, i.e., diffuse proliferation of small to large lymphoid cells of CD3+, CD4+, CD8− immunophenotype accompanied by numerous clusters of epithelioid histiocytes. In LN2, the large cells with CD3+, CD4+, CD8− decreased in number, while numerous CD20+ large cells were discernible. Clonality analysis revealed the persistent presence of an identical T-cell clone in LN1 and LN2. Clonal bands of immunoglobulin heavy (IgH) chain gene were detected in LN2 but not in LN1. S1 and S2 showed diffuse proliferation of small to large lymphoid cells of CD20−, CD3+, CD4+, CD8− in the upper dermis, with obvious epidermotropism. Clonality analysis revealed the presence of a T-cell clone identical to LN1 and LN2 with no B-cell clone, indicating the recurrence of PTCL. In situ hybridization (ISH) for Epstein-Barr virus (EBV) genome revealed that positive signals in the nucleus of large B-lymphoid cells appeared only in LN2.     

Histiocyte-rich, T-cell-rich B-cell lymphoma: a distinct diffuse large B-cell lymphoma subtype showing characteristic morphologic and immunophenotypic features

AIMS: The clinicopathological features of histiocyte-rich, T-cell-rich B-cell lymphoma (HRTR-BCL) were first recognized in 1992. In this study, 60 cases of HRTR-BCL were analysed in order to provide a detailed morphological and immunophenotypical profile of the disorder. METHODS AND RESULTS: HRTR-BCL is easily distinguished from other B-cell lymphomas rich in stromal T-cells by (i) a diffuse or vaguely nodular growth pattern, (ii) the presence of a minority population of CD15-, CD20+ large neoplastic B-cells, (iii) a prominent stromal component composed of both T-cells and non-epithelioid histiocytes, and (iv) the scarcity of small reactive B-cells. These criteria also enable a reliable distinction from lymphocyte-rich classical Hodgkin's lymphoma (CHL), from lymphocyte-predominant Hodgkin's lymphoma (LPHL), paragranuloma type and from peripheral T-cell lymphoma. Based on the morphology of the neoplastic cells and on their frequent bcl-6 immunoreactivity, we speculate that HRTR-BCL may be derived from a progenitor cell of germinal centre origin. CONCLUSIONS: HRTR-BCL presents characteristic clinical features, affecting predominantly middle-aged men who present with advanced stage disease and are at high risk of treatment failure. Considering these distinctive clinicopathological features, recognizing HRTR-BCL as a lymphoma entity may be justified.     

Composite ALK-negative anaplastic large cell lymphoma and small lymphocytic lymphoma involving the right inguinal lymph node

Anaplastic large cell lymphoma and small lymphocytic lymphoma are two lymphoid malignancies with completely distinct morphologies and natural histories. We present a rare case of composite anaplastic large cell lymphoma and small lymphocytic lymphoma in an inguinal lymph node of an otherwise healthy 47-year-old male patient. Immunohistochemical and molecular studies identified the two populations clearly. Their separation is imperative as anaplastic large cell lymphoma can be an aggressive neoplasm and easily overlooked in cases of small lymphocytic lymphoma with a small population of anaplastic large cell lymphoma cells.     

Diffuse large B-cell lymphoma arising in a composite lymphoma with biclonality by flow cytometry and one monoclonal band by PCR

Composite lymphoma (CL) refers to the presence of two or more distinct types of lymphomas in a single organ or tissue. CL is an infrequent finding and may be due to the existence of two genetically related neoplasms, i.e. transformation of a single lymphoma into another lymphoma, or be due to the presence of two clonally unrelated lymphomas. CL composed of more than two lymphomas is even rare. Herein we describe a case of diffuse large B-cell lymphoma (DLBCL) arising in a CL of follicular lymphoma (FL) and small lymphocytic lymphoma (SLL) in an inguinal lymph node of an 85 year old woman. The three lymphomas were morphologically and immunophenotypically distinct while flow cytometry detected two monoclonal B-cell populations. Karyotyping and Polymerase Chain Reaction (PCR) for B-cell clonality each detected a single monoclonal B-cell population. The morphology findings may suggest DLBCL being transformed from FL while Richter transformation from SLL appears to be less likely in our case. Due to the single clone by chromosome study and PCR study, the precise relationships of the three lymphomas are unknown.     

Expression of BAFF-R (BR3) in normal and neoplastic lymphoid tissues characterized with a newly developed monoclonal antibody

BAFF-receptor (BAFF-R) is required for the successful maturation and survival of B-cells. We developed an anti-human BAFF-R monoclonal antibody (mAb), 8A7. The reactivity of 8A7 in normal and neoplastic tissue was examined by performing immunohistochemistry on paraffin-embedded sections. 8A7 reacted with lymphocytes in the mantle and marginal zones, but not with lymphocytes in the interfollicular area. Lymphocytes in the germinal centers were found to be negative or occasionally weakly positive for 8A7. BAFF-R expression was found only in B-cell lymphoma (44/80, positive cases/examined cases): B-lymphoblastic lymphoma 0/3, B-chronic lymphocytic leukemia/small lymphocytic lymphoma 4/4, mantle cell lymphoma 9/11, follicular lymphoma 10/14, diffuse large B-cell lymphoma (DLBCL) 11/25, marginal zone B-cell lymphoma 8/10, lymphoplasmacytic lymphoma 2/2, plasma cell myeloma 0/2, and Burkitt lymphoma 0/9, but not in T/NK cell lymphomas (0/19) or Hodgkin lymphoma (0/10). BAFF-R was expressed in most low-grade B-cell neoplasms and a small number of DLBCL, suggesting that BAFF-R may play an important role in the proliferation of neoplastic lymphoid cells. Thus, the mAb is very useful for further understanding of both healthy B-cell biology and its pathogenic neoplasms.     

Complexities in the diagnosis of large B-cell lymphomas,classic Hodgkin lymphomas and overlapping peripheral T-cell lymphomas simplified: An evidence-based guide

The diagnosis of a large B-cell lymphoma and classic Hodgkin lymphoma (CHL) is often straightforward. However, in select circumstances, these simple diagnoses can be quite complex. In part, diagnostic difficulty may be due to uncertainty in the evaluation of morphologic and immunophenotypic features along a biologic continuum, or alternatively arise from uncertainty in predicting the behavior and outcomes of patients. Here, we systematically discuss and review areas of diagnostic difficulty in the diagnosis of large B-cell lymphomas (LBCL), classic Hodgkin lymphomas (CHL) and peripheral T-cell lymphomas (PTCL). We provide careful data-driven analyses and evidence-based approaches to help guide pathologists and clinicians. We discuss: 1) marginal zone lymphomas with increased large cells versus diffuse large B-cell lymphoma (DLBCL), 2) chronic lymphocytic leukemia with expanded proliferation centers versus diffuse large B-cell lymphoma (DLBCL), 3) chronic lymphocytic leukemia with Hodgkin/Reed-Sternberg-like cells versus CHL arising from chronic lymphocytic leukemia, 4) complex cases of follicular lymphoma versus DLBCL, 5) PTCL with large B-cell proliferations versus PTCL with LBCL, 6) PTCL with Hodgkin/Reed-Sternberg-like cells versus CHL, and finally 7) blastoid/pleomorphic mantle cell lymphoma versus DLBCL. Our evidence and data driven approach may serve as a useful diagnostic guide.     

Composite primary breast diffuse large B-cell lymphoma and T lymphoblastic leukemia/lymphoma: report of a case and review of literature

We reported a rare case of composite diffuse large B-cell lymphoma and T lymphoblastic leukemia/lymphoma (T-LBL) in a 46-year-old woman with progressive enlargement of the breast lump. The patient initially sought care at a local hospital with a single left breast lump without any other physical examination findings. Histopathological analysis of which revealed a diffuse infiltration of tumor cells that were rich in cytoplasm with vesicular chromatin and prominent nucleoli. Further analysis of immunohistochemistry showed a cluster of neoplastic cells which express B-cell markers: CD19, CD20 (weak), CD79a, PAX5 and BCL-2, but negative for T-cell markers such as CD2, CD3, CD5 and CD7. PET-CT showed evidence of lymphadenopathy and splenomegaly, which may indicate lymphoma infiltration. Then a biopsy of bone marrow showed typical features of T-LBL. The aberrant terminal deoxynucleotidyl transferase (TDT) and cCD3 positive T-cell population that lack surface CD10 and CD19 were identified by flow cytometric immunophenotyping. Polymerase chain reaction analysis of the T-cell receptor gamma gene and IgH gene revealed a clonal rearrangement and confirming T-cell clonality. Fluorescence in-situ hybridization (FISH) revealed a deletion of the P53 gene in these T-neoplastic cells may indicate a bad outcome of such disease. Neither the large B-cells nor T-cells were positive for Epstein-Barr virus encoded RNA.