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Hepatosplenic T-cell lymphoma (HSTCL) is a rare and aggressive extranodal T-cell lymphoma that can arise in patients with underlying immune disorders. Others have suggested that tumor necrosis factor (TNF)–α inhibitor therapy for immune disorders increases the risk of HSTCL. To assess for a potential relationship between HSTCL and the use of TNF-α inhibitors, we searched for patients with HSTCL and underlying immune disorders at our institution. We identified 7 patients with a median age of 38 years. Five patients had Crohn disease, 1 ulcerative colitis, and 1 rheumatoid arthritis. In 6 patients, medication history for the immune disorder was available: 6 patients received 6-mercaptopurine or azathioprine, and 2 patients received steroids; no patients received TNF-α inhibitors. In all 7 patients, the histologic, immunophenotypic, and cytogenetic findings were similar to cases of HSTCL that arise in immunocompetent patients. We reviewed the literature and identified 60 patients with immune disorders who subsequently developed HSTCL. These patients were treated with immunosuppressive drugs in 89%, TNF-α inhibitors in 56%, and both therapies in 54%, and 1 (2%) patient was treated with TNF-α inhibitors only. Our cohort and literature review indicates that TNF-α inhibitor therapy is not essential for the development of HSTCL in patients with immunodysregulatory disorders, and implies that immunosuppressive drugs or other factors (eg, genetic predisposition, chronic antigenic stimulation) may be more critical in the pathogenesis in this context. Although these data are observational, they have implications for the use of TNF-α inhibitors in patients with inflammatory bowel disease and other immunodysregulatory disorders. [ABSTRACT FROM AUTHOR]

Hodgkin lymphoma (HL) is classified into 2 largely distinct subgroups, namely nodular lymphocyte predominant HL (NLPHL) and classic HL (CHL). CHL is further divided into nodular sclerosis, lymphocyte-rich, mixed cellularity (MCCHL) and lymphocyte-depleted (LDCHL) subtypes. In industrialized nations, Epstein-Barr virus (EBV) has been associated with all types of CHL, especially the MCCHL and LDCHL subtypes, but is rare in NLPHL. We report 8 cases of EBV-positive NLPHL occurring in patients in the United States. All 8 patients have no history of immunosuppression and presented with localized or systemic lymphadenopathy. Histologically, 6 cases had a vaguely nodular pattern and 2 cases had a nodular and diffuse pattern. In all cases, lymphocyte predominant (LP) cells were observed in a background of small lymphocytes and histiocytes. Immunohistochemical analysis showed that the LP cells in all cases were positive for CD20, CD79a, PAX5, OCT2, and CD45 and were negative for CD15. CD30 was expressed variably in 7 cases. EBV encoded RNA was present in all LP cells in 5 cases and in a subset of LP cells in 3 cases. One patient was treated with radiation therapy and 7 patients received chemotherapy, including 4 of 7 patients who underwent autologous stem cell transplantation. EBV infection is a rare primary or secondary event in NLPHL that correlates with poorer prognosis and often requires more aggressive therapy. The variable expression of CD30 in most of these cases could be the result of EBV infection. [ABSTRACT FROM AUTHOR]

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. TheMCL 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); 6MCLs had blastoid or pleomorphic and 5 small lymphocytic features. The CLL/SLL componentwas 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 theMCL 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. [ABSTRACT FROM AUTHOR]

Langerhans cell histiocytosis is a rare disorder of Langerhans cells, a component of the dendritic cell system, with an unknown pathogenesis. Conventional therapy for patients with Langerhans cell histiocytosis is usually effective, but some patients are refractory to treatment or develop toxicity. Thus, there is a need for innovative therapies. Recently, some cases of Langerhans cell histiocytosis were reported to express platelet-derived growth factor receptors a and ß or c-KIT by immunohistochemistry, and some of these patients had a clinical response to imatinib mesylate. Other hematologic disorders with PDGFRa or PDGFRß gene rearrangements also have responded to imatinib mesylate. The aim of this study was to evaluate immunohistochemical and molecular markers in Langerhans cell histiocytosis that would identify cases for possible treatment with tyrosine kinase inhibitors. We investigated formalin-fixed, paraffin-embedded tissue sections from 14 cases of Langerhans cell histiocytosis. As controls, we included cases of inflammatory dermatitis (n = 5) and dermatopathic lymphadenitis (n = 7). We performed immunohistochemistry for S100, CD1a, c-KIT, and platelet-derived growth factor receptors a and ß. Fluorescence in situ hybridization analysis to detect rearrangements of the PDGFRa or PDGFRß genes was also performed. Four (28.5%) of 14 cases of Langerhans cell histiocytosis were positive for platelet-derived growth factor receptor a, whereas absent/weak expression was seen in 10 cases and all controls. All cases were negative for plateletderived growth factor receptor ß and c-KIT. The fluorescence in situ hybridization studies were also negative in all 8 cases with adequate quality DNA. Our findings suggest that a subset of cases of Langerhans cell histiocytosis may be treated with tyrosine kinase inhibitors due to the expression of platelet-derived growth factor receptor a. Clinical trials that evaluate the use of tyrosine kinase inhibitors in Langerhans cell histiocytosis seem warranted and should evaluate these markers. [ABSTRACT FROM AUTHOR]

Summary: We describe 4 patients aged 62 to 79 years with splenomegaly and bone marrow involvement by splenic B-cell lymphoma who developed more than 55% prolymphocytes in blood. The diagnosis of B-cell prolymphocytic leukemia was considered clinically based on a markedly elevated leukocyte (up to 131.5 × 109/L) or prolymphocyte (up to 86%) count. Splenectomy was performed in all patients, and spleen weight ranged from 1500 to 2380 g. In 3 patients, the neoplasms were classified as splenic marginal zone lymphoma, and in 1 patient, the neoplasm was classified as splenic diffuse red pulp small B-cell lymphoma. In 2 patients, splenectomy preceded a B-cell prolymphocytic leukemia–like picture, and the spleen showed splenic marginal zone lymphoma or splenic diffuse red pulp small B-cell lymphoma with increased (10%-20%) nucleolated cells consistent with prolymphocytes. In the other 2 patients, a B-cell prolymphocytic leukemia–like picture prompted splenectomy. Initial examination of bone marrow in these patients suggested splenic marginal zone lymphoma. The spleen specimens showed extensive involvement by splenic marginal zone lymphoma with numerous prolymphocytes. Flow cytometry immunophenotyping in all cases showed lymphocytes positive for monotypic surface immunoglobulin (bright), pan–B-cell antigens, CD11c, CD22, and FMC7. Immunohistochemical analysis in all patients showed moderate to bright p53 expression in the spleen (n = 3) or bone marrow (n = 2). Annexin A1 and cyclin D1 were negative in all cases. Conventional cytogenetic analysis showed del(7q) in 3 patients. We conclude that splenic B-cell lymphoma of various types can undergo prolymphocytoid transformation with more than 55% prolymphocytes in the blood mimicking B-cell prolymphocytic leukemia. [ABSTRACT FROM AUTHOR]

Summary: Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) is a B-cell neoplasm that is typically CD5 negative. We describe the clinicopathologic, immunophenotypic, and cytogenetic features of 14 cases of CD5+ MALT lymphoma. There were 9 men and 5 women (median age, 68 years; range, 34-87 years). MALT lymphoma was initially diagnosed in salivary glands (n = 4), nasopharynx (n = 2), and 1 case each in conjunctiva, thyroid, stomach, colon, skin, lung, kidney, and retroperitoneum. Two patients had localized disease; 9 had disseminated disease with generalized lymphadenopathy (n = 8), multifocal lymphoma (n = 6), or bone marrow involvement (n = 5). No staging information was available for the remaining patients. None presented with B symptoms, splenomegaly, cytopenias, lymphocytosis, monoclonal gammopathy, or elevated serum lactate dehyrogenase. Serum β2-microglobulin was elevated in 6. Morphologically, the neoplasms had features typical of MALT lymphoma being composed of small- to medium-sized cells with round to slightly irregular nuclear contours and moderate amount of cytoplasm. Lymphoepithelial lesions were noted in 4 cases. CD5 was positive in all cases by immunohistochemistry (n = 12) and/or flow cytometry (n = 11). All cases assessed were negative for cyclin D1 (13/13) and CD10 (11/11). Conventional cytogenetics in 7 cases showed trisomy 3 in 3 and diploid in 4. With a median follow-up of 71 months (range, 2-131 months), overall survival at 5 years was 100%, although 5 patients required chemotherapy. Our results show that CD5 expression is rare in MALT lymphoma, and is often associated with nongastric disease and an increased tendency to present with disseminated disease. Overall survival is excellent with appropriate therapy. [ABSTRACT FROM AUTHOR]

Summary: Fas-associated death domain protein is a key component of the extrinsic apoptotic pathway. In addition, in animal models, Fas-associated death domain protein phosphorylation at serine 194 has been shown to affect cell proliferation, especially in T lymphocytes. The importance of Fas-associated death domain protein phosphorylation at serine 194 for the proliferation of B lymphocytes, however, is uncertain. Here we show in reactive lymph nodes that serine 194 phosphorylated Fas-associated death domain protein is expressed predominantly in the dark (proliferative) zone of germinal centers. In B-cell non–Hodgkin lymphoma cell lines, serine 194 phosphorylated Fas-associated death domain protein levels are substantially higher in highly proliferating cells and lower in serum-starved cells. We also used immunohistochemical analysis to assess Fas-associated death domain protein phosphorylation at serine 194 expression in 122 B-cell non–Hodgkin-type lymphomas. The mean percentage of serine 194 phosphorylated Fas-associated death domain protein positive tumor cells was 81% in Burkitt lymphoma, 41% in diffuse large B-cell lymphoma, 18% in follicular lymphoma, 18% in plasma cell myeloma, 12% in extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue, 11% in mantle cell lymphoma, and 2% in chronic lymphocytic leukemia/small lymphocytic lymphoma (P < .0001, Kruskal-Wallis test). Furthermore, in chronic lymphocytic leukemia/small lymphocytic lymphoma, serine 194 phosphorylated Fas-associated death domain protein was detected predominantly in proliferation centers. In the entire study group, the percentage of cells positive for serine 194 phosphorylated Fas-associated death domain protein correlated significantly with the proliferation index Ki-67 (Spearman R = 0.9, P < .0001). These data provide evidence that serine 194 phosphorylated Fas-associated death domain protein is involved in the proliferation of normal and neoplastic B cells and has features of a novel proliferation marker. [Copyright &y& Elsevier]

Summary: The 8p11 myeloproliferative syndrome is an aggressive neoplasm associated with chromosomal translocations involving the fibroblast growth factor receptor 1 tyrosine kinase gene on chromosome 8p11-12. By our count, 65 cases are currently reported in the literature. This neoplasm affects patients of all ages, with a slight male predominance. Patients often present with peripheral blood eosinophilia without basophilia. Bone marrow examination commonly is hypercellular, with or without eosinophilia, which usually leads to the initial diagnosis of a myeloproliferative neoplasm. Many patients also present with or develop lymphadenopathy. Lymph node biopsy in these patients has commonly shown lymphoblastic leukemia/lymphoma, most often reported as being of T-cell lineage, but bilineal myeloid/T-cell lymphomas and less often a myeloid sarcoma are also reported. The natural history of this neoplasm is to evolve into acute leukemia, usually of myeloid or mixed lineage, and less frequently of T- or B-lymphoid lineage. The prognosis is poor despite aggressive chemotherapy, with a few patients achieving long clinical remission after stem cell transplantation. At the molecular level, all cases carry a chromosomal abnormality involving the fibroblast growth factor receptor 1 (FGFR1) gene at chromosome 8p11, where 10 translocations and 1 insertion have been identified. These abnormalities disrupt the FGFR1 and various partner genes, and result in the creation of novel fusion genes and chimeric proteins. The latter include the N-terminal portion of the partner genes and the C-terminal portion of FGFR1. The most common partner is ZNF198 on chromosome 13q12. In the current World Health Organization classification, the 8p11 myeloproliferative syndrome is designated as “myeloid and lymphoid neoplasms with FGFR1 abnormalities.” [Copyright &y& Elsevier]

Since the first reported case in 1997, over 600 women with breast implant-associated anaplastic large cell lymphoma (BI ALCL) have been reported. BI ALCL is a CD30-positive T-cell lymphoma that carries clonal T-cell receptor gene rearrangements, and a subset of cases harbors mutations in the JAK-STAT signaling pathway. Rarely, other histologic types of lymphoma have been reported in association with breast implants, including fewer than 10 cases of B-cell origin. Here, we describe three additional patients with B-cell lymphoma occurring around breast implants. Two of these patients developed extranodal marginal zone lymphoma in the peri-implant capsule, one of which had a concurrent ALCL within the superficial lining of the capsule. The third patient presented with diffuse large B-cell lymphoma inside the breast parenchyma surrounding her implant. Determining the etiology and risk factors for the development of B-cell lymphomas associated with breast implants remains challenging, given the wide spectrum of histologic features and the rarity of these neoplasms. Ultimately, we document three new cases of B-cell lymphoma arising around breast implants and highlight their clinical and pathologic features in order to expand our understanding of this rare disease presentation. • This article describes three women with breast implants who developed B-cell lymphomas within their peri-implant capsules. • To date, there have only been approximately six similar cases described in the medical literature. • Our case series discusses the wide spectrum of B-cell lymphomas that occur around breast implants. [ABSTRACT FROM AUTHOR]

The current literature credits Keech and Creech with the first report of breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) in 1997. Here we discuss what we consider is the first ever description of BIA-ALCL, a recently recognized entity by the WHO. We unearthed the description of a patient that was diagnosed with primary effusion lymphoma (PEL), surrounding a breast implant in 1996. In light of the current state of knowledge, we evaluated the evidence presented in 1996 and consider that BIA-ALCL is a more appropriate diagnosis rather than PEL. We base our proposal on the following features: 1). clinical presentation of effusion around a breast implant, 2). occurring in an HIV negative patient, 3). absence of EBV co-infection, and 4). a historically questionable demonstration of HHV8. In effect we further support that HHV8 is not related with BIA-ALCL based on the following facts: 1). An extensive review of the literature did not disclose a similar case in the next 24 years, 2). Use of state of the art HHV8 by immunohistochemistry did not disclose any positive case among 30 randomly tested cases. We believe this matter is of importance because in the current WHO, the assertion that PEL is a possible complication of breast implants may lead to a diagnosis with poor prognosis and susceptible of morbidity related with aggressive therapy, in contrast with BIA-ALCL that can be cured with surgery alone. • First ever description of breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) • BIA-ALCL is distinct from primary effusion lymphoma (PEL), a B-cell lineage lymphoma. • BIA-ALCL is not associated with HHV-8. • No support for PEL as a complication of breast implants [ABSTRACT FROM AUTHOR]

The isolated deletion of chromosome 20q [del(20q)] has been observed in both de novo and therapy-related cases of myelodysplastic syndrome (MDS). The clinicopathologic features of de novo MDS with isolated del(20q) are well characterized. However, relatively little is known about therapy-related myeloid neoplasms (t-MNs) with isolated del(20q). In this study, we identified five cases of t-MN and 26 cases of de novo MDS with isolated del(20q) over a 10-year period. All cases had a long latency interval from the treatment of the primary malignancy to the onset of t-MN, and all were associated with frequent bone marrow dysplasia. The del(20q) was the sole abnormality detected at the time of diagnosis of t-MN in three cases, six years prior to diagnosis in one case, and at the time of relapse of acute myeloid leukemia (AML) in one case. Three patients with therapy-related MDS (t-MDS) had a relatively indolent clinical course, whereas two patients presented with AML or developed AML shortly after t-MDS. The patients with de novo MDS with isolated del(20q) presented frequently with anemia and thrombocytopenia which were associated with bone marrow dysplasia. The median overall survival was 64 months. In all cases, del(20q) was present at the time of diagnosis. [ABSTRACT FROM AUTHOR]

• Involvement of cardiac structures by Adult T-cell leukemia/lymphoma (ATLL) is a rare event. • Isolated cardiac valve involvement could be seen in indolent ATLL subtypes. • Consider ATLL as differential diagnosis in HTLV-1 carriers with heart failure symptoms. Adult T-cell leukemia/lymphoma (ATLL) is an aggressive mature T-cell neoplasm caused by infection with the Human T-cell Lymphotropic Virus Type 1 (HTLV-1). Cardiac involvement in patients with ATLL is infrequent, and when it happens it is usually seen in aggressive ATLL subtypes. However, ATLL presenting as isolated cardiac valve involvement is extremely rare. To date, only three histologically proven cases of ATLL with isolated cardiac valve involvement have been reported. Herein, we describe a 61-year-old Peruvian man who presented heart failure symptoms secondary to progressive cardiac valve infiltration. The patient underwent mitral valve replacement with a mechanical prosthesis. Histopathological evaluation of the resected valve revealed leaflet thickening with a nodular appearance due to fibrous tissue containing atypical T-lymphocytes with Foxp3 expression, infiltrating all layers of the resected valve. Interestingly, tumor cells were distributed around an incidental venous malformation (i.e., cavernous hemangioma). Postoperative evaluation demonstrated positive serology for HTLV-1, and a diagnosis of ATLL was established. Postoperative positron emission tomography/computed tomography did not show lesions outside the heart and cell blood counts were within normal range with low level of circulating CD4+ CD25+ lymphoma cell counts (7%); therefore, patient's disease was considered as smoldering ATLL and a "watch and wait" strategy was pursued. Currently, the patient is alive with no progression of disease after 18 months from diagnosis. Isolated cardiac valve involvement by ATLL should be considered in the differential diagnosis of HTLV-1 carriers with progressive heart failure, even when systemic lymphoma involvement is absent or not apparent. [ABSTRACT FROM AUTHOR]

Background Human T-lymphotropic virus (HTLV)-1-associated infective dermatitis (ID) is a rare severe chronic eczema, considered as a harbinger for the development of cutaneous adult T-cell leukemia/lymphoma (ATLL) and/or HTLV-1-associated myelopathy (HAM)/tropical spastic paraparesis (TSP). The pathogenesis of ID remains unclear. High numbers of peripheral blood CD4+ CD25+ FoxP3+ regulatory T cells (Tregs) have been reported in ATLL and HAM/TSP. Objective To investigate the status of Tregs, unknown to date, and the histopathological features of ID. Methods We studied 16 skin biopsies from 15 Peruvian adults and children with ID by immunohistochemistry. Results Histopathological patterns were seborrheic dermatitis-like and lichenoid. Intraepidermal lymphocytes were conspicuous. The infiltrate was composed of a CD3+ T cell infiltrate with a predominance of CD8+ over CD4+ cells. CD4+ CD25+ FoxP3+ Tregs were rare and their numbers were significantly lower than those reported in other inflammatory dermatoses. Conclusion Tregs have an essential role in maintaining immune homeostasis of skin. Treg dysregulation ends in severe clinical manifestations. The clinical presentation of ID, with lesions resembling those seen in patients with atopic dermatitis and with mutations in the FoxP3 gene, is in agreement with a common Treg-deficient skin environment in these disorders, possibly secondary to HTLV-1 infection. [ABSTRACT FROM AUTHOR]

Abstract: Follicular lymphoma (FL) is a prevalent type of non-Hodgkin lymphoma in the United States and Europe. Although, FL typically presents with nodal involvement, extranodal sites are less common, and leukemic phase at diagnosis is rare. There is mounting evidence that leukemic presentation portends a worse prognosis in patients with FL. We describe 7 patients with a pathological diagnosis of FL who presented with a leukemic phase. We compared our cases with 24 additional cases reported in the literature. Based on our results, patients who present with leukemic FL tend to have higher risk disease. Leukemic FL also seems to be associated with a worse prognosis; however, larger studies are needed to confirm our findings. A discrepancy with previously reported cases of FL in leukemic phase raises the possibility of differences attributable to geographic regions. [Copyright &y& Elsevier]

Abstract: Deletions of chromosome 11q[del(11q)] as part of a non-complex karyotype are infrequent in myelodysplastic syndromes (MDS), leaving the clinicopathologic and genetic features largely undefined. From three large medical centers over a 10-year period, we identified 32 MDS cases where del(11q) was present either as a sole (n =23) or associated with another abnormality (n =9), showing an overall 0.6% frequency in MDS. These patients included 15 men and 17 women, with a median age of 68 years. Three were therapy-related, and 29 were primary MDS. These cases were characterized by transfusion-dependent anemia (65%); frequent ring sideroblasts (RS) (59%); bone marrow hypocellularity (22%), and less severe thrombocytopenia. With a median follow-up of 32 months, 9/24 (38%) cases progressed to acute myeloid leukemia (AML), and the overall survival (OS) was 35 months (3–105). Fluorescence in situ hybridization (FISH) showed MLL deletion in 6/10 cases, but no cryptic MLL translocations in all 15 MDS cases tested. In contrast, FISH performed in AML with del(11q) showed MLL rearrangement in 3/17 (18%) cases. In summary, del(11)q occurring in a non-complex karyotype is predominantly associated with primary MDS, lack of cryptic MLL rearrangements, and shows characteristic clinicopathological features. These clinicopathological features are likely attributed to commonly deleted regions of 11q and their involved genes. [Copyright &y& Elsevier]