Proliferation Of High Endothelial Venules Research Articles

Angioimmunoblastic T-cell lymphoma and Kaposi sarcoma: A fortuitous collision?

Follicular helper T-cell (TFH) lymphoma of the angioimmunoblastic-type (AITL), one of the most prevalent T-cell lymphomas, typically encompasses proliferation of high endothelial venules and Epstein-Barr virus-positive immunoblasts, but neither infection with HHV8 nor association with Kaposi's sarcoma (KS) have been described. The aims of this study are to characterise the association between AITL and HHV8 infection or KS. Three male patients aged 49-76 years, HIV-negative, with concurrent nodal involvement by AITL and KS, were identified from our files and carefully studied. Two patients originated from countries where endemic KS occurs, including one with cutaneous KS. The lymphomas featured abundant vessels, expanded follicular dendritic cells and neoplastic TFH cells [PD1+ (three of three), ICOS+ (three of three), CXCL13+ (three of three), CD10+ (two of three), BCL6 (two of three)] but lacked EBV+ immunoblasts. The foci of KS consisted of subcapsular proliferations of ERG+, CD31+ and/or CD34+ , HHV8+ spindle cells. High-throughput sequencing showed AITL-associated mutations in TET2 (three of three), RHOA (G17V) (three of three) and IDH2 (R172) (two of three), which were absent in the microdissected KS component in two cases. Relapses in two patients consisted of AITL, without evidence of KS. No evidence of HHV8 infection was found in a control group of 23 AITL cases. Concurrent nodal involvement by AITL and KS is rare and identification of both neoplastic components may pose diagnostic challenges. The question of whether the association between AITL and KS may be fortuitous or could reflect the underlying immune dysfunction in AITL remains open.

Follicular T-cell lymphoma: a short review with brief discussion of other nodal lymphomas/lymphoproliferative disorders of T-follicular helper cell origin

Follicular peripheral T-cell lymphoma (F-PTCL) is a newly recognized provisional entity in the 2017 World Health Organization Classification revision of hematolymphoid neoplasms. It is a rare and under-recognized manifestation of peripheral T-cell lymphoma that is associated with a typically aggressive clinical course. Cases feature a predominantly follicular or perifollicular growth pattern and exhibit strong and consistent expression of T-follicular helper (TFH) markers. These cases distinctly lack histologic features commonly associated with angioimmunoblastic T-cell lymphoma, such as an associated polymorphous infiltrate, proliferation of high endothelial venules or expanded follicular dendritic meshworks. A relatively specific t(5;9)(q33;q22) rearrangement, leading to ITK-SYK fusion is seen in about 20% of cases. Herein, we summarize key features of F-PTCL and briefly review the evolving relationship to other nodal T-cell lymphomas/lymphoproliferative disorders of TFH-derivation.

Morphologic Spectrum of Lymphadenopathy in Adult-onset Immunodeficiency (Anti-interferon-γ Autoantibodies).

Adult-onset immunodeficiency syndrome (AOIS) caused by anti-interferon-γ autoantibodies is an emerging disease. Affected patients present typically with systemic lymphadenopathy, fatigue, and fever. We studied 36 biopsy specimens, 31 lymph nodes, and 5 extranodal sites, of AOIS confirmed by serum autoantibody or QuantiFERON-TB Gold In-Tube assay. We describe the morphologic features and the results of ancillary studies, including special stains, immunohistochemistry, and molecular testing. The overall median age of these patients was 60.5 years (range, 41 to 83 y) with a male-to-female ratio of 20:16. All biopsy specimens showed nontuberculous mycobacterial infection, and most cases showed the following histologic features: capsular thickening with intranodal sclerosing fibrosis, irregularly distributed ill-formed granulomas or histiocytic aggregates with neutrophilic infiltration, interfollicular expansion by a polymorphic infiltrate with some Hodgkin-like cells that commonly effaces most of the nodal architecture and proliferation of high endothelial venules. In situ hybridization analysis for Epstein-Barr virus-encoded RNA showed scattered (<1%) to relatively more common (4% to 5%) positive cells in 29 of 30 (97%) tested specimens, reflecting immune dysregulation due to an interferon-γ defect. In the 31 lymph node specimens, 23 (74%) cases showed increased immunoglobulin G4-positive plasma cells (4 to 145/HPF; mean, 49.7/HPF) with focal areas of sclerosis reminiscent of immunoglobulin G4-related lymphadenopathy, 4 (13%) cases resembled, in part, nodular sclerosis Hodgkin lymphoma, and 9 (29%) cases mimicked T-cell lymphoma. Among 33 patients with available clinical follow-up, 20 (61%) showed persistent or refractory disease despite antimycobacterial therapy, and 1 patient died of the disease. We conclude that the presence of ill-defined granulomas, clusters of neutrophils adjacent to the histiocytic aggregates, and some Epstein-Barr virus-positive cells are features highly suggestive of AOIS. A high index of clinical suspicion and awareness of the morphologic features and differential diagnosis of AOIS are helpful for establishing the diagnosis.

Exclusive B-cell phenotype of primary prostatic lymphomas: a potential role of chronic prostatitis.

Primary prostatic lymphomas (PPL) is exceedingly rare. The aim of this study was to investigate the largest series of PPL obtained from a nationwide expert pathologist network, and thus try to understand the pathophysiology of these tumours. Up to 66000 lymphoma cases have been collected and submitted for central expert review by the French Lymphopath network. We confirm the low frequency of PPL (n=77; 0.12%), all cases being of B-cell origin. Diffuse large B-cell lymphoma and small lymphocytic lymphoma were the most frequent subtypes, comprising 31% and 26% of cases respectively, followed by mucosa-associated lymphoid tissue (MALT)/lymphoplasmacytic lymphoma (19%), follicular lymphoma (12%), mantle cell lymphoma (6%), Burkitt lymphoma (4%), and unclassified lymphoma (1%). Clinical data obtained in 25 cases suggests that PPLs are rather indolent tumours. Our hypothesis for B-cell recruitment in the prostatic tissue was derived from the observation in chronic inflammation (prostatitis) of frequent heterotopic proliferation of high endothelial venules (HEVs). The latter are dedicated to lymphocyte entry into secondary lymphoid organs, here putatively driving circulating clonal B-lymphocytes from the blood into the inflamed prostate. This may account for the relatively high incidence of small lymphocytic lymphoma consistently reported in series of primary or secondary prostatic lymphoma. As in other organs or glands, chronic inflammation may promote antigen-dependent intraprostatic MALT lymphoma and diffuse large B-cell lymphoma development. PPLs are exclusively of B-cell origin, and chronic inflammation resulting from the proliferation of high endothelial venules could play some role in their development.

Spontaneous Malignant T Cell Lymphoma in a Young Male Common Marmoset (&lt;i&gt;Callithrix jacchus&lt;/i&gt;)

We histopathologically and immunohistochemically investigated a case of malignant lymphoma that spontaneously developed in a male common marmoset at two years of age. Beginning at two years four months of age, the animal had an enlargement of the submandibular and inguinal lymph nodes, small subcutaneous nodules near the right breast and an approximately fivefold increase in peripheral lymphocyte count compared with the previous examination value. The postmortem findings at two years eight months of age showed lymphadenopathy with enlargement of the thymus and spleen. Small- to intermediate-sized neoplastic lymphocytes had diffusely proliferated in the enlarged nodes. The neoplastic cells were pleomorphic and had irregularly shaped nuclei. The nuclear chromatin staining revealed hyperchromatism in the small-sized cells, and the intermediate-sized cells exhibited vesicular staining. An immunohistochemical examination indicated that the neoplastic lymphocytes were positive for CD3 and negative for CD20, thus suggesting that they had originated from T cells. In addition, the proliferation of high endothelial venules and reactive epithelioid histiocytes was observed. Scattered tingible body-laden macrophages were infrequently detected. Neoplastic lymphocytes were also observed in the thymus, spleen, heart, lungs, liver, kidneys, adrenal glands and femoral and sternal bone marrow. This malignant lymphoma in a young male common marmoset was considered to fit the category of “peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS)” according to the new WHO system of classification.

A Targeted Mutational Landscape of Angioimmunoblastic T-Cell Lymphoma: Association Between Advanced Age and Mutations in TET2 and DNMT3A

Abstract 299Angioimmunoblastic T-cell lymphoma (AITL) is a subtype of T-cell lymphoma that manifests with a broad array of neoplastic and paraneoplastic manifestations, including generalized lymphadenopathy, hepatosplenomegaly, systemic symptoms, rash and hypergammaglobulinemia. AITL accounts for approximately 20% of T-cell lymphomas and 1–2% of all non-Hodgkin lymphomas (NHL). Median survival among patients with AITL is less than 3 years, although the course of illness varies widely. Histologic examination of AITL characteristically demonstrates proliferation of high endothelial venules and a polymorphic infiltrate, malignant cells that resemble CD4+ follicular helper T-cells and occasional EBV-positive lymphoid cells. The genetics of AITL remain almost completely undefined, in part because of the low tumor cell fraction and the abundance of non-malignant bystander cells. We reasoned that targeted sequencing of selected genes of interest would increase coverage and thereby enable the detection of low frequency variants present with malignant AITL cells.To define a targeted mutational landscape of AITL, we performed exon capture and next-generation sequencing of all coding exons of 197 genes known to be recurrently altered in cases of NHL. Single nucleotide variants (SNVs) and insertions/deletions were confirmed by manual review of sequencing reads and a subset was validated by Sanger sequencing of tumor and germline tissue. Twenty-six cases collected from three sites in the USA had adequate tumor specimens available and resulted in high-quality reads (median depth of coverage∼300). Median age among the 26 cases was 66.5 years (range 30–89). Twelve (46%) patients were male. Among 21 cases with adequate clinical annotation, all 21 had advanced stage disease (11 stage 3, 10 stage 4), 13 (62%) had B-symptoms and 19 (90%) had an ECOG performance score of 0–2. Ten patients received CHOP-like regimens, 4 received non-anthracycline containing chemotherapy regimens, 5 received prednisone monotherapy, 2 received cyclosporine monotherapy, and one patient underwent allogeneic stem cell transplantation after cytoreduction with alemtuzumab. Among the 17 patients with staging after first-line treatment, 8 (47%) achieved a complete response, 3 (18%) achieved a partial response, 1 (6%) had stable disease and 5 (29%) had progression of disease. Median overall survival among the 26 patients was 420 days with a median follow-up of 426 days (range 21–3532).Recent studies have identified both TET2 and DNMT3A mutations in a small number of AITL samples as well as hematopoietic stem cells from the same patients. From the 26 cases, we identified 28 TET2 mutations (13 frameshift, 8 nonsense, 5 missense, 2 splice site) in 17 (65.4%) cases, including 5 cases with 2 TET2 mutations and 2 cases with 3 TET2 mutations. Among the latter, the fractions of mutant reads suggested that one mutation was present within all tumor cells and the other 2 mutations were present in subclones. Six of 17 cases with TET2 mutations also harbored mutations in DNMT3A, compared with 0 of 9 cases that lacked TET2 mutations (p=0.06). Median age for patients with wild-type TET2 was 56 years (range 30–83), 68 years for patients with one TET2 mutation (range 55–89), and 77 years for patients with 2 or 3 TET2 mutations (range 59–84; p<10−4). Median age for patients with wild-type DNMT3A was 64 years (range 30–84) and 75.5 years for patients with mutated DNMT3A (range 64–89; p=0.03).Known gain-of-function mutations were identified at JAK3 V722I (n=2) and IDH2 R172K (n=1). Frame-shift mutations were recovered in ABCA7 (n=1), ARID1B (n=1), CREBBP (n=2), GNAS (n=1), IKZF2 (n=2), PRDM1 (n=2), SMARCA2 (n=1), and TNFRSF14 (n=1). Nonsense mutations were recovered in ALPK2 (n=1), CCND3 (n=2), and CHD8 (n=2). Only 2 cases harbored TP53 mutations (M133R, S261_splice). Additional missense variants were identified across a large number of genes, including several previously described in the COSMIC database.In conclusion, the genetics of AITL vary broadly across cases, with a small number of genes previously associated with NHL harboring recurrent mutations. Mutations of DNMT3A commonly occur in combination with one or more mutations in TET2. Mutation of either locus is associated with advanced age, supporting the hypothesis that the mutations are acquired over time within hematopoietic stem cells. Disclosures:Horwitz:Seattle Genetics: Consultancy, Research Funding; Allos: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy; Genzyme: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy; Johnson & Johnson: Consultancy; Infinity Pharmaceuticals, Inc.: Research Funding. Weinstock:Novartis: Consultancy, Research Funding.

A novel t(1;8)(q25;p11.2) translocation associated with 8p11 myeloproliferative syndrome

A novel t(1;8)(q25;p11.2) translocation associated with 8p11 myeloproliferative syndrome

Angioimmunoblastic Lymphoma With Proliferative Glomerulonephritis: A Rare Association

Abstract Introduction Angioimmunoblastic T-cell lymphoma (AILT) is a subtype of peripheral T-cell lymphomas characterized by a polymorphous infiltrate involving lymph nodes, with a prominent proliferation of high endothelial venules and follicular dendritic cells along with systemic disease. It accounts for only 1%-2% of non-Hodgkin lymphomas. It usually involves peripheral lymph nodes, liver, spleen, bone marrow, and skin. Proliferative glomerulonephritis with AILT is extremely rare and is reported in only 5 cases in the literature. We describe a unique case of proliferative glomerulonephritis without immune deposits in a patient with AILT. Patients and Methods A 68-year-old male presented with complaints of shortness of breath, fever, and weakness since 3 months. Physical examination revealed generalized lymphadenopathy with multiple, nontender, mobile lymph nodes with average size between 2-5 cm and hepatosplenomegaly. 1+ pitting edema was noted on the lower extremities, and skin examination revealed evidence of generally distributed pigmented skin macules associated with itching. Patient clinical course was worsened by a progressive renal failure and nephrotic range proteinuria. Axillary lymph node biopsy revealed architectural effacement, vascular growth with monoclonal T-cell population with T-cell receptor gamma gene restriction consistent with angioimmunoblastic T-cell lymphoma. Kidney biopsy revealed proliferative glomerulonephritis with increased mesangial cellularity and endocapillary proliferation and mild interstitial fibrosis. Immunofluorescence showed focal 1+ C3 staining in the glomerular capillary walls and mesangium. There were no immune deposits on electron microscopy. Patient required 1 episode of dialysis with improvement in renal function. A single cycle of chemotherapy with the CHOP regimen (cyclophosphamide, doxorubicin, vincristine, and prednisone) was given. However, the patient developed neutropenic sepsis and died. Results The occurrence of proliferative glomerulonephritis with AILT is extremely rare. Most of the cases described so far had immune deposits. Our case is unique since the kidney biopsy did not show any evidence of immune deposits at any site. Mechanisms proposed to explain the renal lesions in lymphoid malignancies include expression of tumor antigens, autologous nontumor antigens, viral or fetal antigens, immune complex deposition and disordered T-cell function. Conclusion In our opinion, cell-mediated immune reaction and/or alternate complement pathway activation (as evidenced by focal C3 staining) might have contributed to the glomerulonephritis in this case. The number of cases with this presentation is very few and the optimum management is not known. This case adds to the literature and helps us in better understanding the disease.

Differentiating germinal center‐derived lymphomas through their cellular microenvironment

Recent studies on normal and malignant B-cells have provided evidence that the germinal center (GC) of lymphoid follicles exerts a role in B-cell physiology and malignancy. GC-derived lymphomas include both B-cell and T-cell lymphomas. Remarkably, tumor cells of GC-derived lymphomas proliferate in close association with cellular environment that retains key features of normal GC cellular microenvironment. Neoplastic follicles in follicular lymphoma contain, in addition to follicular dendritic cells (FDC) other non-neoplastic cells including macrophages and GC T-cells. In addition to aggregates of FDCs, the background infiltrate of nodular lymphocyte predominant Hodgkin lymphoma includes small B-cells, T-cells, and histiocytes. Typically, most of the lymphocyte predominant (LP) cells are ringed by CD3+/CD4+ T-cells expressing CD57, PD1, BCL6, and MUM1/IRF4. By contrast, Reed-Sternberg cells of classic Hodgkin lymphoma (cHL) are surrounded by CD3+/CD4+ T-cells expressing CD40L. Unlike cHL and other peripheral T-cell lymphomas, the AITL microenvironment characteristically contain a prominent proliferation of high endothelial venules and FDC. Thus, these findings shed new light on the characterization of GC-derived lymphomas and may help in the differential diagnosis and acknowledge several novel pathogenetic mechanisms on these lymphomas. Am. J. Hematol., 2009. (c) 2009 Wiley-Liss, Inc.

Angiogenic mediators of the angiopoietin system are highly expressed by CD10‐positive lymphoma cells in angioimmunoblastic T‐cell lymphoma

Angioimmunoblastic T-cell lymphoma (AILT) is a malignant disease of peripheral T-cell origin that is characterized by a prominent proliferation of high endothelial venules in the lymph node. To investigate angiogenic mechanisms in AILT we measured the angiogenic mediator gene expression levels in the lymph nodes of 54 non-Hodgkin lymphoma patients, by immunostaining and quantitative reverse transcription polymerase chain reaction. Angiogenic mediators angiopoietin (Ang) 1 (ANGPT1), Ang2 (ANGPT2) and their receptor, Tie2 (TEK), vascular endothelial growth factor (VEGF; VEGFA) and its receptor, VEGFR2 (KDR), and hepatocyte growth factor (HGF) and its receptor, c-Met (MET) were all more highly expressed in AILT lymph nodes (16 cases) than in B-cell lymphomas (24 cases). Moreover, significantly higher Ang1 and Tie2 expression was detected in AILT cases with CD10-positive neoplastic T-cells by comparison with unspecified peripheral T-cell lymphoma (14 cases). Immunostaining confirmed the expression of Ang1 and VEGF by both neoplastic T-cells and follicular dendritic cells. These results suggest that the angiopoietin system may play an important role in the development of high vascularity in AILT lymph nodes. Consequently, as neoplastic T-cells and follicular dendritic cells are both increased in AILT and may represent an important source of angiogenic mediators, targeting these cells with anti-angiogenic strategies might represent a novel therapy for AILT.

Adult T-cell Lymphoma/Leukemia With Angioimmunoblastic T-cell Lymphomalike Features: Report of 11 Cases

In adult T-cell lymphoma/leukemia (ATLL), the neoplastic lymphoid cells are usually medium-sized to large, often with pronounced nuclear pleomorphism compatible with the diagnosis of diffuse pleomorphic peripheral T-cell lymphoma. We describe here 11 patients with the rare morphologic variant of ATLL, angioimmunoblastic T-cell lymphoma (AILT)-like type. The examined lymph nodes showed proliferation of high endothelial venules and presence of various infiltrating inflammatory cells including plasma cells and eosinophils. The lymphoma cells were medium-to-large size with clear cytoplasm. These findings were suggestive of AILT. However, immunohistochemical features of AILT, namely, CD10 and CXCL13 expression in lymphoma cells and proliferation of CD21-positive follicular dendritic cells, were not detected. Two cases were CXCR3-positive, whereas 9 expressed CCR4, which are usually positive in ATLL. All patients were positive for antiadult T-cell leukemia/lymphoma-associated antigen, which is a specific antibody for human T-cell lymphotropic virus type-I. Southern blot analysis revealed proviral DNA integration in lymphoma cells in 9 patients. The latter was not evident in the first biopsy of 2 patients but in the second biopsy obtained within several months after the first biopsy revealed definite proviral integration. Almost all patients showed aggressive clinical course and poor survival (median survival: 5 mo). This is the first report of ATLL with AILT-like morphologic features.

A 68-Year-Old Man With Shortness of Breath and Peripheral Edema

We report a case of angioimmunoblastic T-cell lymphoma in a patient who presented with the typical clinical features of generalized lymphadenopathy: bilateral pleural effusions, splenomegaly, ascites, and polyclonal hypergammaglobulinemia. Angioimmunoblastic T-cell lymphoma is one of the more specific peripheral T-cell lymphomas accounting for approximately 15% to 20% of cases and approximately 1% to 2% of all non-Hodgkin lymphomas. Involved lymph nodes reveal partial effacement of normal architecture by a polymorphic infiltrate composed of small-to-intermediate-sized lymphocytes, plasma cells, eosinophils, and histiocytes with prominent proliferation of high endothelial venules and follicular dendritic cells. Neoplastic T cells are small to intermediate in size, show abundant clear cytoplasm with distinct membranes, are predominantly CD4 positive, and often show aberrant coexpression of CD10. The clinical course is aggressive, with a median survival of less than 3 years. Most patients succumb to infectious complications rather than tumor burden, making the administration of aggressive chemotherapy difficult.

Angioimmunoblastic T- Cell Lymphoma by Flow Cytometric Analysis.

Background: Angioimmunoblastic T cell lymphoma (AILT) is a peripheral T- cell lymphoma characterized by systemic disease, a polymorphous infiltrate involving lymph nodes with prominent proliferation of high endothelial venules and follicular dendritic cells. We present a novel technique for the presumptive diagnosis of AILT cases by flow cytometric analysis. The diagnosis of AILT was confirmed by histolopathologic features, immunohistochemical stains and molecular studies.Method: Specimens: Fresh groin excision lymph nodes. Flow cytometric analysis utilizing side scatter versus CD45. Case 1 (figure 1): The gated population consists of 10–12% B cells and 56–61% T cells. CD3, CD4 and CD5 stain 56–61% of the gated cells, while CD7 stains 41% of the gated cells, consistent with aberrant partial loss of CD7 by T cells. A population of abnormal T cells expresses CD10 with CD2, CD3, CD4 and CD7 but not with CD19 (B cells) consistent with aberrant CD10 coexpression by a subset of the T cells (12–19% of the gated cells). Staining for CD34 highlights less than 2% immature cells staining while CD64 stains less than 2% monocytic cells. Surface kappa and lambda staining does not show restriction (kappa: lambda 1–2:1). Cytoplasmic kappa and lambda staining is not interpretable due to non-specific antibody binding. Case 2 (figure 2): The gated population consists of 69% T- cells and 28–33% B- cells. A population of abnormal T cells expresses CD10 with CD2, CD3, CD4 and CD7 but not CD19 consistent with aberrant CD10 expression by a subpopulation of T cells (8–11% of gated cells). Intracellular B cell kappa lambda light chain restriction is not present and there is no aberrant co-expression of CD5, CD10 or CD43 by B cells. The diagnosis of AILT was confirmed by standard morphologic, immunoperoxidase and molecular methods subsequently in both of these cases.Discussion: Aberrant CD10 expression on neoplastic T cells has been shown with immunohistochemical staining of paraffin embedded tissue in AILT. Our cases show aberrant coexpression of CD10 by CD2, CD3, CD4 and CD7 positive T cells in more than 10% of gated cells by Flow cytometric analysis.Conclusion: Flow Cytometric analysis is a useful and reproducible tool for immunophenotyping AILT cells and should be considered for presumptive diagnosis of AILT. [Display omitted] [Display omitted]

CD4+/bcl-6+ Peripheral T-Cell Lymphoma with Follicular Involvement: A Distinct Type of Nodal Peripheral T-Cell Lymphoma with Multiple T-Cell Clones.

We studied six cases of a novel type of nodal peripheral T-cell lymphoma. Three cases with this disease were recently described by de Leval et al. (de Leval L, Savilo E, Longtine J, et al. Peripheral T-cell lymphoma with follicular involvement and a CD4+/bcl-6+ phenotype. Am J Surg Pathol 2001; 25:395–400). The entity was named peripheral T-cell lymphoma with follicular involvement because of its distinctive histological features. We report an additional six well-characterized cases and describe the molecular and cytogenetic findings. The neoplastic T-cells of this lymphoma type express CD4 and Bcl-6, and home to the B-lymphoid follicles. This suggests an origin of the lymphoma from an as yet poorly characterized subset of Bcl-6 expressing intra-follicular T-helper cells. Of interest, the cytogenetic data and/or the study of T-cell receptor gamma gene rearrangements revealed more than one clone in each case. Cytogenetics further revealed complex karyotypes without recurrent chromosomal aberrations. We also studied the presence of somatic mutations in the 5′ untranslated region of the BCL-6 gene in four of the cases but no somatic hypermutation was detected. Clinically, the cases presented with widespread lymph node involvement at diagnosis and multiple relapses occurred after treatment. All patients received a CHOP-based chemotherapy regimen, later followed by high dose chemotherapy with stem cell rescue in five patients. One patient died with lymphoma and hemophagocytic syndrome 24 months after diagnosis, one patient is alive with disease after 27 months from diagnosis, whereas the other four patients are in complete remission 12 to 124 months after diagnosis. In conclusion, we confirm that peripheral T-cell lymphoma with follicular involvement is a distinct lymphoma type and we show that the lymphoma is oligo-clonal. The clinical findings are those of an intermediately aggressive lymphoma type. Although minimal lymph node infiltration with lymphoma cells at diagnosis and oligo-clonality is also characteristic of angio-immunoblastic T-cell lymphoma, we believe that peripheral T-cell lymphoma with follicular involvement is a distinct T-cell lymphoma type. In contrast to angio-immunoblastic T-cell lymphoma it is characterized by the typical infiltration of lymphoma cells in B-lymphoid follicles, coagulation necrosis, the absence of proliferation of high endothelial venules and follicular dendritic cells in T-cell areas, as well as the absence of EBV infection. It is likely that T-cell lymphoma with follicular involvement arises from Bcl-6+ intra-follicular T-cells. No recurrent genetic defects have been identified but the oligo-clonal nature of the lymphoma is intriguing. The latter suggests that the triggering oncogenic factors are external, such as infection.

Angioimmunoblastic T-cell lymphoma with hyperplastic germinal centers: a clinicopathological and immunohistochemical study of 10 cases.

An absence of germinal centers is one of the histological characteristics of angioimmunoblastic T-cell lymphoma (AITL). We report here 10 unusual cases of AITL with hyperplastic germinal centers. The clinical presentation of each patient was characterized by generalized lymphadenopathy, constitutional symptoms and polyclonal hypergammaglobulinemia. The initial biopsy findings of each patient were similar and were characterized by hyperplastic germinal centers with ill-defined borders and a proliferation of high endothelial venules (HEV). In the paracortical area there was a mixed infiltrate including irregularly shaped clusters or small nests of clear cells in all cases. Moreover, the clear cells invaded the lymphoid follicles, resulting in expansion of the germinal centers, except for one case. Immunohistochemistry revealed that the tumor cells, including clear cells, were CD4-expressing T cells. Some of the atypical lymphocytes were also Bcl-6-positive. A majority of the follicular dendritic cell networks showed a normal/reactive or an expanded/disrupted pattern in all cases. Moreover, three lesions possessed a few large irregularly shaped proliferations of follicular dendritic cells around the HEV Four cases progressed to AITL within a few years. The present 10 cases probably represent an early stage of AITL preceding follicular dendritic cell hyperplasia. Detection of clear cells, Bcl-6-positive atypical T lymphocytes, and foci of irregularly shaped proliferation of follicular dendritic cells appears to be critical for early diagnosis and treatment of AITL with hyperplastic follicles.

Migratory patterns of thoracic duct lymphocytes into bronchus-associated lymphoid tissue of immunized rats.

Lymphocytes continuously circulate between the bloodstream and lymphoid organs, and their migration into lymphatic tissues presumably occurs through selective mechanisms. Although bronchus-associated lymphoid tissue (BALT) is known as an inductive tissue of the common mucosal immune system, little is known about how effectively the lymphocytes in the blood vessels migrate into the BALT, thereby enabling the BALT to act as an effector tissue in the immunologic responses of the lungs. To analyze whether or not thoracic duct lymphocytes (TDL) from immunized and nonimmunized rats possess different migratory patterns to the BALT, 5-(6)-carboxyfluorescein diacetate succinimidyl ester (CFSE)-labeled TDL were injected into rats with BALT hyperplasia that was produced by intratracheal administration of TNP-KLH, and then the number of labeled cells in the BALT were examined by immunohistochemical methods. We studied the following three groups at 12 h after the injection: group A, intraintestinally immunized donors and intratracheally immunized recipients; group B, nonimmunized donors and intratracheally immunized recipients; group C (control group), nonimmunized donors and nonimmunized recipients. Time course studies 0.5, 4, 12, and 24 h after the injection were done in groups A and C. In a cytokinetic study, larger numbers of CFSE-labeled lymphocytes were found at 12 h and 24 h in group A than in group C. At 12 h after the injection, the absolute number of CFSE-labeled lymphocytes per BALT was significantly higher in group A than in group B (p < 0.05), and was lowest in group C. Histologically, there was a marked proliferation of high endothelial venules (HEV), with findings of adhesion and influx of lymphocytes inside the HEV in group A. These observations indicate that the immunized BALT actively recruits immunized TDL through a specific mechanism of lymphocyte-endothelium recognition in HEV, which partially explains the process of BALT development as an effector tissue for local immunity.

Cell Dynamics and Expression of Tumor Necrosis Factor (TNF)-α, Interleukin-6, and TNF Receptors in Angioimmunoblastic Lymphadenopathy-Type T Cell Lymphoma

Angioimmunoblastic lymphadenopathy (AILD)-type T cell lymphoma is histologically characterized by a mixed infiltrate of atypical T cells and B cells including B immunoblasts and plasma cells as well as eosinophils accompanied by proliferation of high endothelial venules. These morphological peculiarities are widely believed to reflect an abnormal pattern of cytokine expression. To clarify the cell dynamics and cytokine expression pattern in the lymph nodes of AILD-type T cell lymphoma, the frequency of proliferating/apoptotic cells and localization of tumor necrosis factor (TNF)-α and interleukin (IL)-6 producing cells were determined. Double staining was performed for (1) cell markers and Ki-67 antigen, (2) cell markers and the terminal deoxytransferase-mediated dUTP nick end labeling (TUNEL) method, or (3) cell markers and cytokines. The proliferating cell ratio in atypical T cells of AILD-type T cell lymphoma determined by Ki-67 labeling was 20.2 ± 5.0%, while other peripheral T cell lymphomas (PTL) exhibited a ratio of 32.9 ± 2.5%. TUNEL-positive apoptotic cells were 0.8 ± 0.1% of total cells in AILD-type T cell lymphoma. They were dominantly atypical cells with positive T cell markers. In contrast, lymphoma cells in other types of PTL or paracortical cells in reactive follicular hyperplasia had only 0.3 ± 0.1 or 0.4 ± 0.1% TUNEL-positive cells, respectively. Thus, lymphoma cells in AILD-type T cell lymphoma demonstrated suppressed proliferating activity and enhanced apoptosis when compared to other types of PTL. TNF-α-producing cells were observed in all of the lymph nodes from AILD-type T cell lymphoma cases (15/15) and positive staining was obtained in the majority of atypical T cells and scattered macrophages. In contrast, IL-6 was localized to clusters of atypical T cells in some of the cases (9/15). Further, the expression of TNF-α, IL-6, and TNF receptors I and II (TNFRI and TNFRII) was examined by RT-PCR. The TNF-α message (2/2) and IL-6 message (2/2) was present in the lymph nodes of AILD-type T cell lymphoma by examination using RT-PCR, while both messages were negative in control cases (0/7). As far as an expression of mRNA for TNF receptors in AILD-type T cell lymphoma cases, mRNA for TNFRI was definitely expressed in both of the cases (2/2) while TNFRII mRNA was weakly expressed in one case (1/2). Overexpression of TNF-α as well as TNFRI may play a role in controlling T cell proliferation through an autocrine (T cell–T cell interaction) and paracrine (macrophage–T cell interaction) fashion. IL-6, which was also expressed by part of lymphoma cells of AILD-type T cell lymphoma, facilitates the proliferation of B cells, plasma cells, and T cells or endothelial cells in the lymph nodes of AILD-type T cell lymphoma.

Epithelioid haemangioma (Angiolymphoid hyperplasia with eosinophilia) and kimura’s disease in chinese

Though Kimura’s disease has often been considered to be identical to angiolymphoid hyperplasia with eosinophilia (epithelioid haemangloma), recent studies suggest that they are different clinicopathologic entities. We have made a detailed morphological comparison between 10 cases of epithelioid haemangioma and 40 cases of Kimura’s disease occurring in the Chinese population. The epithelioid haemangiomas occurred in the subcutis, skin and maxillary antrum, whereas Kimura’s disease affected the subcutis, major salivary glands and lymph nodes. Distinctive features of epithelioid haemangiomas were exuberant proliferation of vessels lined by cuboidal to hobnail endothelial cells with irregular nuclei and cytoplasmic vacuoles, fibromyxoid matrix, involvement of muscular coat of blood vessels, and zonation of inflammatory infiltrate towards the peripheral portion of the lesion. Distinctive features of Kimura’s disease were florid lymphoid infiltrate with prominent lymphoid follicles, vascularization of germinal centre, germinal centre necrosis, marked eosinophilia with or without eosinophil abscess formation, proliferation of high endothelial venules, and sclerosis. The histological features suggest that epithelioid haemangloma is a proliferation of atypical endothelial cells, possibly neoplastic, that has attracted a variable inflammatory component, whereas Kimura’s disease is primarily an inflammatory condition in which high endothelial venules are usually present.

Epithelioid haemangioma (angiolymphoid hyperplasia with eosinophilia) and Kimura's disease in Chinese.

Although Kimura's disease has often been considered to be identical to angiolymphoid hyperplasia with eosinophilia (epithelioid haemangioma), recent studies suggest that they are different clinicopathological entities. In this study, we have made a detailed morphological comparison of 10 cases of epithelioid haemangioma and 40 cases of Kimura's disease occurring in the Chinese population. The epithelioid haemangiomas occurred in the subcutaneous tissue, skin and maxillary antrum, whereas Kimura's disease affected the subcutaneous tissue, major salivary glands and lymph nodes. Distinctive features of epithelioid haemangiomas were exuberant proliferation of vessels lined by cuboidal to hobnail endothelial cells with irregular nuclei and cytoplasmic vacuoles, fibromyxoid matrix, involvement of muscular coat of blood vessels and zonation of inflammatory infiltrate towards the peripheral portion of the lesion. Distinctive features of Kimura's disease were florid lymphoid infiltrate with prominent lymphoid follicles, vascularization of germinal centres, germinal centre necrosis, marked eosinophilia with or without eosinophil abscess formation, proliferation of high endothelial venules, and sclerosis. The histological features suggest that epithelioid haemangioma is a proliferation of atypical endothelial cells, possibly neoplastic, that is associated with a variable inflammatory infiltrate, whereas Kimura's disease is primarily an inflammatory condition in which high endothelial venules are usually found.