Immunophenotypic classification regarding prognosis in peripheral T cell lymphoma, NOS, and nodal T follicular helper T cell lymphoma, angioimmunoblastic-type.

This study aimed to determine the clinicopathological predictive factors of peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS), and nodal T-follicular helper cell lymphoma, angioimmunoblastic-type (nTFH, AI-type). In this single-centered, retrospective study, medical records of 59 patients who were diagnosed with PTCL, NOS, or nTFH, AI-type from March 2007 to September 2022 were reviewed. The clinicopathological variables, including immunohistochemistry(IHC) subgroups, distinguishing TBX21 from the GATA3 subgroups were analyzed. Overall, 28 patients (75.7%) in the TBX21 group were PTCL, NOS. There were 9 (24.3%) patients in the GATA3 group. In univariable analyses, lymphoma subtype, age, and performance status were associated with progression-free survival (PFS), and overall survival (OS). In multivariable analyses, lymphoma subtype, and performance status were related to PFS and OS (P = 0.012, P < 0.001, P = 0.006, and P < 0.001, respectively). The GATA3 subgroup tended to have a worse prognosis in univariable analyses; however, it became more insignificant in multivariable when lymphoma subtype and performance status were adjusted (P = 0.065, P = 0.180, P = 0.972, and P = 0.265, respectively). The double-positive group showed variable prognoses of better PFS and worse OS. PD-1 and PD-L1 were associated with the EBV in situ hybridization (P = 0.027, and P = 0.005), and PD-1 was associated with CD30 expression (P = 0.043). This study demonstrated the potential of IHC classification to predict prognosis for PTCL, NOS, as well as nTFH AI-type, although further validation is necessary. Treatments targeting CD30, PD-1, and PD-L1 appear promising for lymphoma treatment.

Follicular helper T-cell-related lymphomas.

In this issue of Blood, Wang et al describe the occurrence and pathogenetic relevance of IDH2R172 mutations in angioimmunoblastic T-cell lymphoma (AITL).

IDH2R172 mutations define a unique subgroup of patients with angioimmunoblastic T-cell lymphoma.

Angioimmunoblastic T-cell lymphoma (AITL) is a common subtype of peripheral T-cell lymphoma (PTCL) with a poor prognosis. We performed targeted resequencing on 92 cases of PTCL and identified frequent mutations affecting RHOA, TET2, DNMT3A, and isocitrate dehydrogenase 2 (IDH2). Although IDH2 mutations are largely confined to AITL, mutations of the other 3 can be found in other types of PTCL, although at lower frequencies. These findings indicate a key role of epigenetic regulation in the pathogenesis of AITL. However, the epigenetic alterations induced by these mutations and their role in AITL pathogenesis are still largely unknown. We correlated mutational status with gene expression and global DNA methylation changes in AITL. Strikingly, AITL cases with IDH2(R172) mutations demonstrated a distinct gene expression signature characterized by downregulation of genes associated with TH1 differentiation (eg, STAT1 and IFNG) and a striking enrichment of an interleukin 12-induced gene signature. Ectopic expression of IDH2(R172K) in the Jurkat cell line and CD4(+) T cells led to markedly increased levels of 2-hydroxyglutarate, histone-3 lysine methylation, and 5-methylcytosine and a decrease of 5-hydroxymethylcytosine. Correspondingly, clinical samples with IDH2 mutations displayed a prominent increase in H3K27me3 and DNA hypermethylation of gene promoters. Integrative analysis of gene expression and promoter methylation revealed recurrently hypermethylated genes involved in T-cell receptor signaling and T-cell differentiation that likely contribute to lymphomagenesis in AITL.

Pathobiology and molecular profiling of peripheral T-cell lymphomas.

Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of rare diseases, usually manifesting clinical aggressiveness. Although important novel insights into the pathobiology of nodal PTCL have been gained recently from molecular profiling studies and clinico-pathological analyses, the pathogenetic molecular lesions remain to be deciphered for most entities. Angioimmunoblastic T-cell lymphoma (AITL) comprises CD4+ CXCL13+ neoplastic cells displaying overlapping immunophenotypical and molecular features with normal follicular helper T cells. This derivation might account for the presence of a prominent non-neoplastic component in AITL tissues and the clinical manifestations of the disease reflective of an immunological dysfunction. ALK+ anaplastic large cell lymphoma (ALCL), defined by ALK gene translocation with various gene partners, is composed of CD30+ ALK+ cells with a cytotoxic phenotype and usually carries a good prognosis. ALK- ALCL, now considered as a distinct disease entity, is morphologically and immunophenotypically similar to ALK+ ALCL, except for ALK expression, but has distinctive molecular features. PTCL, not otherwise specified (PTCL, NOS), the largest PTCL category, which is derived from activated CD4+ (or CD8+) T cells, is markedly heterogeneous, including at the molecular level. Gene expression profiling approaches have identified novel biomarkers of potential therapeutic interest, and suggest the existence of molecularly distinct PTCL, NOS subgroups.

[Clinicopathological analysis of patients with angioimmunoblastic T-cell lymphoma (AILT)].

We retrospectively analyzed the clinical course and prognosis of 11 patients with angioimmunoblastic T-cell Lymphoma (AILT). Median patient age was 62 years old (range 39 to 85). All patients were in clinical stage III or IV. Clinical features included B symptoms, hepatosplenomegaly, skin rushes, pleural effusion, ascites and polyclonal hypergammaglobulinemia. The disease can be classified into three categories based on histological findings: 3 cases of AILT with hyperplastic germinal centers, 4 cases of typical AILT, and 4 cases of AILT with numerous clear cells. As the initial therapy, 10 patients received combination chemotherapy and only 1 patient received autologous peripheral blood stem cell transplantation. Seven patients achieved CR and 4 showed PD. The response rate was 63% and the median survival time was 20 months. One patient survived in CR for 122 months. Patients with AILT demonstrating hyperplastic germinal centers and no bone marrow infiltration were able to achieve long-term survival. The survival time of AILT demonstrated a wide range. It was thought that further consideration of the prognostic factors and stratification was required.

Th1, Th2, and activated T-cell marker and clinical prognosis in peripheral T-cell lymphoma, unspecified: comparison with AILD, ALCL, lymphoblastic lymphoma, and ATLL.

A new World Health Organization classification was recently proposed. However, classification of peripheral T-cell lymphomas remains to be clarified. Particularly, unspecified type was considered as a heterogeneous category. Here we studied the expressions of chemokine receptors, Th1-associated CXCR3 and CCR5 and Th2-associated marker ST2(L), and activated T-cell receptor OX40/CD134 in 185 patients with nodal T-cell lymphoma, and evaluated the relationship to prognosis. Their expression patterns correlated with the specific subtype of nodal T-cell lymphoma, such as angioimmunoblastic T-cell lymphoma (AILD), anaplastic large cell lymphoma (ALCL), and in peripheral T-cell lymphoma (PTCL), unspecified. In AILD, almost all cases were immunoreactive for OX40/CD134 (96%) and for CXCR3 (89%). In ALCL, all cases were immunonegative for OX40/CD134, and only a few cases (24%) were immunoreactive for CXCR3, whereas almost all cases (94%) were positive for ST2(L). Cases of PTCL, unspecified, were divided into 2 groups; group 1 (cases positive for either ST2(L), CCR5, or CXCR3) tended to show favorable prognosis compared with group 2 (cases negative for ST2(L), CCR5, and CXCR3). Our results indicate that further subtyping of PTCL, unspecified, into groups 1 and 2 could be significant for evaluating prognosis and understanding the functional role of these tumors.

Peripheral T-cell lymphomas: clinical features and prognostic factors of 92 cases defined by the revised European American lymphoma classification.

The purpose of this study was to better define the clinical features and natural history of peripheral T-cell lymphomas (PTCL) entities included in the Revised European American lymphoma (REAL) classification. Cases of PTCL were retrieved from the records of the Department of Pathology and classified according to the REAL classification. In addition, cases of anaplastic large cell lymphoma (ALCL) were divided into classical, small cell, and primary cutaneous subtypes, and immunostaining for the anaplastic large-cell kinase (ALK) protein was performed on all cases of ALCL. Clinical features, response to therapy and survival were abstracted. Ninety-two cases of PTCL with adequate clinical information were retrieved. There were 40 cases of ALCL (30 classical, 7 small cell variant, 3 primary cutaneous), 28 PTCL, unspecified, 13 angioimmunoblastic T-cell lymphoma and 11 with other entities. The patients had a median age of 48 years with a range of 6-84 and had an estimated overall survival (OS) of 49% and progression-free survival (PFS) of 22% at 5 years. The International Prognostic Index (IPI) was a significant prognostic factor for both progression-free and OS. Histology was a significant predictor of PFS with anaplastic large cell having the best prognosis. ALK expression was not associated with an improved progression-free or overall-survival in patients with systemic T-cell ALCL. In conclusion, the REAL classification describes distinct PTCL entities. The IPI is the most important predictor of progression-free and OS in patients with PTCL. ALK expression may not provide prognostic information for systemic ALCL.

[Heterogeneous Epstein-Barr virus infection patterns in peripheral T cell lymphoma of the angioimmunoblastic lymphadenopathy type]. / Heterogene Epstein-Barr Virus Infektionsmuster beim peripheren T-Zellenlymphom vom Typ der angioimmunoblastischen Lymphadenopathie.

32 cases of T cell lymphoma of angioimmunoblastic lymphadenopathy type (AILD-TCL) were investigated for their association with Epstein-Barr virus (EBV). Polymerase chain reaction (PCR) for detection of EBV-DNA and in situ hybridization for EBV-encoded small nuclear RNAs (EBER) produced almost identical results, showing that all but one of AILD-TCL cases contained EBV genomes. Three distinctive patterns of EBV infection were observed after immunophenotypical characterization of EBER positive cells: 1. predominant infection of B-immunoblasts (26% of the cases), 2. predominant infection of neoplastic T cells (42% of the cases) and 3. infection of few small lymphocytes (32% of the cases). EBV-encoded latent membrane protein was frequently detectable in cases exhibiting patterns 1 and 2. These findings suggest that, in AILD-TCL patients B cells and especially T cells are highly susceptible to a persistent EBV infection which may lead to a growth advantage of infected cells.

Angioimmunoblastic lymphadenopathy and related disorders: a retrospective look in search of definitions.

The recent report of an immunoblastic lymphadenopathy (IBL)-like T cell lymphoma has rekindled questions about the nature, reactive or neoplastic, of IBL, angioimmunoblastic lymphadenopathy (AIL), and lymphogranulomatosis X (LgX) and blurred the criteria for their diagnosis. We looked in the literature and our own data for a categorization of AIL (IBL, LgX) and related disorders, needed for future prospective studies. Specific differences in the original histologic definitions and discordant immunophenotypic data may warrant the separate consideration of AIL, IBL and LgX and their subdivision into predominantly T cell or B cell lesions. DNA hybridization and cytogenetic studies of the processes sharing histologic features of AIL (IBL, LgX) demonstrate a continuum of disorders from purely reactive to frankly malignant, which may be categorized as follows: (1) those without evidence of clonality by any of three parameters (immunophenotypic, immunogenotypic, and cytogenetic), for which only the term AIL (IBL, LgX) might be reserved; (2) those with evidence of clonality by all parameters, or AIL (IBL, LgX)-like lymphomas; and (3) those that, due to any discordance among the three parameters, do not fit into either of the above categories, and for which the term AIL (IBL, LgX)-like dysplasias is proposed. This intermediate group seems to be composed of unstable lymphoproliferative conditions, in which a predominant component of normal cells coexists with clonal population(s) that may either disappear with time or selectively proliferate and develop into frank lymphoma.

Clinicopathologic, immunophenotypic, and immunogenotypic analyses of immunoblastic lymphadenopathy-like T-cell lymphoma.

Immunoblastic lymphadenopathy (IBL)-like T-cell lymphoma is a distinct peripheral T-cell lymphoma, which closely resembles angioimmunoblastic lymphadenopathy with dysproteinemia (AILD) and/or IBL, but is characterized by focal or sheet-like proliferation of immunoblasts and pale cells of T-cell nature. In this report, 36 patients with IBL-like T-cell lymphoma were analyzed. The disease is clinically characterized by generalized lymph node swelling, hepatosplenomegaly, fever, skin rash, polyclonal hypergammaglobulinemia, marked male predominance, predilection for the elderly, and poor prognosis. There was no association with human T-cell leukemia virus type I or human immunodeficiency virus. IBL-like T-cell lymphoma may be divided into two categories (CD4+ type and CD8+ type) by surface marker analysis. It can also be divided into three categories on the basis of the histologic findings of distribution of morphologically recognizable tumor cells: nine cases of "inconspicuous type," six cases of "patchy type," and 21 cases of "diffuse type." Two cases of "inconspicuous type" converted later to "diffuse type." DNA hybridization analyses in the ten recent cases revealed that three of four "inconspicuous types" and five of six "diffuse types" showed clonal rearrangement of T-cell receptor-beta chain gene without rearrangement of immunoglobulin heavy chain gene, providing strong evidence for clonal proliferation of T cells.

Immunoblastic lymphadenopathy, angioimmunoblastic lymphadenopathy, and IBL-like T-cell lymphoma. A spectrum of T-cell neoplasia.

Thirty cases of immunologically determined and histologically diagnosed immunoblastic lymphadenopathy (IBL), angioimmunoblastic lymphadenopathy (AILD), and IBL-like T-cell lymphoma were clinicopathologically reviewed. Clinical manifestations and laboratory findings did not reveal significant differences in these three groups. IBL, AILD, and IBL-like T-cell lymphoma showed a spectrum of histologic changes, in which proliferation of pale cells was a critical diagnostic point for the histologic malignancy. Immunostaining for their subsets revealed that 3 of 21 cases showed T4+ phenotype and the remaining 19 cases showed T8+ phenotype. Three of seven immunohistochemically determined T8+ cases simultaneously expressed Leu7+ phenotype. The latter cells were consistent with large granular lymphocytes in one case, but no clinicopathological differences from the other T8+ cases were present. IBL and AILD were considered to be T-cell malignancies, which show a spectrum of histologic features from T-cell dysplasia to peripheral T-cell lymphoma (IBL-like T-cell lymphoma). Despite intensive chemotherapy, prognosis was poor in T8+ cases of which half of the patients died within 1 year. T4+ cases showed better prognosis, but a higher incidence of synchronous second primary cancers was recognized.

Peripheral T-cell lymphomas: histologic, immunohistologic, and clinical characterization.

A review of 40 cases of peripheral T-cell lymphoma identified at our institution between March 1983 and December 1985 revealed a clinically, histologically, and immunologically diverse group of neoplasms that were difficult to classify by conventional histomorphologic criteria for non-Hodgkin's lymphomas. These lymphomas were frequently extranodal at the time of initial manifestation (52%), and their clinical aggressiveness correlated with three major histologic categories--small lymphocytic, diffuse mixed, and large cell. Of the 40 lymphomas, 18 exhibited distinctive histologic features that allowed assignment of these cases into one of four subgroups: (1) angioimmunoblastic lymphadenopathy, (2) lymphomatoid granulomatosis, (3) Hodgkin's-like disease, and (4) Lennert's lymphoma (lymphoepithelioid lymphoma). Study of all our cases that fulfilled the morphologic criteria for lymphomatoid granulomatosis or angioimmunoblastic lymphadenopathy by using immunologic methods for identification of B-cell and T-cell antigens has shown these neoplasms to be peripheral T-cell lymphomas. Therefore, we now consider these earlier proposed entities to be distinct histologic variants of peripheral T-cell lymphoma.

Bone marrow histology in Waldenström's macroglobulinaemia. Clinical relevance of subtype recognition.

Bone marrow biopsies of 137 patients with Waldenström's macroglobulinaemia (WM), 26 with non-secretory immunocytoma and 32 with benign monoclonal gammopathy were processed for histologic evaluation. Bone marrow involvement was found in 110 (80%) initially, and in 24 (18%) in sequential biopsies. 3 types were distinguished: lymphoplasmacytoid (47%), lymphoplasmacytic (42%) and polymorphous (11%) with median survivals of 74, 25 and 12 months, respectively. When grouped according to the tumour cell mass in the biopsies, the median survivals were 55, 21 and 8 months for less than 20 vol%, 20-50 vol% and greater than 50 vol% respectively; in each subtype, the tumour cell mass correlated with the disease progression. 6 clinical variables were also found prognostically significant. These results demonstrate that (i) 98% of patients with WM have bone marrow involvement; (ii) the lymph node sub-classification is applicable to the bone marrow and has both clinical and prognostic significance; (iii) patients may be staged according to the tumour cell burden in the bone marrow biopsy.

[Nosologic position of angioimmunoblastic lymphadenopathy. Apropos of 2 debatable cases]. / Sulla posizione nosologica della linfadenopatia angioimmunoblastica. A proposito di due casi controversi.

Two cases of lymphadenopathy grouped together by a common histologic diagnosis of angio-immunoblastic lymphadenopathy (A.I.L.) have been described. While in the first case there was a recent vaccination with BCG and tests positive for toxoplasmosis, the second case did not reveal any important anamnestic elements. The first case appeared to respond to antiprotozoan therapy while the second underwent lymphomatous degeneration with cerebral involvement. In view of the different clinical developments the existing nosologic position of A.I.L. comes under discussion. The great difficulty with which A.I.L. is demarcated from forms of reactive or neoplastic lymphadenopathy is emphasized by this example. Essential towards this is the study of lymphocyte markers and their in vitro function.