Genomic profiling of peripheral T-cell lymphoma, unspecified, and anaplastic large T-cell lymphoma delineates novel recurrent chromosomal alterations

To characterize genetic alterations in peripheral T-cell lymphoma, not otherwise specified (PTCL NOS), and anaplastic large T-cell lymphoma (ALCL), 42 PTCL NOS and 37 ALCL [17 anaplastic large cell kinase (ALK)-negative ALCL, 9 ALK-positive ALCL, 11 cutaneous ALCL] were analyzed by comparative genomic hybridization. Among 36 de novo PTCL NOS, recurrent chromosomal losses were found on chromosomes 13q (minimally overlapping region 13q21, 36% of cases), 6q and 9p (6q21 and 9p21-pter, in 31% of cases each), 10q and 12q (10q23-24 and 12q21-q22, in 28% of cases each), and 5q (5q21, 25% of cases). Recurrent gains were found on chromosome 7q22-qter (31% of cases). In 11 PTCL NOS, high-level amplifications were observed, among them 3 cases with amplification of 12p13 that was restricted to cytotoxic PTCL NOS. Whereas cutaneous ALCL and ALK-positive ALCL showed few recurrent chromosomal imbalances, ALK-negative ALCL displayed recurrent chromosomal gains of 1q (1q41-qter, 46%), and losses of 6q (6q21, 31%) and 13q (13q21-q22, 23%). Losses of chromosomes 5q, 10q, and 12q characterized a group of noncytotoxic nodal CD5+ peripheral T-cell lymphomas. The genetics of PTCL NOS and ALK-negative ALCL differ from other T-NHLs characterized genetically so far, among them enteropathy-type T-cell lymphoma, T-cell prolymphocytic leukemia, and adult T-cell lymphoma/leukemia.     

BCL-2 family proteins in peripheral T-cell lymphomas: correlation with tumour apoptosis and proliferation

The present study investigated expression levels of the anti-apoptotic proteins BCL-2, BCL-XL and MCL-1 and the pro-apoptotic proteins BAX and BCL-XS in a series of 112 peripheral T-cell lymphomas (PTCLs) classified according to the WHO classification. Using immunohistochemical methods and a 10% cut-off, each protein was detected in a subset of PTCLs: BCL-2 in 46%, BCL-XS in 49%, BAX in 57%, BCL-XL in 57%, and MCL-1 in 65%. The mean percentage of positive cells for these proteins varied significantly among the PTCL types. Only two types of PTCL, ALK-positive anaplastic large cell lymphoma (ALCL) and enteropathy-type T-cell lymphoma, had a distinctive pattern of expression; all were BCL-2-negative and MCL-1-positive. The mean percentage of BAX-positive and BCL-XS-positive tumour cells was higher in ALK-positive ALCL than in ALK-negative ALCL or other types of PTCL (p = 0.06 and p = 0.01, respectively, Kruskal-Wallis test). MCL-1 was detected significantly more frequently (p = 0.01, chi-square test) and at higher levels (p = 0.0001, Kruskal-Wallis test) in ALK-positive ALCL and ALK-negative ALCL than in other PTCL types. The apoptotic rate, evaluated by the TUNEL assay, correlated inversely with BCL-2 expression (p = 0.035). The proliferation index, assessed by the MIB-1 antibody, correlated with expression levels of MCL-1 (R = 0.42, p = 0.003), BCL-2 (R = 0.32, p = 0.027), BAX (R = 0.33, p = 0.014), and BCL-XL (R = 0.34, p = 0.015) (Spearman rank). In conclusion, BCL-2 family proteins are expressed by a subset of PTCLs and their levels correlate with some histological types, apoptotic rate, and proliferation index. Expression of these proteins may explain the poor response of many types of PTCL to standard chemotherapy. These proteins may also provide novel targets for experimental therapy.     

T-cell lymphomas in children

T-cell lymphomas in children are rare and compromise a rather limited spectrum of entities. Relatively frequently observed are precursor T-cell lymphomas mainly presenting as mediastinal tumors with or without leukemia and ALK-positive anaplastic large cell lymphomas (ALCL) with nodal or extra nodal manifestations. In contrast to adults, where peripheral T-cell lymphoma (PTCL) is the most frequent T-cell neoplasia, PTCL in children is exceptional and remains a challenging diagnosis even for experienced haematopathologists. Other rare T-cell lymphomas occasionally seen in children are panniculitis like T-cell lymphomas, NK/T-cell lymphomas and hepatosplenic gamma delta-lymphomas. Of note angioimmunoblastic T-cell lymphoma is never seen in children. Mimickers of T-cell lymphomas like viral or immunological disorders in children are more frequent than manifest T-cell lymphomas and knowledge of these reactive conditions and their differential diagnosis is essential. The recognition of typical histopathological and clinical features along with knowledgeable use and interpretation of immunohistochemical and molecular markers are mandatory for a reliable diagnosis of childhood T-cell lymphomas.     

Anaplastic Large Cell Lymphoma

Session 8 of the 2005 Society of Hematopathology/European Association for Haematopathology Workshop was devoted to anaplastic large cell lymphoma (ALCL). Most cases submitted were anaplastic lymphoma kinase (ALK)+ ALCL highlighting unusual clinical settings, histologic variants, and variant translocation partners. Cases submitted as ALK- ALCL emphasized the immunohistochemical overlap with classical Hodgkin lymphoma (eg, CD15+/CD30+). It was also clear that consensus histologic and immunohistochemical criteria for the diagnosis of ALK-ALCL are lacking. Many expressed the opinion that ALK-ALCL is not a distinct entity at the immunophenotypic or genetic level and is better designated as peripheral T-cell lymphoma (PTCL), unspecified. Others suggested that the histologic features of ALK-ALCL are distinctive nevertheless and that this diagnosis has meaning that is lost by designating these neoplasms as PTCL, unspecified. This session also included CD30+ anaplastic lymphomas involving skin in which the differential diagnosis included cutaneous ALCL and systemic ALK-ALCL.     

Evaluation of FoxP3 expression in peripheral T-cell lymphoma

Peripheral T-cell lymphomas (PTCLs) are biologically heterogeneous and have not been successfully correlated with specific T-cell subsets. We investigated PTCL, not otherwise specified (NOS), angioimmunoblastic T-cell lymphoma (AILT), and anaplastic large cell lymphoma (ALCL) cases for FoxP3 expression to determine a potential derivation from regulatory T (Treg) cells. One PTCL-NOS case strongly expressed FoxP3 in the neoplastic T cells and showed unusual histomorphologic features with a dense infiltration of the lymph node by immunoblastic T cells and almost no reactive background infiltrate. The patient died shortly after diagnosis, suggesting that biologic properties of Treg cells may have contributed to the rapidly fatal clinical course. All remaining PTCL-NOS and AILT cases showed FoxP3 positivity only in the reactive infiltrate. Among ALCL cases, 4 of 6 ALK+ cases displayed weak and inhomogeneous FoxP3 expression in the tumor cells. FoxP3+ PTCL-NOS presumably derived from bona fide Treg cells occurs but seems rare in the Western population.     

Immunoreactivity of CD99 in non-Hodgkin's lymphoma: unexpected frequent expression in ALK-positive anaplastic large cell lymphoma

To verify the spectrum of CD99-expressing lymphoid malignancy, an immunohistochemical study for CD99 was carried out in 182 cases of non-Hodgkin's lymphoma, including 21 lymphoblastic lymphomas, 11 small lymphocytic lymphomas, 9 mantle cell lymphomas, 12 follicular lymphomas, 37 diffuse large B cell lymphomas, 18 Burkitt's lymphomas, 28 NK/T-cell lymphomas, 8 angioimmunoblastic T-cell lymphomas, 23 peripheral T-cell lymphomas, unspecified, and 15 systemic anaplastic large cell lymphomas. CD99 was positive in all T-lymphoblastic lymphomas and in 60% of B-lymphoblastic lymphomas. Majority of T and NK cell lymphomas were negative for CD99, except anaplastic large cell lymphomas (ALCLs). Eight of 15 cases (54%) of ALCLs reacted with anti CD99 antibody. Seven of 10 (70%) ALK positive ALCLs expressed CD99, whereas only 1 of 5 (20%) ALK negative ALCLs were positive. Of the mature B-cell lymphomas, 5.4% (2/37) of diffuse large B cell lymphomas and 11.1% (2/18) of Burkitt's lymphomas expressed CD99. In conclusion, CD99 is infrequently expressed in mature B and T cell lymphomas, except ALK-positive ALCL. High expression of CD99 in ALK-positive ALCL is unexpected finding and its biologic and clinical significances have yet to be clarified.     

ALK-negative anaplastic large-cell lymphoma demonstrates similar poor prognosis to peripheral T-cell lymphoma, unspecified

AIMS: Anaplastic large cell lymphoma (ALCL) is classically considered a clinicopathological entity separate from other nodal mature T-cell lymphomas (TCL). Recently, the anaplastic lymphoma kinase (ALK) protein was shown to identify a subgroup of nodal ALCL with an excellent prognosis, whereas ALK-negative ALCLs are more heterogeneous. The aim of this study was to investigate the clinicopathological parameters in relation to clinical behaviour of ALK-negative ALCL compared with other nodal mature TCL, i.e. peripheral TCL, unspecified (PTCL-NOS) and angioimmunoblastic lymphoma (AILT). METHODS AND RESULTS: Clinicopathological data of ALK-positive (n = 28) and ALK-negative (n = 46) ALCL; PTCL-NOS (n = 47); and AILT (n = 12) were analysed for their prognostic significance. While ALK-positive ALCL shows favourable clinical features and a good prognosis, ALK-negative ALCL, PTCL-NOS and AILT are all associated with high age groups, advanced disease stage, and poor prognosis (<45% 5-year survival). In multivariate analysis of overall survival time, performed in the combined group of ALK-negative nodal mature T-cell lymphomas, only age and the International Prognostic Index (IPI) remained independent prognostic parameters, while lymphoma subtype (ALCL versus PTCL-NOS versus AILT) gave no additional information. CONCLUSIONS: The distinction between ALK-negative ALCL and PTCL-NOS or AILT is of limited clinical relevance as they show comparable poor prognosis. In these lymphoma subtypes, only age and the IPI are of significant prognostic value.     

963例成熟T和自然杀伤细胞/T细胞淋巴瘤的临床病理特征分析

目的 观察广东地区不同类型成熟T和自然杀伤(NK)细胞/T细胞淋巴瘤及其亚型的临床病理特点.方法 按WHO(2008版)标准重新评估广东地区2002-2006年1137例成熟T和NK/T细胞淋巴瘤患者.由多名血液病理医师复查,补做必要的免疫组织化学染色及原位杂交.结果 963例确诊为成熟T和NK/T细胞淋巴瘤,占同期所有淋巴瘤20.1%(963/4801),发生于结内319例(33.1%),结外644例(66.9%);非特殊型外周T细胞淋巴瘤293例(30.4%);结外鼻型NK/T细胞淋巴瘤281例(29.2%);间变性大细胞淋巴瘤(ALCL)198例(20.6%);血管免疫母细胞性T细胞淋巴瘤(AILT)46例(4.8%).男女比为1.99:1,发病中位年龄为44岁.非特殊型外周T细胞淋巴瘤好发于55～64岁;结外鼻型NK/T细胞淋巴瘤好发于25～54岁;间变性淋巴瘤激酶(ALK)阳性ALCL多见于年轻人而阴性多见于中老年人;AIIJT好发于65～74岁.结论 广东地区成熟T和 NK/T细胞淋巴瘤多见于结外,好发于男性,总体发病与年龄增长无明显关系,但具体类型有不同的年龄侧重群;常见的类型依次为非特殊型外周T细胞淋巴瘤、结外鼻型NK/T细胞淋巴瘤及ALCL;EB病毒感染与NK/T细胞淋巴瘤关系密切.     

Agresywne chłoniaki z obwodowych limfocytów T

Peripheral T-cell lymphomas (PTCL) are a heterogeneous group of relatively rare lymphoid malignancies. In Europe they account for approximately 15% of all lymphomas. Results of treatment of aggressive PTCL are poor and differ significantly from what has been achieved in recent years in the treatment of B-cell lymphomas. Currently, only patients with anaplastic large cell lymphoma ALK (+) have more than 50% chance of long-term survival. CHOP protocol should not be considered a standard of care, however, in the absence of alternatives it is used in clinical practice. Consolidation therapy with autologous haematopoietic stem cell transplantation (ASCT) improves response rate. This review summarizes treatment options for most common aggressive PTCL: anaplastic large cell lymphoma, angioimmunoblastic lymphoma, peripheral T-cell lymphoma NOS, NK/T-cell lymphoma, enteropathy associated lymphoma and hepatosplenic T-cell lymphoma.     

The nucleophosmin-anaplastic lymphoma kinase fusion protein induces c-Myc expression in pediatric anaplastic large cell lymphomas

The majority of pediatric anaplastic large cell lymphomas (ALCLs) carry the t(2;5)(p23;q35) chromosomal translocation that juxtaposes the dimerization domain of nucleophosmin with anaplastic lymphoma kinase (ALK). The nucleophosmin-ALK fusion induces constitutive, ligand-independent activation of the ALK tyrosine kinase leading to aberrant activation of cellular signaling pathways. To study the early consequences of ectopic ALK activation, a GyrB-ALK fusion was constructed that allowed regulated dimerization with the addition of coumermycin. Expression of the fusion protein caused a coumermycin-dependent increase in cellular tyrosine phosphorylation and c-Myc immunoreactivity, which was paralleled by a rise in c-myc RNA. To assess the clinical relevance of this observation, c-Myc expression was determined in pediatric ALK-positive and -negative lymphomas. Co-expression of c-Myc and ALK was seen in tumor cells in 15 of 15 (100%) ALK-positive ALCL samples, whereas no expression of either ALK or c-Myc was seen in six of six cases of ALK-negative T-cell lymphoma. C-Myc may be a downstream target of ALK signaling and its expression a defining characteristic of ALK-positive ALCLs.     

Pitfalls in diagnostic hematopathology �C Part II

The overlapping features of malignant lymphomas create a diagnostic “grey zone” , and lead to the invention of “grey zone lymphomas”. There are several major grey zone lymphomas: 1) Lymphomas with overlapping features of Hodgkin lymphoma and large B-cell lymphoma; 2) Lymphomas with overlapping features of Burkitt lymphoma and diffuse large B-cell lymphoma; 3) Lymphomas with overlapping features of nodular lymphocyte predominant Hodgkin lymphoma and T-cell/histiocyte rich large B-cell lymphoma; 4) Lymphomas with overlapping features of Hodgkin lymphoma, anaplastic large cell lymphoma (ALCL) and peripheral T-cell lymphoma (PTCL); 5) T-cell classical Hodgkin lymphoma and ALCL-HL. The second review of this series will be dedicated to discussion of the “grey zone” features of the lymphomas and how to narrow down the “grey zone” between those lymphomas.     

Cytotoxic protein expression in natural killer cell lymphomas and in αβ and γδ peripheral T-cell lymphomas

Lymphomas with T-cell phenotype represent a heterogeneous group of diseases differing in histopathology, tumour site, and cell origin. They include peripheral T-cell lymphomas (PTCLs) derived from αβ cells, but also some recently recognized entities such as γδ hepatosplenic lymphomas and natural killer (NK) cell lymphomas. Only a few studies have investigated the possibility that at least some PTCLs could be derived from lymphocytes with cytotoxic potential. In order to investigate this possibility, 60 cases of PTCL, including 27 cases expressing the αβ T-cell receptor (TCRαβ), 15 TCRγδ cases and 18 cases expressing neither TCR (TCR silent), as well as 14 cases of NK-cell lymphomas, were studied by immunohistochemistry for the expression of TIA-1, perforin, and granzyme B proteins. Expression of TIA-1 is characteristic of cytotoxic cells regardless of their activation status, whereas expression of perforin and granzymes is highly increased in activated cytotoxic cells and correlates with the induction of cytolytic activity. All NK-cell lymphomas (11 sinonasal, three systemic cases) expressed TIA-1, perforin, and granzyme B in most tumour cells. All γδ PTCLs (15 cases) expressed TIA-1 protein in most tumour cells, with a different cytotoxic antigen profile in hepatosplenic γδ PTCL (TIA-1+, perforin−, granzyme B−) and in non-hepatosplenic γδ PTCLs (three nasal, one skin, one lung), the latter expressing the three cytotoxic proteins. Of the 45 cases of αβ and TCR silent PTCL, 15 (33 per cent) were considered to be derived from cytotoxic lymphocytes with expression of at least one cytotoxic protein (TIA-1, 15/45; perforin, 10/41; granzyme B, 14/38) in tumour cells. This cytotoxic protein expression appeared to be related to the site of localization, since 7/13 (54 per cent) extranodal and only 8/32 (25 per cent) nodal αβ and TCR silent PTCLs expressed TIA-1, and to histology, since this pattern was observed in a proportion of anaplastic (6/8, 75 per cent) and pleomorphic (8/17, 47 per cent) lymphomas, but not in AILD-type NHL (0/16). Taken together, our data suggest that NK-cell lymphomas and non-hepatosplenic γδ PTCLs represent tumours of activated cytotoxic NK cells and γδ T cells, respectively; that hepatosplenic γδ PTCLs represent tumours of non-activated cytotoxic γδ T cells; and that a small proportion of αβ and TCR silent PTCLs, mostly extranodal cases, or nodal anaplastic lymphomas, represent tumours of cytotoxic T cells. © 1997 John Wiley & Sons, Ltd.     

ALK-negative anaplastic large cell lymphoma with “Hodgkin-like” cytomorphology and nuclear expression of PAX5

Anaplastic lymphoma kinase negative systemic anaplastic large cell lymphoma (ALK-ALCL) is a CD30+ T-cell malignant lymphoma which may involve both lymph nodes and extranodal tissues, showing important clinical differences from ALK-positive ALCL (ALK + ALCL). ALK- ALCL is considered a specific entity by the 2016 World Health Organization (WHO) classification of hematolymphoid neoplasms.We describe an exceptional case of ALK- ALCL with a striking “Hodgkin-like” cytomorphology and a very uncommon nuclear expression of PAX5.     

Nodal T-cell lymphomas with a T-follicular helper cell phenotype

The discovery and characterisation of T-follicular helper (TFH) cells, a distinct functional subset of T-helper cells has led to the recognition that some peripheral T-cell lymphomas (PTCLs) have a TFH cell immunophenotype. Due to the overlap in clinical, morphological, immunophenotypic and genetic characteristics, the revised 4^th edition to the WHO classification recognises one umbrella category of ‘angioimmunoblastic T-cell lymphoma and other nodal TCLs of TFH cell origin’. This review provides a brief overview of TFH cells with special emphasis on function and phenotype and a more detailed discussion of clinical, morphologic, immunophenotypic and genotypic characteristics of AITL, follicular T-cell lymphoma and nodal PTCL with TFH phenotype which constitute nodal TCLs of TFH origin. Secondary B-cell proliferations (often EBV positive) and features that help differentiate reactive lymphoid hyperplasia and other types of lymphoma, including PTCL, NOS and secondary B-cell lymphomas and classic Hodgkin lymphoma, from nodal TCLs with a TFH phenotype are discussed.     

Fine-needle aspiration biopsy of anaplastic large cell lymphoma, small cell variant with prominent plasmacytoid features: case report

Anaplastic large cell lymphoma (ALCL), according to the new WHO classification, is a diagnosis limited to T/NK cell lymphomas. We present a case that demonstrates a new morphologic variant of ALCL with significant possible pitfalls for the cytopathologist. A fine-needle aspiration biopsy of a cervical lymph node showed a cellular aspiration comprised of medium-sized plasmacytoid cells in a discohesive and focally loosely cohesive pattern. The cytologic diagnosis confirmed the presence of malignancy and noted the prominent plasmacytoid features. An accompanying comment favored melanoma and included a broad differential. No cell block was available for immunohistochemical stains. Immunophenotyping of the subsequent excisional node biopsy showed an anaplastic lymphoma kinase (ALK)-positive ALCL. This case illustrates a new variant of ALCL. Although ALCL variants, such as small cell and lymphohistiocytic, are well recognized, the plasmacytoid features are an additional potential source for misdiagnosis. This case report shows that a cytopathologist should include ALK-positive ALCL in the differential diagnosis of plasmacytoid proliferations cell because of the clinical importance of the ALK-positive ALCL.     

Differential expression of T-bet, a T-box transcription factor required for Th1 T-cell development, in peripheral T-cell lymphomas

We studied T-bet expression in 91 cases of peripheral T-cell lymphoma (PTCL) by immunostaining and found expression in 42 cases (46%), including all 5 lymphoepithelioid lymphoma cases and 12 (86%) of 14 angioimmunoblastic lymphoma cases, but only 9 (25%) of 36 anaplastic large cell lymphoma cases. Expression of T-bet in PTCL correlates with expression of other markers of Th1 T-cell differentiation, including CXCR3 (P < .0001), CD69 (P = .0013), LEF-1 (P = .0007), and OX40/CD134 (P = .005), and absence of expression of markers of Th2 T-cell differentiation, including CD30 (P = .0001) and CXCR4 (P = .0144). Of 22 cases of PTCL immunoreactive for all Th1-associated markers previously studied and nonreactive for Th2-associated markers, 20 (91%) were immunoreactive for T-bet. Of 22 PTCL cases immunoreactive for Th2-associated markers studied and nonreactive for all Th1-associated markers studied, 4 (18%) were immunoreactive for T-bet. The remaining 47 PTCL cases (52%) exhibited incomplete or mixed staining for Th1- and Th2-associated markers, with 18 (38%) of 47 immunoreactive for T-bet. T-bet is a new marker that may contribute to the diagnosis and subtyping of PTCLs. T-bet expression in these neoplasms provides further support for a model of PTCL in which tumor subsets express markers of, and may be derived from, Th1- or Th2-committed T cells.     

A small cell variant of ALK-positive, CD8-positive anaplastic large cell lymphoma with primary subcutaneous presentation mimicking subcutaneous panniculitis-like T-cell lymphoma

ALK-positive anaplastic large cell lymphoma (ALK+ ALCL) is an uncommon non-Hodgkin's lymphoma of T-cell origin, the majority of which express CD4 and show frequent pan-T-cell antigen loss. While most cases of ALK+ ALCL have the common pattern characterized by anaplastic morphology with hallmark cells, a less common but well-recognized variant with a small cell pattern may pose a diagnostic challenge. We report a case of ALK+ ALCL with small cell morphology and CD8 subset restriction in a 53-year-old male patient who presented primarily with multiple recurrent subcutaneous nodules with histopathologic features simulating a subcutaneous panniculitis-like T-cell lymphoma (SPTCL). The case was initially diagnosed as SPTCL but was reconsidered as ALK+ ALCL when the incidental finding of CD30 positivity on a subsequent biopsy prompted an ALK immunostain, which turned out to be positive in the neoplastic T-cells. The diagnosis of ALK+ ALCL, small cell variant, was then confirmed by detection of an ALK gene rearrangement by FISH analysis. This report highlights a case of ALK+ ALCL with a deceiving clinical and histopathologic presentation, and emphasizes the value of immunohistochemical panel studies and genetic tests in such cases to avoid diagnostic errors.