Angioimmunoblastic T‐cell lymphoma

The disease currently recognized as angioimmunoblastic T-cell lymphoma (AITL) was first described in the 1970s as a clinical syndrome characterized by generalized lymphadenopathy, hepatosplenomegaly, anaemia and hypergammaglobulinaemia (Frizzera et al, 1974; Lukes Lennert, 1979). The lymph node histology was observed to show a number of distinctive features such as the partial effacement of normal architecture by a polymorphic inflammatory infiltrate, including large blasts and marked vascular proliferation. Based on these histological appearances, the disease was initially referred to by a variety of terms, including immunoblastic lymphadenopathy (Lukes Sasaki it is now recognized that the architectural changes in AITL fall into three overlapping patterns (Ree et al, 1998, 1999; Attygalle et al, 2002a). In pattern I (20% of the patients), there is a preservation of the lymph node architecture. Hyperplastic B-cell follicles with poorly developed mantle zones and ill-defined borders are easily identifiable in the cortex of the lymph node. These merge into the expanded paracortex containing a polymorphic infiltrate of lymphocytes, transformed large lymphoid blasts, occasional multinucleate cells that are reminiscent of Reed–Sternberg cells (RS), plasma cells, macrophages and eosinophils within a prominent vascular network (Fig 1). Histological appearances of AITL (H + E). (A) A pattern I–II patient in whom the architecture is partly preserved. Despite paracortical expansion, the follicles can be identified in low-power view. (B) A pattern II patient in whom architecture is effaced by a polymorphic infiltrate with marked vascular proliferation. (C) A pattern II patient with a depleted follicle surrounded by characteristic clear cells. (D) A high-power view of polymorphic infiltrate and prominent vessels in the paracortical area. (E) Aggregates of large clear cells, which are a typical feature of AITL. (F) A pattern II patient with marked FDC proliferation. Pattern II (30% of the patients) is characterized by the loss of the normal architecture, except for the presence of occasional depleted follicles with concentrically arranged follicular dendritic cells (FDC). In some patients, FDC proliferation extending beyond the follicles can be seen. The remainder of the node shows a polymorphic infiltrate with increased numbers of transformed lymphoid blasts and vascular proliferation similar to that described for pattern I (Fig 1). In pattern III (50% of the patients), the normal architecture is completely effaced and no B-cell follicles are present. Prominent irregular proliferation of FDCs can be seen in haematoxylin and eosin (H Attygalle et al, 2002a). The reproducibility of the diagnosis based on histological appearances appears to be high, at least amongst expert haematopathologists (Rudiger et al, 2002). In most patients, histological examination has to be supplemented by additional ancillary tests. The histological diagnosis may be problematic in a small number of patients as the morphology and phenotypic features can overlap with a variety of reactive and neoplastic conditions, such as reactive lymphadenopathies, multicentric Castleman's disease, diffuse large B-cell lymphoma and classical Hodgkin's lymphoma (Attygalle et al, 2002a). Although generalized lymphadenopathy is the main presenting sign and the diagnosis of AITL rests on histological examination of the lymph node, many patients have evidence of extranodal involvement at the time of diagnosis. The most frequently involved extranodal sites include the bone marrow, spleen, skin and lungs. The histological appearances in these sites are usually non-specific but mimic some of the features described in the lymph node, including increased vascularity and a polymorphic inflammatory infiltrate with or without clear cells (Seehafer et al, 1980; Ghani Brown et al, 2001). Cytological features of malignancy can rarely be identified, and tumour involvement can only be shown by immunohistochemistry and molecular clonality analysis (Martel et al, 2000; Murakami et al, 2001). Immunohistochemistry shows the expansion of the interfollicular areas by a diffuse infiltrate of CD3+ T cells. In most patients, CD4+ T cells dominate but there is usually an intermixed population of CD8+ T cells. The B-cell markers CD20 and CD79a highlight the residual follicle centre and mantle zone B cells as well as many of the large transformed blasts and RS-like cells in the interfollicular areas. In some instances, these can be numerous, mimicking a large B-cell lymphoma or classical Hodgkin's lymphoma, though they are typically polytypic for light chain expression. As described by histology, one of the most distinctive features of AITL is the proliferation of FDC which is best appreciated with immunostaining for the FDC markers CD21, CD23 or CD35 (Leung et al, 1993; Raymond et al, 1997; Jones et al, 1998; Bagdi et al, 2001). In early cases (pattern 1), the FDC proliferation can be minimal and limited to a few follicles. In more advanced cases (Pattern II and III), the FDC are seen to extend into the interfollicular area and wrap around the arborizing vessels (Attygalle et al, 2002a) (Fig 2). Immunophenotype of AITL (immunohistochemistry). (A) A low-power view of CD21 staining, highlighting marked FDC proliferation. (B) A high-power view of CD21 staining showing the FDC wrapping around small vessels, which is a characteristic feature of AITL. (C) CD3 staining, most cells are positive, including large lymphoid cells. (D) CD4 staining in the same area as (C): most CD3-positive cells also express CD4. (E) A pattern II case stained for CD10. Numerous small to medium cells expressing CD10 are seen surrounding the follicle, and spilling into the paracortex is shown. Note the weaker reactivity of follicle centre B cells. (F) The same area as (E) double-stained for CD20 in brown and CD10 in blue. CD20 cells are limited to the follicle centre whereas CD10-positive T cells surround the follicle. (G) A low-power view of a pattern II patient's sample stained for CD10. There are numerous aggregates of CD10-positive cells. (H) A high-power view of one of the aggregates shown in (G). The CD10-positive T cells correspond to the clear cells seen in H Turner et al, 2001). In haematopathology, CD10 has been extensively used for the diagnosis of lymphomas because of its restricted expression by the precursor B-cell and follicle centre B-cell compartments (Chu et al, 2000; Dogan et al, 2000). In both lung (Shipp et al, 1991) and prostate cancer (Papandreou et al, 1998), CD10 has been shown to regulate tumour survival in vivo by decreasing extracellular neuropeptide concentrations and inhibiting certain signal transduction pathways (Sumitomo et al, 2000, 2001). In lymphocytes, its expression is largely restricted to B-cell compartments with a typically high rate of apoptosis (Chu et al, 2000). CD10 is not expressed by normal peripheral T cells or nodal peripheral T-cell lymphomas, but is induced in T cells undergoing apoptosis during HIV infection in both in vivo and in vitro experiments (Cutrona et al, 1999). This close association with CD10 expression and apoptosis suggests that CD10 plays a role in the regulation of lymphocyte survival. In AITL, it appears that most, if not all, tumour cells express CD10, and CD10-positive T cells account for only a fraction of the infiltrate, varying from around 5% of all cells in pattern II patients to up to 30% of all cells in pattern III patients (Fig 2). Interestingly in early cases, the CD10-positive cells have low-grade cytology and a relatively low proliferation fraction. CD10-positive T cells are intimately related to the residual reactive B-cell follicles and the expanded FDC meshwork, some being located within the follicle centres and others in the area surrounding the follicles. As the tumour progresses (patterns II and III), the tumour cells spill into the interfollicular area but retain the intimate association with the FDC meshwork. This suggests that the FDC microenvironment may be important for tumour growth. Moreover, in many patients, the neoplastic cells stain for CD4, CD57 and B-cell lymphoma-6 (Bcl-6), markers expressed by normal follicle centre T cells, suggesting that the tumour may have derived from this cell population (Ree et al, 1999; de Leval et al, 2001; Yuan et al, 2002). The neoplastic T cells in extranodal dissemination may retain the expression of CD10 and this may aid diagnosis (Attygalle et al, 2002b). There appears to be a substantial immune activation in the peripheral blood and lymph nodes of AITL patients compared with the reactive lymph nodes or other peripheral T-cell lymphomas. The evidence for this includes increased levels of serum soluble interleukin 2 (IL-2) receptor, CD30 and CD8 molecules (Pizzolo et al, 1990), and also the expression of an array of cytokines such as tumour necrosis factor alpha, and et al, 1993; et al, et al, 2000). studies the expression of T-cell activation markers have shown an increased expression of the receptor family et al, receptor et al, 2000), and which is a of early T-cell activation et al, 1988; et al, 1998; et al, 2000; et al, 2001; Attygalle et al, 2002a). The of clonality from the large are in of the to be during these studies was the presence of an expanded monoclonal B-cell population in a significant of This has to the that AITL is a of T-cell lymphomas and B-cell lymphomas, but not a clinicopathological However, the current evidence suggests that these patients also fall within the of AITL. These patients typically increased numbers of cells, and it is thought that the B-cell by molecular analysis of lymph node within this It is likely that this is an that to the immunodeficiency associated with the AITL, to other that are associated with et al, 2002). a subset of AITL patients on to develop diffuse large B-cell lymphomas et al, et al, 1993; et al, or lymphoma et al, 1979). The studies on the changes in AITL have been by a number of including the of the tumour and of tumour cells by a large number of reactive cells. of on changes from These are in Approximately of AITL patients have cytogenetic observed by the use of and et al, 1988; et al, et al, et al, et al, are seen in of the and of an X are the most seen in AITL, but these are also in other peripheral T-cell lymphomas. and showed that half the patients which is a that is in other lymphomas et al, This was to be consistent with the development of in AITL. The being the of in cells because of and the of aberrant cells to the immune by the of aberrant and a of monoclonal proliferation. However, at the first T-cell receptor shows clonal T-cell that the tumour is at the not by cytogenetic that have a low The presence of T-cell and the expansion of B-cell the as to which cells the aberrant In one using a the of immunophenotype and it was shown that the aberrant with were CD3 T cells et al, It is that the seen in AITL from B cells that are likely to have an The proportion of aberrant cells reported on compared with is consistent with the morphology of AITL, with a few neoplastic cells an of reactive cells et al, In a the of on clinical only the presence of aberrant was to be an and no on survival et al, known to be in have rarely been in AITL. and expression and and that both are suggesting that this is not in the majority of AITL patients et al, 2001). The other that has been is of the of the a role in the development of diffuse large B-cell lymphomas. Despite the expression of in most patients with AITL (Ree et al, 1999; Attygalle et al, Yuan et al, no were in the of the et al, 2001). lymphoma is the of cancer in in the with patients of these are peripheral T-cell lymphomas, and AITL for of all lymphomas (Rudiger et al, with an patients in the in a centre suggests that AITL patients are being that the may be (Ree et al, 1998; Attygalle et al, 2002a). AITL is a disease of the with most patients presenting within the and (Tobinai et al, 1988; et al, et al, et al, 1999; Attygalle et al, 2002a). There is no of the disease to et al, et al, et al, 1999; Attygalle et al, 2002a). The patients have a and have been reported in the and small suggests that the of AITL may be in than (Rudiger et al, 2002). AITL typically with systemic characterized by B and generalized lymphadenopathy, mimicking an infectious The majority of patients show and and a skin is also seen in a half of The reported of presenting and observed in AITL are in III (Tobinai et al, 1988; et al, et al, 1999). show the presence of anaemia and there is and both the and the rate are A significant proportion of patients have including a and immune The most and are shown in (Tobinai et al, 1988; et al, et al, 1999). A number of have been reported in association with AITL. These include anaemia et al, (Seehafer et al, 1980; et al, 2001; et al, et al, et al, and disease et al, 1999). The clinical syndrome of AITL with a of inflammatory and neoplastic and the changes in peripheral blood and on bone examination are usually of the lymph node may be but is rarely because cytological appearances can be within normal and architectural features be the same a also has limited The diagnosis of AITL can only be by biopsy and histological examination of one of the lymph where characteristic features can be best the and clinical of AITL are limited because of the of the disease. of the is based on small patient numbers and a limited number of case The clinical of the AITL remains with a survival of than and a survival of around et al, et al, 1999). patients of infectious rather than tumour suggesting that an immunodeficiency to the agent and such as with or without and with or without or have been reported et al, et al, et al, et al, 1999). Although a rate of can be with appears to be to et al, 1999). Other including with et al, 2000), et al, et al, 1999; et al, and et al, 1999). on neoplastic T cells may an important role in the of but once studies are limited to a few case has been used as agent in a few patients, either or in AITL, with et al, 2002). There are published data the of by blood cell in this of lymphoma patients after with this et al, 1999). AITL is a systemic disease characterized by the monoclonal proliferation of T cells expressing CD3 and CD4. In most patients, the tumour cells are by numerous cells. This a number of both diagnosis and the of the of the tumour cells, not the clinical of these patients remains in the of other lymphomas. In this the of the aberrant expression of CD10 as of neoplastic T cells of AITL be This an phenotypic for diagnosis for the first as well as a to the of AITL tumour cells. in with AITL on the we in the of the disease and in to in large clinical