• Peripheral T-cell lymphoma;
  • immunohistochemistry;
  • follicular helper T cells

While our knowledge of the normal cellular counterparts of B-cell lymphomas contributes much to the meaningful classification of these neoplasms, our understanding of the cellular ontogeny of mature (peripheral) T-cell lymphomas (PTCL) is much less advanced and their classification is suboptimal. Thus, while there is considered sufficient evidence to classify some PTCL, such as angioimmunoblastic T-cell lymphoma (AITL), an aggressive lymphoma recently shown to have the immunophenotype of follicular helper T (TFH) cells (Dogan et al, 2003; de Leval et al, 2007), as discrete entities, most are subsumed into the biologically and clinically heterogeneous group of PTCL-unspecified (PTCL-U). Amongst PTCL-U, an uncommon subset with a follicular growth pattern (PTCL-F) is particularly poorly understood. Some PTCL-F harbour a t(5;9)(q33;q22)/ITK-SYK, but their cellular origin is unascertained and their proper classification uncertain, leading to difficulties in diagnosis and clinical management (de Leval et al, 2001; Jiang et al, 2005; Ikonomou et al, 2006; Streubel et al, 2006). This report demonstrates the derivation of a typical case of PTCL-F from germinal centre (GC) TFH cells, highlighting a clinical and pathological overlap with AITL.

A 27-year-old man presented with a flu-like illness, jaundice, widespread lymphadenopathy and splenomegaly. Lymph node biopsy showed a T-cell non-Hodgkin lymphoma. There was no skin rash, arthritis, effusion or bone marrow involvement (Ann Arbor stage III). Laboratory investigations showed an auto-immune haemolytic anaemia, mild thrombocytopenia, raised lactate dehydrogenase, positivity for anti-smooth muscle auto-antibody but no hypergammaglobulinaemia. The patient received six courses of CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone) chemotherapy resulting in a complete remission but relapsed with widespread lymphadenopathy 14 months later. An autologous peripheral blood stem cell transplant induced a second complete remission, but four months later the patient developed a haemophagocytic syndrome. Despite treatment with ciclosporin A, dexamethasone and etoposide, he died of a disseminated mycosis.

The lymph node sampled (Fig 1) showed partial architectural effacement by lymphoma. The cortex contained numerous, variably sized follicles, the GCs of which contained varying numbers of residual B cells together with many medium-sized to large atypical T cells with clear cytoplasm, irregular nuclei and frequent mitoses. Similar cells also infiltrated follicular mantle zones. The expanded paracortex contained several smaller follicles, often with depleted GCs, many of which also contained atypical T cells. The atypical cells were not confined to follicles however, and were also found in-between follicles. The paracortical infiltrate was accompanied by reactive lymphocytes, plasma cells and occasional eosinophils, and by a notable proliferation of arborising high endothelial venules. Immunohistochemical staining showed the atypical T cells to express CD2, CD3, CD4, and CD5, but not CD8, CD10 or CD30. In addition, they expressed proteins recently shown to be characteristic of GC TFH cells: CXCL13, PD-1, SAP, NFATc1, Bcl6 and CD57. A minor, dispersed interfollicular population of large reactive B cells showed polytypic expression of immunoglobulin light chains and was Epstein–Barr Virus Early RNA (EBER) negative. Staining for CD21 showed follicular dendritic cells (FDC) to be largely confined to follicles with only subtle and focal expansion and little tendency to encircle vessels. Polymerase chain reaction-based analysis of lymphocyte clonality showed monoclonal rearrangements of TCRB@ and TCRG@ but not IGH@, IGK@ or IGL@. Interphase fluorescence in situ hybridisation showed no evidence of an ITK-SYK translocation.


Figure 1.  Morphological and immunohistochemical features of PTCL-F. (A) Prominent follicular architecture (H&E ×40); (B) expansion of germinal centres by atypical lymphoid cells with clear cytoplasm (H&E ×200); (C) interfollicular region showing a regressed follicle and prominent vasculature (H&E ×40); (D–J) expression of CD3, CD4, CXCL13, PD1, SAP, CD57, but not CD20 as labelled (immunohistochemistry ×200, inset ×600); (K) expression of Bcl6: left panel – Bcl6 (single immunohistochemistry ×200), right panel – triple immunohistochemistry (×600) for Bcl6 (brown), PD1 (blue) and CD20 (red) showing numerous PD1+ Bcl6+ neoplastic T cells and occasional CD20+ Bcl6+ germinal centre B cells; (L) expression of NFATc1: left panel – NFATc1 (single immunohistochemistry ×200), right panel – triple immunohistochemistry (×600) for Pax5 (brown), NFATc1 (purple) and PD1 (red) showing numerous PD1+ NFATc1+ Pax5− neoplastic T cells within a follicle in comparison to smaller PD1− NFATc1+ Pax5− reactive cells outside the follicle.

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The few reports of PTCL-F describe preferential localisation of neoplastic T cells within either GCs or expanded mantle zones (de Leval et al, 2001; Jiang et al, 2005; Ikonomou et al, 2006; Streubel et al, 2006), but the T cell subset to which these cells belong and their microanatomical origin are matters of debate. While some authors suggested an origin from intrafollicular T cells (Ikonomou et al, 2006), others proposed colonisation of follicles by extrafollicular T cells (Jiang et al, 2005). The application of routinely used immunohistochemical markers alone has shown typical expression of Bcl6 and/or CD10, but has failed to resolve these issues due to both heterogeneity amongst cases and a lack of specificity and sensitivity of these antibodies for intrafollicular T cells. In contrast, we used a panel of novel markers recently identified by gene expression profiling and immunohistochemistry to be characteristically expressed together in TFH cells, but not in other T-cell subsets (Chtanova et al, 2004, 2005; Vinuesa et al, 2005; Roncador et al, 2007), to demonstrate a robust TFH immunophenotype in our case. This, together with the preferential localisation of the neoplastic cells within GCs, is strong evidence that the PTCL-F described here is derived from intrafollicular TFH cells.

Based largely upon the overlapping immunophenotype of AITL (Bcl6+ CD10+) and PTCL-F and the association of the neoplastic cells in AITL with expanded FDC meshworks or, in early histological stages, with the periphery of lymphoid follicles, an association between these two lymphomas has been proposed. This idea has gained recent support from the demonstration that the neoplastic T cells of AITL have the immunophenotype of TFH cells (CXCL13+, PD1+, SAP+) (de Leval et al, 2007; Roncador et al, 2007). Our finding, that at least some PTCL-F are derived from the same T-cell subset, further strengthens this association. Interestingly, while our case lacks many of the cardinal features of AITL (i.e. the expanded FDC meshworks of pattern II/III, an associated EBV-positive B cell population, and CD10 expression) and is a much more florid lymphoproliferation than the morphological pattern I of AITL, it does show several of the microenvironmental features associated with AITL such as an arborising paracortical network of blood vessels and regressed follicles (Dogan et al, 2003). Moreover, the autoimmune manifestations observed in the present case are also typical of AITL (Dogan et al, 2003). Although some PTCL-F have been reported to relapse as diffuse PTCL-U without features of AITL (Ikonomou et al, 2006), whether at least some TFH-derived PTCL-F represent a microanatomical variant, an early morphological stage or a forme fruste of AITL clearly merits further investigation.

TFH cells are specialised T cells that orchestrate many facets of B-cell immunity and peripheral tolerance, including the generation and selection of CG B cells and the generation of memory B cells and class-switched plasma cells (Vinuesa et al, 2005). The development and function of TFH cells result from the pleiotropic actions of cell surface and secreted proteins, such as OX40, CD40ligand, ICOS, PD1, CXCL13, IL-10 and IL-21. The dysregulation of these proteins in TFH-derived lymphomas may play a role in both tumour development and the immunological dysfunction that characterises AITL. The recognition of the range of lymphoma subtypes derived from TFH cells is thus important, not only for meaningful classification of PTCL, but also to identify cases which might be susceptible to novel therapeutic approaches.


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  2. References
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