In lymph nodes, AITL displays distinctive pathological features that may be categorized according to three overlapping architectural patterns, as described by Attygalle et al (2002). In typical cases (pattern III, AITL without follicles), AITL is characterized by complete loss of architecture, often with capsular and perinodal infiltration sparing the peripheral sinus, and absence of residual B-cell follicles (Fig 1A). The hallmark features of AITL are: (i) a diffuse polymorphous infiltrate including variable proportions of atypical neoplastic T cells, admixed with small lymphocytes, histiocytes or epithelioid cells, immunoblasts, eosinophils and plasma cells, (ii) prominent branching high endothelial venules, and (iii) irregular proliferation of follicular dendritic cells (FDCs) (Fig 1B–D).
The lymphoma cells are medium-sized cells with round or slightly irregular nuclei, abundant clear cytoplasm and tend to form small clusters around high endothelial venules (Willenbrock et al, 2005). In less typical cases, the neoplastic cells are smaller with only slight pleomorphism and atypia, and without striking clear cell components. These are mature αβ CD4+CD8− T-cells, which frequently show aberrant loss or reduced expression of CD7, surface CD3 and/or CD4 and may show partial CD30 expression in up to one-third of the cases (Willenbrock et al, 2001; Lee et al, 2003; Stacchini et al, 2007; Karube et al, 2008). The tumour cells are often outnumbered by reactive T cells, and usually the ratio of CD4 to CD8-positive cells is preserved (Merchant et al, 2006). Aberrant expression of CD10 by the neoplastic cells (Fig 2A) is observed in around 80% of the cases, but is often heterogeneous (detected on an often minor subset of the tumour cells, and of variable intensity) (Attygalle et al, 2002, 2007a; Yuan et al, 2005; Dorfman et al, 2006; Karube et al, 2008; Mourad et al, 2008). Since minor populations of CD3+/CD10+ have been detected in normal lymph nodes, the specificity and threshold for abnormal CD10+ T-cell populations remains, however, to be clarified (Cook et al, 2003; Dupuis et al, 2006; Stacchini et al, 2007). AITL tumour cells express several markers of follicular helper T cells (TFH), normally located in the light zone of reactive germinal centres (Fig 2B–D) (Vinuesa et al, 2005). Strikingly, cytoplasmic expression of the CXCL13 chemokine, a specific marker of normal TFH cells, is expressed in the neoplastic cells of virtually all AITL cases (Grogg et al, 2005; Dupuis et al, 2006). Additional TFH markers that have been demonstrated in AITL by immunohistochemistry include the cell surface molecules CXCR5, CD154, programmed death-1 (PD-1) (a member of the CD28 costimulatory receptor family resulting in negative regulation of T-cell activity), inducible costimulator (ICOS) (a CD28 homologue with costimulatory function in T-cell activation and expansion) and cytoplasmic SAP (SLAM-associated protein) (Dorfman et al, 2006; Krenacs et al, 2006; Roncador et al, 2007; Xerri et al, 2008; Rodriguez-Justo et al, 2009; Yu et al, 2009). Expression of BCL6, a transcription factor characteristic of the TFH subset of CD4+ cells, is another phenotypic marker of AITL tumour cells (Ree et al, 1999; Yuan et al, 2005). On tissue sections the distribution and intensity of the immunostains observed for the different TFH markers tend to correlate and, similar to CD10, show a relationship to the FDC meshwork. For diagnostic purposes, CXCL13, PD1, ICOS and BCL6 currently represent the most useful and robust immunohistochemical TFH markers.
Expanded FDC meshworks, typically associated with vessels, can be seen by morphology alone when prominent and are best highlighted by immunohistochemistry using classical FDC markers (CD21, CD23, CNA.42 and/or CD35), among which CD21 appears to be the most sensitive (Fig 1D).(Leung et al, 1993; Troxell et al, 2005).
Varying numbers of small B cells and polytypical plasma cells are distributed randomly in single cells or as small clusters in association with FDC aggregates. In addition, a population of large B-blasts, which may sometimes mimic Reed-Sternberg cells, usually infected by Epstein-Barr virus (EBV), is almost invariably present (Anagnostopoulos et al, 1992; Weiss et al, 1992).
Morphological variants. Besides the most common pattern III, two other patterns are recognized (Attygalle et al, 2002). In pattern I (AITL with hyperplastic follicles), the lymph node has a partially preserved architecture and contains hyperplastic follicles with poorly developed mantles, merging into the paracortex expanded by a polymorphous infiltrate that often comprises inconspicuous neoplastic cells, which tend to distribute around the follicles (Fig 3A) (Ree et al, 1998). In pattern II (AITL with depleted follicles) occasional depleted follicles are present (Fig 3B). In contrast with pattern III, FDC are normal or only minimally increased in patterns I and II (Attygalle et al, 2002). Patterns I to III have been documented in consecutive biopsies and are thought to represent progressive stages of the disease and to reflect morphological evolution rather than clinical progression, as patients with pattern I usually show advanced stage disease (Ree et al, 1998; Attygalle et al, 2002, 2007b; Rodriguez-Justo et al, 2009).
Figure 3. Morphological variants of angioimmunoblastic T-cell lymphoma. (A) AITL pattern I showing a reactive hyperplastic follicle with an attenuated mantle zone and surrounded by a rim of neoplastic clear cells (original magnification ×100). (B) AITL pattern II showing an infiltrate of small neoplastic cells around a regressive (Castleman-like) follicle (original magnification ×100). (C) AITL rich in clear cells (original magnification ×400). (D) Epithelioid variant of AITL comprising an abundant histiocytic background (original magnification ×200). (E) AITL rich in B-cell blasts highlighted by CD20 immunostaining and (F) showing EBV infection (EBER in situ hybridization) (original magnification ×400).
Download figure to PowerPoint
Other morphological variants are described according to cell content. The clear cell-rich variant of AITL designates a subset of cases comprising an overt lymphomatous proliferation of sheets of ‘clear’ neoplastic cells (Fig 3C) (Merchant et al, 2006). The epithelioid variant of AITL is characterized by a high content of epithelioid cells in small, poorly defined clusters (Fig 3D) (Patsouris et al, 1989). A subset of AITL contain a high proportion of large B-cell blasts (>25%) (B-cell-rich AITL), which are usually but not always infected by EBV (Fig 3E–F). In some cases, the proliferation of EBV-positive B-cell blasts may be so prominent that they form diffuse confluent sheets; in these cases a diagnosis of EBV-positive lymphoproliferation or EBV-positive diffuse large B-cell lymphoma may be rendered. This complication occurs most commonly during the evolution of the disease, but more rarely can be the presenting histological picture. EBV-negative large B-cell lymphoma or plasma cell proliferations can also occur occasionally (Zettl et al, 2002; Attygalle et al, 2007b; Willenbrock et al, 2007).
Extranodal organs. Bone marrow involvement is often subtle, appearing as small single or multiple nodular or interstitial foci of infiltration in a paratrabecular or non-paratrabecular distribution. The infiltrates have a mixed composition of T and B cells, including atypical clear cells and are associated with blood vessel proliferation. Massive tumour replacement of hematopoietic tissues is exceptional (Sakai et al, 2007). In addition, secondary reactive marrow changes (polyclonal plasmacytosis, erythroid hyperplasia, eosinophilia, myelofibrosis, or haematophagocytosis) are frequently observed. They may obscure the lymphomatous foci and be misdiagnosed as other proliferative or reactive haematopoietic conditions (Grogg et al, 2007; Cho et al, 2009).
Different histopathological aspects can be seen in skin biopsies, ranging from subtle non-specific mild perivascular lymphocytic infiltrate to, more rarely, an overtly lymphomatous infiltration (Martel et al, 2000; Ortonne et al, 2007). In most instances, eosinophils, vascular hyperplasia and large immunoblasts are not obvious. EBV-positive cells are rarely demonstrated (Martel et al, 2000; Brown et al, 2001). A florid epithelioid or granulomatous reaction has been described in occasional cases, which may mimic sarcoidosis or an infectious process (Scarabello et al, 2002; Suarez-Vilela & Izquierdo-Garcia, 2003; Pujol et al, 2005; Jayaraman et al, 2006).
The distribution of the atypical lymphoid infiltrates in other organs is less well characterized. Tonsillar involvement may be subtle with preservation of reactive follicles, and may be difficult to demonstrate. Spleen involvement occurs in the form of nodules in the white and/or the red pulp. Not all symptomatic manifestations may result from direct tumour infiltration, for example, effusions are usually non-neoplastic in nature and their cause is poorly understood.