How I Diagnose Angioimmunoblastic T-Cell Lymphoma

Yi Xie, MD, PhD; Elaine S. Jaffe, MD


Am J Clin Pathol. 2021;156(1):1-14. 

In This Article

Morphology and Immunohistochemistry

Lymph nodes involved by AITL typically show partial or complete architectural effacement with perinodal extension, but peripheral cortical sinuses are often spared. The infiltrate is usually diffuse or paracortical, composed of a polymorphous population of small- to medium-sized lymphocytes, scattered immunoblasts, histiocytes, plasma cells, and eosinophils amid prominent networks of arborizing high endothelial venules (HEVs). Follicles are typically regressed or absent, but there is a proliferation of FDCs in extrafollicular regions, often surrounding the HEVs.[25] The neoplastic T cells are usually small to medium in size with clear cytoplasm, clustering around HEVs and enwrapped by FDC meshworks.[26] In some cases, the neoplastic cells may be sparse or lack overt cytologic atypia or distinct clear cell morphology. Some cases may contain numerous large B immunoblasts or abundant plasma cells, obscuring the tumor cell population. Multinucleated HRS-like cells may be seen.[27] There are rare cases rich in epithelioid histiocytes, resembling granulomatous reaction or lymphoepithelioid lymphoma. In other cases, there may be a relatively monotonous proliferation of atypical lymphocytes with sparse inflammatory component, simulating PTCL, not otherwise specified.[28]

Three overlapping histologic patterns have been described in AITL[29] Table 1. Most cases fall into histologic patterns II and III, with the typical morphologic features as described above. In pattern II, there are occasional regressed follicles, while pattern III is characterized by complete architectural effacement with no residual B-cell follicles.[29] The type I pattern is less common but can be particularly difficult to identify. Often, the lymph nodes show largely retained architecture with hyperplastic follicles, imparting an overall reactive appearance.[25,30] The follicles usually have ill-defined borders with attenuated or obliterated mantle zones surrounded by a rim of atypical clear cells. In less obvious cases, the tumor cells may be inconspicuous and are best recognized by immunohistochemical study. Progression of patterns I to III has been documented in sequential biopsy specimens and is thought to represent morphologic evolution rather than clinical progression of the disease.[15,25]

Immunohistochemistry of the lymph node shows expansion of the paracortex by a diffuse infiltrate of T cells. The B-cell areas are often reduced and sometimes compressed in the far cortex of the lymph node, which can be a helpful clue to the diagnosis of AITL. Scattered large B blasts, often CD30+ and EBV+, are frequently found among the T-cell infiltrate.[31] FDC markers, CD21 and CD23, typically highlight extensive FDC meshworks outside of the follicles. However, in some cases, the abnormal FDC pattern may be focal. In AITL with type I pattern, CD21 and CD23 usually show only subtle sprouts of FDCs extending beyond the germinal centers. The expanded dendritic cells may actually represent fibroblastic reticular cells, which are a lineage closely related to FDC and can upregulate expression of CD21 and CD23. These "pre-FDCs" arise in a perivascular location.[32]

Immunohistochemical assessment of the tumor cell phenotype plays a key role in the diagnosis of AITL. Immunophenotypically, the neoplastic cells are T-cell receptor (TCR) α/β T cells with expression of pan–T-cell markers (eg, CD2, CD3, and CD5), although aberrant loss or downregulation of one or more T-cell markers (commonly CD3, CD5, or CD7) is frequently observed.[33] By flow cytometry, loss of surface CD3 is very commonly seen and can be a clue to the diagnosis.[34] In a subset of the cases, the cells may show partial expression of CD30. The neoplastic cells are usually CD4+ and also express multiple TFH-related antigens, including PD1/CD279, CD10, BCL6, CXCL13, ICOS, SAP, c-MAF, CD200, and CXCR5.[9,29,35–39] It is important to note that these markers are not always specific, and conversely, not all TFH markers can be detected in an otherwise typical case of AITL. Moreover, attention should be paid to the intensity and distribution of TFH markers, and staining pattern should correlate with morphology. Because reactive paracortical T cells with weak and variable expression of PD1 are almost invariably present, only strong staining of PD1 is diagnostically useful.[40,41] CD10 is usually positive in only a small subset of the neoplastic cells and may show variable staining intensity. Among the TFH markers, PD1/CD279 and ICOS are reported to be most sensitive, whereas CXCL13 and CD10 are less sensitive but more specific.[42] As such, the 2016 WHO classification suggests that at least two (ideally three) TFH markers be expressed by the neoplastic cells to diagnose a case of PTCL as having a TFH phenotype.[43] Table 2 summarizes immunohistochemical markers commonly used to diagnose AITL in routine clinical practice.

Possibly owing to the inherent function of the neoplastic cells as TFH, AITL is frequently accompanied by a proliferation of B cells. Findings that can be seen include polyclonal or clonal proliferation of large B cells, HRS-like cells, and plasma cells, which can be positive or negative for EBV. Studies have reported that more than 80% of AITLs contain a variable number of EBV-positive B cells, ranging from isolated or small clusters of B immunoblasts to focally confluent EBV-positive large B cells.[31,44] This proliferation may be so marked as to suggest a diagnosis of EBV-positive diffuse large B-cell lymphoma (DLBCL), either at initial diagnosis or during disease course.[15,44,45] Alternatively, the EBV-positive B cells may resemble HRS cells both morphologically and phenotypically, leading to a mistaken diagnosis of CHL.[27,46] The expansion of EBV-infected cells was thought to be related to defective immune surveillance for EBV.[24] However, rare cases with EBV-negative HRS-like cells have also been reported, suggesting other mechanisms for the abnormal B-cell proliferation.[46] As discussed below, the B cells in AITL may harbor mutations in TET2, similar to the neoplastic T cells, suggesting possibly common mutational events in a hematopoietic stem cell.[47,48]

AITL is also often associated with plasmacytosis.[49,50] Sometimes the plasma cells may be abundant, obscuring the underlying neoplastic T cells.[50] In rare instances, patients may have marked peripheral blood and/or bone marrow plasmacytosis.[19,51,52] The plasma cell expansions in AITL are thought to result from the increased release of cytokines such as interleukin (IL)–6 or IL-10.[53] The plasma cells in most cases are polyclonal and EBV negative, but clonal plasma cell proliferations also have been reported.[49,50]