March 2009
Written by Michael J. Papez, MD, 4th year Resident in Pathology at the University of North Carolina, Chapel Hill, North Carolina.

Diagnosis
High-grade malignant lymphoma, peripheral T cell, type not further specified, with unusual variant features which have been described as "follicular T cell lymphoma".

Case History
The patient is a 64 year old male with widespread retroperitoneal, axillary and inguinal lymphadenopathy, with profound constitutional symptoms including fever and weight loss. A left axillary and a right inguinal node were excised.

Microscopy
At low power, a follicular architecture is appreciated within the enlarged node, with variably-sized and somewhat poorly-defined follicles overwhelming the normal compartments of the lymph node (see Figure 1).

High magnification views show the nodular process to consist of large lymphoid cells with irregular nuclei and considerable pale cytoplasm, in contrast to the large centroblasts of a residual germinal center, which display smooth nuclear contours and basophilic cytoplasm (compare cellular appearances in a Giemsa-stained preparation in Figure 2).
Foci of fibrinous necrosis are noted centrally within some nodules. In the background, there is a striking vascular response with proliferation of venules, and variably delicate and dense fibrosis is seen amidst smaller lymphocytes and eosinophils. These features may be the first subtle clues provided by traditional H&E stains that this is a T cell process and not a much more common B-cell lymphoma (see Figure 3).

Ancillary Studies
Flow cytometry immunophenotyping of the lymph node detected a population of large lymphoid cells that expressed the T cell markers CD2, CD4, CD5, and CD7; this T cell population also expressed CD10 (which can be expressed by follicular center T-cells) and CD30 (which can be expressed in activated T-cells as well as anaplastic large cell lymphoma and occasionally in peripheral T-cell lymphoma). Immunohistochemical stains performed on paraffin sections show the neoplastic cells to exhibit a moderately high labeling for the nuclear proliferation marker Ki-67 and to be positive for T cell markers CD3 and CD43 with variable expression of CD30; the neoplastic cells are negative for CD20. Follicle center origin is supported by expression of both BCL6 and CD10 by neoplastic cells; in addition, CD35 highlights follicular dendritic cells intimately associated with nodules of tumor cells (see Figures 4 and 5).

In this unusual case, gene rearrangement studies were pursued and provided additional support for the diagnosis in that the PCR technique was negative for detecting a clonal IgH gene rearrangement and positive for a clonal T cell receptor gamma gene rearrangement.

Discussion
Malignant lymphomas of B cell origin are much more common than their T cell counterparts. When a follicular architecture is identified at low power, pathologists are appropriately biased toward B cell processes, particularly B cell follicular lymphoma but also other B cell lymphomas including mantle cell lymphoma, nodular lymphocyte predominant Hodgkin lymphoma, and follicular infiltration by marginal zone lymphoma or small lymphocytic lymphoma; various lymphoma mimics also must be considered. This case is exceptional in that, in spite of the follicular growth pattern on H&E slides, the definitive flow cytometric, immunohistochemical, and molecular studies all indicate that this is a T cell neoplasm. The follicular subtype of peripheral T cell lymphoma is recognized in the 2008 WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues as a variant of peripheral T cell lymphoma, not otherwise specified (1).

A small series described by de Leval et al. in 2001 best correlates with the current case (2). The suspected origin of the follicular variant of peripheral T cell lymphoma, based on immunophenotype, is intrafollicular CD4+ T-helper cells; as in this case, such cells are CD2+, CD4+, CD5+, CD7+, and CD8-. Akin to their follicle center B cell counterpart, they are also CD10+ and BCL6+ and associated with a nodular network of CD35+ follicular dendritic cells.

Recently, questions have been raised regarding the relationship of the follicular variant of peripheral T cell lymphoma to angioimmunoblastic T cell lymphoma (AITL). Traditionally, AITL has been identified by a polymorphous cellular infiltrate (including eosinophils, plasma cells, and lymphocytes), collections of arborizing high endothelial venules and, in more advanced cases, aggregates of neoplastic cells with clear cytoplasm. Recent studies, as exemplified by Merchant et al., have expanded upon the morphologic findings in making the diagnosis of AITL; lymph node effacement, extranodal extension, B cell 'peripheralization', and follicular dendritic cell proliferation are additional helpful findings in diagnosing AITL (3). However, early cases of AITL remain notoriously difficult to recognize. In one early phase/variant of AITL, rare, non-aggregated neoplastic cells can invade normal follicles and can possibly resemble the follicular variant of peripheral T cell lymphoma (this has been referred to as the 'early follicular phase' of AITL). This dilemma was discussed in the 2005 SHP/EAHP Symposium on T-cell and NK-cell malignancies and in subsequent publications (4).

Our case provides solid evidence of a morphologic distinction between the follicular variant of peripheral T cell lymphoma and AITL, in that neoplastic T cells clearly aggregate in nodules that are intimately associated with networks of follicular dendritic cells. Even so, this example of follicular variant of peripheral T cell lymphoma does share some features with AITL in that neoplastic cells spill out from the follicles to involve the interfollicular compartment where they are accompanied by a polymorphous inflammatory infiltrate and venular proliferation. In addition, as in AITL, the neoplastic cells in this case strongly mark with antibodies against follicle center cell antigens CD10 and BCL6. These similarities between the current case and AITL support the notion that the two entities are derived from a common precursor cell, the follicular T helper cell.

Unfortunately, the distinction between the follicular variant of peripheral T cell lymphoma and AITL is as yet academic only - they are treated similarly and have somewhat poor outcomes with the latest study produced by the International T cell Lymphoma Project reporting a 5 year overall survival of 32% for both AITL and peripheral T cell lymphoma, not otherwise specified (5).

References

1. Swerdlow S, Campo E, Harris N, et al., (Eds.)
   WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th ed. Lyon, France, IARC Press, 2008:p306-311.
2. de Leval L, Savilo E, Longtine J et al.
   Peripheral T-Cell Lymphoma With Follicular Involvement and a CD4+/bcl-6+ Phenotype. Am J Surg Pathol 2001;25(3):395-400. More online »
3. Merchant S, Amin M, Viswanatha D.
   Morphologic and Immunophenotypic Analysis of Angioimmunoblastic T-Cell Lymphoma. Am J Clin Pathol 2006;126:29-38. More online »
4. Warnke R, Jones D, His E.
   Morphologic and Immunophenotypic Variants of Nodal T-Cell Lymphomas and T-Cell Lymphoma Mimics. Am J Clin Pathol 2007;127:511-527. More online »
5. International T-Cell Lymphoma Project:
   International Peripheral T-Cell and Natural Killer/T-Cell Lymphoma Study: Pathology Findings and Clinical Outcomes. J Clin Oncol 2008;26(25):4124-4130. More online »

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