Expansion of PD1-positive T Cells in Nodal Marginal Zone Lymphoma: A Potential Diagnostic Pitfall

Abstract

The diagnosis of nodal marginal zone lymphoma (NMZL) can be challenging, with the differential diagnosis including other low-grade B-cell lymphomas, reactive hyperplasia, and even some cases of peripheral T-cell lymphoma (PTCL). PTCL may have a perifollicular growth pattern mimicking NMZL. We and others have noted an atypical distribution of T-follicular helper (TFH) cells in some cases of NMZL. This study was prompted by the diagnosis of NMZL in several cases in which a marked increase of TFH cells, as determined by staining for programmed death-1 (PD1), had prompted suspicion for a diagnosis of PTCL. We analyzed PD1 staining in 48 cases of NMZL to characterize the extent and pattern of the PD1-positive infiltrate. Three main patterns of PD1 staining were identified: follicular pattern (peripheral, n=16; central, n=9; mixed, n=3), diffuse pattern (n=4), and a reduced or normal staining pattern in residual follicles (n=16). A comprehensive analysis of other TFH markers was undertaken in 14 cases with a high content of PD1-positive cells that were confirmed as B-cell lymphoma by clonality analysis. We describe in detail 5 of these cases in which PTCL was an initial consideration. This study illuminates the diverse immunohistochemical patterns encountered in NMZL and highlights a diagnostic pitfall important for diagnostic accuracy.

FIGURE 1.

Patterns of PD1-positive cells. A, Follicular pattern with peripheral PD1 staining. Four cases showing the spectrum of PD1 expression. B, Follicular pattern with a central accumulation of intrafollicular PD1-positive cells. C, Diffuse pattern showing moderate extrafollicular PD1 staining. D, Normal. Strongly PD1-positive cells are confined to and show polarization within reactive follicles.

FIGURE 2.

Follicular pattern mimicking PTCL. Case 1. A, The neoplastic cells have a perifollicular growth pattern around reactive follicles (H&E). B, CD20 stains reactive germinal centers and perifollicular atypical B cells. C, Most of the perifollicular cells are T cells (CD3) that express PD1(D), ICOS (E), and CXCL13 (F). G, PAX5 (red) and PD1 (brown) coexpression is not present, confirming that PD1 is not expressed by B cells.

FIGURE 3.

Follicular pattern mimicking PTCL. Case 2. A, The lymph node is effaced by a diffuse, vaguely nodular proliferation (H&E) composed of B cells (CD20) (B) surrounding nodules of T cells (CD3) (C) that express PD1 (D). E, Weak BCL6 expression is present in a similar distribution to the PD1-positive areas, which are also predominantly CD4 positive (F) and contain fewer CD8-positive T cells (G).

FIGURE 4.

Follicular pattern mimicking PTCL. Case 8. A, A nodular proliferation effaced the lymph node (H&E). B, CD20 stains B cells at the periphery of the nodules. C, The center of the nodules shows a marked accumulation of T cells (CD3) that express strong PD1 (D), ICOS (E), and BCL6 (F). A subset of cells expresses CXCL13 (G) and CD10 (H).

FIGURE 5.

Diffuse pattern mimicking PTCL. Case 12. A, There is a nodular and interfollicular infiltrate in the lymph node (H&E) composed of serpiginous nodules of B cells (CD20) (B) and a heavy T-cell infiltrate (CD3) (C) with diffuse expression of PD1 in the extrafollicular areas (D). E, PAX5 (red) positive cells do not express PD1 (brown) consistent with the expression of PD1 on T cells. Case 13. F, There is diffuse architectural effacement (H&E) with significant numbers of T cells (CD3) (G). H, BCL6 is strongly positive in residual follicles, with focal weak interfollicular staining. I, PD1 is strongly expressed in follicles, but also shows moderate extrafollicular staining.