Programmed death-1 (PD-1) is a marker of germinal center-associated T cells and angioimmunoblastic T-cell lymphoma

Abstract

Programmed death-1 (PD-1), a member of the CD28 costimulatory receptor family, is expressed by germinal center-associated T cells in reactive lymphoid tissue. In a study of a wide range of lymphoproliferative disorders, neoplastic T cells in 23 cases of angioimmunoblastic lymphoma were immunoreactive for PD-1, but other subtypes of T cell and B cell non-Hodgkin lymphoma, as well as classic Hodgkin lymphoma, did not express PD-1. The pattern of PD-1 immunostaining of neoplastic cells in angioimmunoblastic lymphoma was similar to that reported for CD10, a recently described marker of neoplastic T cells in angioimmunoblastic lymphoma. Tumor-associated follicular dendritic cells in cases of angioimmunoblastic lymphoma were found to express PD-L1, the PD-1 ligand. In addition, PD-1-positive reactive T cells formed rosettes around neoplastic L&H cells in 14 cases of nodular lymphocyte predominant Hodgkin lymphoma studied. These findings, along with data from previous studies, suggest that angioimmunoblastic lymphoma is a neoplasm of germinal center-associated T cells and that there is an association of germinal center-associated T cells and neoplastic cells in nodular lymphocyte predominant Hodgkin lymphoma. PD-1 is a useful new marker for angioimmunoblastic lymphoma and lends further support to a model of T-cell lymphomagenesis in which specific subtypes of T cells may undergo neoplastic transformation and result in specific, distinct histologic, immunophenotypic, and clinical subtypes of T-cell neoplasia.

FIGURE 1

PD-1 immunostaining in tonsil. Tonsil with follicular hyperplasia and germinal center formation (A). Germinal centers contain numerous CD20-positive B cells (B), and CD3-positive T cells (C), which are also present in the interfollicular T-cell zone. PD-1 immunostaining highlights the vast majority of germinal center-associated T cells (D), but few T cells in the interfollicular T-cell zone. (A, hematoxylin and eosin (H&E), × 100; B-D, immunostaining with hematoxylin counterstain, × 100, with insets at × 400). Double immunostaining for PD-1, B-cell, and T-cell markers in tonsil with follicular hyperplasia and germinal center formation (E, F), stained for PD-1 (brown) and CD3 (red), showing dual stained cells (E). Tonsil was also stained for PD-1 (brown) and CD20 (red) showing separately stained PD-1-positive and CD20-positive cells (F). (A, H&E, × 100; B-D, immunostaining with hematoxylin counterstain, × 100; C and D insets, immunostaining with hematoxylin counterstain, × 200; E and F, immunostaining with hematoxylin counterstain, × 200).

FIGURE 2

PD-1 immunostaining in nodular lymphocyte predominant Hodgkin lymphoma. Lymph node involved by nodular lymphocyte-predominant Hodgkin lymphoma, showing a nodular proliferation of L&H (popcorn) cells surrounded by small lymphocytes (A). The neoplastic L&H cells show immunostaining for the B-cell marker CD20 (B), whereas the surrounding small lymphocytes show immunostaining for T-cell marker CD3 (C). A subset of the CD3-positive T cells form rosettes around the neoplastic L&H cells and are PD-1 positive (D). L&H cells are immunoreactive for PD-1 ligand PD-L1 (D, inset). (A, H&E, × 400; B-D, immunostaining with hematoxylin counterstain, × 400; D inset, immunostaining with hematoxylin counterstain, × 400).

FIGURE 3

PD-1 immunostaining in angioimmunoblastic lymphoma. Lymph node involved by angioimmunoblastic lymphoma, showing numerous intermediate size lymphoid cells with round to irregular nuclei and clear cytoplasm, along with a proliferation of small blood vessels (A). Immunostaining reveals the presence of numerous CD3-positive T cells (B), and a CD23-positive FDC meshwork is associated with the T-cell infiltrate (C). A significant subset of CD3-positive cells express PD-1 (D). Scattered CD20-positive B cells were also present (not shown). (A, H&E, × 200; B-D, immunostaining with hematoxylin counterstain, × 200).

FIGURE 4

Comparison of PD-1, CD10, and bcl-6 immunostaining in angioimmunoblastic lymphoma. Lymph node involved by angioimmunoblastic lymphoma, showing numerous intermediate size lymphoid cells with round to irregular nuclei and clear cytoplasm, along with a proliferation of FDCs and small blood vessels (A). Immunostaining reveals the presence of numerous CD3-positive T cells (B), CD21-positive FDCs (C), PD-1-positive cells, which account for a significant subset of CD3-positive cells (D), CD10-positive cells, which account for a smaller subset of CD3-positive cells (E), and bcl-6-positive cells, which account for a minor percentage of cells present (F). (A, H&E, × 200; B-F, immunostaining with hematoxylin counterstain, × 200).

FIGURE 5

PD-L1 immunostaining in angioimmunoblastic lymphoma. Lymph node involved by angioimmunoblastic lymphoma (A) with CD21-positive FDCs present in expanded networks (B) where foci of PD-1-positive cells are present (C). Immunostaining reveals the presence of numerous PD-L1-positive cells (D) closely associated with PD-1-positive cells. The pattern of PD-L1 staining is similar to that seen with CD21, a marker of FDCs (B). (A, H&E, × 400; B-D, immunostaining with hematoxylin counterstain, × 400).