| Abstract|| |
We present a rare case of lymphocyte-rich classical Hodgkin lymphoma (LRCHL), which exhibited different expression patterns of programmed death-1 (PD-1) in nodular and interfollicular areas. A 57-year-old male patient presented with neck masses. Neck computed tomography showed enlargement of multiple lymph nodes in right Level II and III. Histologic examination of the excised lymph node revealed LRCHL with nodular and interfollicular patterns. Immunohistochemical analysis for PD-1 revealed a small number of weakly stained cells in the interfollicular area. PD-1 (+) cells were markedly increased in cell number and staining intensity in the nodular area and formed rosettes around the tumor cells.
Keywords: Hodgkin lymphoma, lymphocyte-rich, programmed death-1
|How to cite this article:|
Go JH. Expression pattern of programmed death-1 in lymphocyte-rich classical Hodgkin lymphoma according to the growth patterns. Indian J Pathol Microbiol 2016;59:538-40
|How to cite this URL:|
Go JH. Expression pattern of programmed death-1 in lymphocyte-rich classical Hodgkin lymphoma according to the growth patterns. Indian J Pathol Microbiol [serial online] 2016 [cited 2020 Nov 27];59:538-40. Available from: https://www.ijpmonline.org/text.asp?2016/59/4/538/191819
| Introduction|| |
Programmed death-1 (PD-1) is markedly elevated in tumor infiltrating T-cells of some types of Hodgkin lymphoma (HL).  Increased numbers of PD-1 (+) cells is a negative prognostic factor for classical HL (cHL).  Blockade of the PD-1 signaling pathway may be a potentially effective immunologic strategy for the treatment of HL.  However, the observation of a higher number of PD-1 (+) lymphocytes in lymphocyte-rich cHL (LRCHL) and nodular lymphocyte predominant HL (NLPHL), which have better prognosis than other types,  suggests that the nature of PD-1 (+) cells may be different in LRCHL and NLPHL from other types of HL. In NLPHL, tumor infiltrating T-cells consistently express PD-1, forming rosettes around the tumor cells in nearly all cases. , However, the expression pattern of PD-1 has not been fully described in LRCHL, especially according to the growth pattern. Herein, we report a case of LRCHL exhibiting nodular and interfollicular patterns, with a special emphasis of PD-1 expression pattern and its significance.
| Case Report|| |
A 57-year-old male patient was admitted because of the right neck mass for 1 week. He had no specific symptoms. Neck computed tomography showed enlargement of multiple lymph nodes in right Level II and III. Excised lymph nodes were nearly totally effaced with discernible internodular growth pattern. The tumor cells were mostly scattered between the small nodules, which consisted of CD20 (+), IgD (+) small lymphocytes of mantle zones with a rather cohesive CD23 (+) follicular dendritic network. Many large tumor cells were scattered between B-cell nodules in the background of predominant small lymphocytes and aggregates of epithelioid cells. Weakly PD-1 stained cells were also present and did not form tumor rosette [Figure 1]. Neutrophils or eosinophils were not found. The tumor cells expressed CD30, CD15, and Oct-2, but were negative for CD20 or CD3. These findings were consistent with the interfollicular growth pattern of LRCHL. In the periphery of the lymph node, vague nodular growth pattern was recognized. Immunohistochemistry showed irregular expansions of CD20 (+) and IgD (+) mantle cells with expanded and disintegrated meshworks of CD23 (+) follicular dendritic cells. A few tumor cells in and at the edge of the expanded mantle zones showed the same immunophenotype as the interfollicular tumor. Notably, PD-1 (+) cells were markedly increased in cell number and staining intensity compared with the area of the interfollicular tumor. These PD-1 (+) cells formed rosettes around the tumor cells [Figure 2].
|Figure 1: A small number of weakly programmed death - 1 stained cells is present between the small B - cell nodules in interfollicular tumor (a) and does not form rosettes around Oct - 2 (+) tumor cells (b)|
Click here to view
|Figure 2: Programmed death - 1 (+) cells are markedly increased in cell number and staining intensity in nodular areas (a), which form rosettes around the Oct - 2 (+) tumor cells (b)|
Click here to view
| Discussion|| |
This study demonstrates a diminished expression of PD-1 from the nodular to the interfollicular areas in LRCHL. As well, PD-1 rosettes were limited to the nodular areas and were not observed in diffuse areas.
LRCHL was recently defined as subtype of cHL, , and accounts for only 3-5% of all cases of HL.  Diagnostic criteria of LRCHL include scattered Hodgkin and Reed-Sternberg (HRS) cells with classical immunophenotype in a cellular background of small lymphocytes without admixture of eosinophils and neutrophils and without sclerosis.  Two morphologic variants have been identified according to growth pattern (nodular vs. interfollicular and diffuse).  Our case corresponded to LRCHL with nodular and interfollicular growth patterns.
PD-1 is a key regulator of tumor immune escape,  and is involved in the evasion of tumor immunity.  Persistent stimulation from tumor antigens induces PD-1 overexpression by tumor infiltrating lymphocytes and binding of PD-ligand (PD-L) to PD-1 on T-cells functionally silences the activation of tumor-associated T-cells and leads to impaired cell survival and effector function, producing a tumor permissive microenvironment. 
HRS cells showed strong membranous expression of PD-L1 in most cases of cHL.  However, previous analyses of PD-1 (+) cells in HL have yielded conflicting results. One study reported a paucity of PD-1 expression in the cHL microenvironment,  while in another study PD-1 was markedly elevated in tumor infiltrating T-cells of HL.  Increased level of PD-1 (+) infiltrating lymphocytes has been found to be a stage-independent negative prognostic factor of overall survival for cHL. 
However, with regard to the subtype, the number of PD-1 (+) lymphocytes is reportedly higher in LRCHL and NLPHL than other types of cHL.  These features suggest that the types and characteristics of PD-1 (+) cells could differ according to the histologic type. In NLPHL, tumor infiltrating T-cells consistently express PD-1, forming rosettes around the neoplastic cells in nearly all cases. , However, the presence of rosettes is not a unique and defining feature of NLPHL; it also occurs in LRCHL. 
Although PD-1 expression has been described on exhausted T-cells, PD-1 is also a marker of follicular helper T-cells (T FH ).  The presence and histologic distribution of T FH is being harvested to explore HL pathogenesis.  The presence of PD-1 rosettes might reflect the germinal center (GC) origin of the tumor cells in NLPHL and a substantial proportion of LRCHL.  In NLPHL, the tumor cells preserve the expression of a full B-cell program, and the presence of T FH surrounding tumor cells suggests that GC microenvironment is also maintained. However, the B-cell program and the GC microenvironment are lost in cHL. In LRCHL, the GC microenvironment is at least partially preserved, although the B-cell program disappeared in tumor cells. 
In NLPHL, PD-1 rosettes are limited to the nodular areas, not in diffuse areas, and the intensity of the immunostaining with PD-1 seems to diminish gradually from the nodular to the diffuse areas.  These findings were recapitulated in the present case of LRCHL. Therefore, a PD-1 rich microenvironment may inhibit tumor progression in NLPHL and LRCHL, and could be associated with better prognosis in these tumors. In terms of HL development, LRCHL is considered as an early stage in the spectrum of cHL, which progresses to mixed cellularity or nodular sclerosis cHL with the disappearance of PD-1 (+) T FH microenvironment.
Taken together, the findings support the speculation that the types of PD-1 (+) cells are different between the nodular and the interfollicular patterns of LRCHL. Further studies exploring the characteristics and clinical significance of PD-1 (+) cells are needed in both nodular and interfollicular areas of LRCHL compared with other types of cHL.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Yamamoto R, Nishikori M, Kitawaki T, Sakai T, Hishizawa M, Tashima M, et al. PD-1-PD-1 ligand interaction contributes to immunosuppressive microenvironment of Hodgkin lymphoma. Blood 2008;111:3220-4.
Muenst S, Hoeller S, Dirnhofer S, Tzankov A. Increased programmed death-1+ tumor-infiltrating lymphocytes in classical Hodgkin lymphoma substantiate reduced overall survival. Hum Pathol 2009;40:1715-22.
Nam-Cha SH, Roncador G, Sanchez-Verde L, Montes-Moreno S, Acevedo A, Domínguez-Franjo P, et al. PD-1, a follicular T-cell marker useful for recognizing nodular lymphocyte-predominant Hodgkin lymphoma. Am J Surg Pathol 2008;32:1252-7.
de Jong D, Bosq J, MacLennan KA, Diebold J, Audouin J, Chasle J, et al. Lymphocyte-rich classical Hodgkin lymphoma (LRCHL): Clinico-pathological characteristics and outcome of a rare entity. Ann Oncol 2006;17:141-5.
Anagnostopoulos I, Hansmann ML, Franssila K, Harris M, Harris NL, Jaffe ES, et al. European task force on lymphoma project on lymphocyte predominance Hodgkin disease: Histologic and immunohistologic analysis of submitted cases reveals 2 types of Hodgkin disease with a nodular growth pattern and abundant lymphocytes. Blood 2000;96:1889-99.
Nam-Cha SH, Montes-Moreno S, Salcedo MT, Sanjuan J, Garcia JF, Piris MA. Lymphocyte-rich classical Hodgkin's lymphoma: Distinctive tumor and microenvironment markers. Mod Pathol 2009;22:1006-15.
Xia Y, Jeffrey Medeiros L, Young KH. Signaling pathway and dysregulation of PD1 and its ligands in lymphoid malignancies. Biochim Biophys Acta 2016;1865:58-71.
Dorfman DM, Brown JA, Shahsafaei A, Freeman GJ. Programmed death-1 (PD-1) is a marker of germinal center-associated T cells and angioimmunoblastic T-cell lymphoma. Am J Surg Pathol 2006;30:802-10.
Smeltzer JP, Jones JM, Ziesmer SC, Grote DM, Xiu B, Ristow KM, et al. Pattern of CD14+ follicular dendritic cells and PD1+ T cells independently predicts time to transformation in follicular lymphoma. Clin Cancer Res 2014;20:2862-72.
Jai Hyang Go
Department of Pathology, Dankook University College of Medicine, Cheonan, Chungnam
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2]