The programmed cell death 1 (PD1)/PD1 ligand (PD-L1) axis plays an important role in tumor cell escape from immune control and has been most extensively investigated for therapeutic purposes. However, PD-L1 immunohistochemistry is still not used widely for diagnosis. We review the diagnostic utility of PD-L1 (by clone SP142) immunohistochemistry in large-cell lymphomas, mainly consisting of classic Hodgkin lymphoma (CHL) and diffuse large B-cell lymphoma (DLBCL). Neoplastic PD-L1 (nPD-L1) expression on Hodgkin and Reed-Sternberg cells is well-established among prototypic CHL. Of note, EBV+ CHL often poses a challenge for differential diagnosis from peripheral T-cell lymphoma with EBV+ non-malignant large B-cells; their distinction is based on the lack of PD-L1 expression on large B-cells in the latter. The nPD-L1 expression further provides a good diagnostic consensus for CHL with primary extranodal disease conceivably characterized by a combined pathogenesis of immune escape of tumor cells and immunodeficiency. Compared with CHL, the nPD-L1 expression rate is much lower in DLBCL, highlighting some specific subgroups of intravascular large B-cell lymphoma, primary mediastinal large B-cell lymphoma, and EBV+ DLBCL. They consist of nPD-L1-positive and -negative subgroups, but their clinicopathological significance remains to be elucidated. Microenvironmental PD-L1 positivity on immune cells may be associated with a favorable prognosis in extranodal DLBCL. PD-L1 (by SP142) immunohistochemistry has helped us to understand the immune biology of lymphoid neoplasms possibly related by immune escape and/or immunodeficiency. However, knowledge of these issues remains limited and should be clarified for diagnostic consensus in the future.
Diffuse large B-cell lymphoma (DLBCL) is the most common type of malignant lymphoma with biologically and clinically heterogeneous features. Recently, the tumor microenvironment of this disease has been recognized as an important biological aspect of tumor development and therapeutic targets. Recurrent genetic alterations play significant roles in immune recognition of lymphoma cells. In particular, novel genetic alterations promoting phagocytosis were identified, suggesting a potential therapeutic strategy targeting the “don’t eat me” signal.
We compared the two methods of assessing CD30 protein expression in DLBCL and TCL specimens routinely employed at our hospital, immunohistochemistry (IHC) and flow cytometry (FCM), using the same clone of the anti-CD30 antibody (Ber-H2) in 123 patients with DLBCL and 28 patients with TCL. FCM was more sensitive than IHC, especially in cases with low expression. In three cases of TCL and two cases of DLBCL, there was discordance between these two methods. Two of these TCL cases were ALCL and one was peripheral T-cell lymphoma, NOS, but ALCL was unable to be excluded. One of two cases of DLBCL was an anaplastic variant of DLBCL. The data suggested that CD30 was undetectable, though rare, by FMC in several cases. Based on this study, a combination of IHC and FCM is recommended for the reliable and quantitative detection of CD30.
It is widely accepted that the tumor microenvironment plays an important role in the progression of lymphoid malignancies. Interaction between the tumor and its surrounding immune cells is considered a potential therapeutic target. For example, anti-programmed cell death 1 (PD-1) antibody stimulates the surrounding exhausted immune cells to release PD-1/PD-L1, thereby leading to the regression of PD-L1-positive tumors. Recently, biological phenomena, such as trogocytosis and exosome-mediated transport were demonstrated to be involved in establishing and maintaining the tumor microenvironment. We found that trogocytosis-mediated PD-L1/L2 transfer from tumor cells to monocytes/macrophages is involved in immune dysfunction in classic Hodgkin lymphoma. Exosomes derived from Epstein-Barr virus (EBV)-associated lymphoma cells induce lymphoma tumorigenesis by transferring the EBV-coding microRNAs from the infected cells to macrophages. In this review, we summarized these biological phenomena based on our findings.