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Abstract
Aims: Programmed death-1 (PD-1) is expressed by germinal center-associated helper T-cells and acts as a negative regulator of the immune system. PD-1 is encountered on tumor cells of angioimmunoblastic T-cell lymphoma and is a postulated diagnostic marker in chronic lymphocytic leukemia (CLL/SLL). Recent data suggest prognostic importance of PD-1 in follicular lymphoma (FL). We assessed the diagnostic potential and the prognostic importance of PD-1 in B-cell lymphomas.Methods: Distribution of PD-1+ lymphocytes in B-cell lymphomas was studied on 403 cases. Correlation with known biologic and clinical key data was performed. Prognostic cut-off scores were determined by receiver operating curve analysis. Results: PD-1+ tumor-infiltrating lymphocytes were numerous in extranodal marginal zone lymphomas and FL. Their amount decreased from FL grade 1 to grade 3 and to FL with transformation to diffuse large B-cell lymphoma. An increased amount of PD-1 tumor-infiltrating lymphocytes above the prognostic cut-off score (> 2.8%) was a positive prognostic factor of disease-specific survival (DSS) in FL-patients. Five percent of the studied 66 CLL/SLL cases showed unequivocal PD-1 positivity of neoplastic cells.Conclusions: Increased number of PD-1+ tumor-infiltrating lymphocytes is associated with significantly improved DSS in FL and may be useful to predict its heterogeneous clinical behavior. PD-1 has probably limited diagnostic value for primary histopathological CLL/SLL diagnostics.
Highlights
Programmed death-1 (PD-1) is a member of the CD28 costimulatory receptor superfamily
In this study we significantly expand existing quantitative and qualitative data on diagnostic and prognostic utility of PD-1-positive tumor-infiltrating lymphocyte number in B-cell lymphomas [10,20], confirming their prognostic significance in follicular lymphoma (FL) as well as the decrease of these cells in secondary diffuse large B-cell lymphomas (DLBCL) arising from FL [17]
Our study has several advantages: (i) We used clear morphological analyses, always referring to 1 mm2, independent from the size of the individual field analyzed; (ii) The standardized approach using tissue microarray (TMA) ensured consistency in the area of tissue being considered; (iii) Sampling of tissue for TMA cores was performed independent of PD-1 staining, ensuring that there was no preferential treatment of PD-1 hot spots; (iv) All TMA were stained within one procedure, minimizing the probability of staining biases; (v) receiver operating characteristic (ROC)
Summary
Programmed death-1 (PD-1) is a member of the CD28 costimulatory receptor superfamily It is expressed on a subset of thymocytes and is upregulated on activated T-cells, B-cells and myeloid cells [24,25]. S. Muenst et al / Diagnostic and prognostic utility of PD-1 in B cell lymphomas tal components, like FOXP3-positive tumor-infiltrating lymphocytes, in follicular lymphoma (FL) and in classical Hodgkin lymphoma [1,17,23]. We performed a large scale morphometric and clinico-pathological study to systematically characterize the distribution and the prognostic importance of PD-1-positive tumor-infiltrating lymphocytes in various B-cell lymphoma entities as well as to study the possible expression of PD-1 by B-cell lymphoma tumor cells
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