Previous studies showed that most cases of ALK⁺ anaplastic large-cell lymphoma (ALK⁺ALCL) do not express SHP1, a tyrosine phosphatase and an important negative regulator for cellular signaling pathways such as that of JAK/STAT. To fully assess the biologic significance of loss of SHP1 in ALK⁺ALCL, we transfected SHP1 plasmids into 2 SHP1^-, ALK⁺ALCL cell lines, Karpas 299 and SU-DHL-1. After 24 hours of transfection, pJAK3 and pSTAT3 were decreased, and these changes correlated with down-regulation of STAT3 downstream targets including cyclin D3, mcl-1, and bcl-2. Expression of SHP1 in these 2 cell lines also resulted in marked decreases in the protein levels of JAK3 and NPM-ALK, and these effects were reversible by proteosome inhibitor MG132. Conversely, when SHP1 expression in SUP-M2 (a SHP1⁺ ALK⁺ALCL cell line) was inhibited using siRNA, pSTAT3, pJAK3, JAK3, and NPM-ALK were all up-regulated. Coimmunoprecipitation studies showed that SHP1 was physically associated with JAK3 and NPM-ALK. SHP1 expression in Karpas 299 and SU-DHL-1 led to significant G₁ cell cycle arrest but not apoptosis. To conclude, loss of SHP1 contributes to the pathogenesis of ALK⁺ALCL by 2 mechanisms: (1) it leaves the tyrosine phosphorylation and activation of JAK3/STAT3 unchecked and (2) it decreases proteosome degradation of JAK3 and NPM-ALK.

Purpose: Tumor microenvironment influences the behavior of follicular lymphoma (FL), although the specific cell subsets involved are not well known. The aim of this study was to determine the impact of programmed cell death 1 (PD-1) –positive inhibitory immunoregulatory lymphoid cells in the clinicobiologic features and outcome of patients with FL.Patients and Methods: We examined samples from 100 patients (53 men and 47 women; median age, 54 years) at diagnosis, as well as in 32 patients at first relapse, with a recently generated monoclonal antibody against PD-1. The cells were quantified using computerized image analysis. Additional analysis consisted of double immunofluorescence and flow cytometry.Results: PD-1 expression was alternative to FOXP3 in lymphoid cells from both reactive tonsils and FL. At diagnosis, the median percentage of PD-1–positive cells was 14% (range, 0.1% to 74%). Patients with grade 3 FL, poor performance status, and high serum lactate dehydrogenase showed lower numbers of PD-1–positive cells. After a median follow-up of 6.2 years, patients with PD-1–positive cells ≤ 5% (n = 25), 6% to 33% (n = 50), and more than 33% (n = 25) had a 5-year progression-free survival rate of 20%, 46%, and 48% (P = .038) and overall survival (OS) of 50%, 77%, and 95% (P = .004), respectively. PD-1 and FL International Prognostic Index maintained prognostic value for OS in multivariate analysis. Patients with PD-1–positive cells ≤ 5% showed a higher risk of histologic transformation. At that time, transformed diffuse large B-cell lymphomas had lower percentage of PD-1–positive cells than FL.Conclusion: A high content of PD-1–positive cells predicted favorable outcome of FL patients, whereas a marked reduction is observed in transformation.

Purpose: To define the clinical and pathologic characteristics of primary cutaneous small/medium CD4⁺ T-cell lymphoma (PCSM-TCL) and identify parameters of prognostic significance. Patients and Methods: We have investigated 24 patients with primary cutaneous lymphomas composed of small/medium mature T-cells with a βF1, CD3, CD4⁺ and/or noncytotoxic, CD8^– and CD30^– phenotype. The proliferation index and CD8⁺ infiltrating cells were quantified with an automated image analysis system. Results: Sixteen patients presenting with solitary or localized plaques or small nodules (< 3 cm) had an indolent course. Only three patients experienced repeated cutaneous relapses, and none of them died as a result of the disease after 1 to 168 months (median, 17 months) of follow-up. The tumors had a low proliferation (median Ki-67, 9% ± 5%) and an intense infiltrate of reactive CD8⁺ (median, 20% ± 11.7%). Five patients presenting with rapidly evolving large tumors or nodules (≥ 5 cm) had an aggressive disease and died with extracutaneous dissemination 18 to 36 months after diagnosis (median, 23 months). These tumors had a significantly higher proliferation (median Ki-67, 22% ± 11.3%; P < .05) and lower number of infiltrating CD8⁺ (median, 1% ± 3%; P < .05) than the previous group. A third group of three patients had a peculiar clinical presentation with multifocal relapsing lesions without extracutaneous dissemination after a long period of follow-up ranging from 41 to 92 months. Histologically, these cases had an intense infiltrate of eosinophils. Conclusion: PCSM-TCL is a heterogeneous group of tumors with differentiated clinical and pathological characteristics with impact in the outcome of the patients.