Anaplastic large cell lymphomas are peripheral T-cell lymphomas that are characterized by a proliferation of large anaplastic blasts expressing CD30. In children, systemic anaplastic large cell lymphomas often present at advanced clinical stage and harbor translocations involving the anaplastic lymphoma kinase (ALK) gene leading to the expression of chimeric anaplastic lymphoma kinase (ALK)-fusion proteins. Primary cutaneous anaplastic large cell lymphoma is regarded as an ALK-negative variant confined to the skin and is part of the spectrum of primary cutaneous CD30-positive T-cell lymphoproliferative disorders. Thirty-three of 487 pediatric patients registered within the Anaplastic Large Cell Lymphoma-99 trial (1999 to 2006) presented with a skin limited CD30-positive lymphoproliferative disorder. In 23 of the 33 patients, material for international histopathological review was available, and the cases were studied for histopathological, immunophenotypical and clinical features as well as for breaks within the ALK gene. Five of 23 cases and one additional case (identified after closure of the trial) expressed ALKprotein. Complete staging excluded any other organ involvement in all children. Expression of ALK proteins was demonstrated by immunohistochemistry in all cases and the presence of breaks of the ALK gene was genetically confirmed in 5 evaluable cases. The histopathological and clinical picture of these skin-restricted ALK-positive lymphomas was indistinguishable from that of cutaneous anaplastic large cell lymphoma. Five children presented with a single skin lesion that was completely resected in 4 and incompletely resected in one. Three of these patients received no further therapy, 2 additional local radiotherapy, and one chemotherapy. All children remain in complete remission with a median follow up of seven years (range 1-8 years). We present 6 pediatric cases of ALK-positive primary cutaneous anaplastic large cell lymphomas. After thorough exclusion of systemic involvement, therapy confined to local measures seems to be sufficient to induce cure. ©2013 Ferrata Storti Foundation. This is an open

Tumor-associated macrophages (TAM) have been ascribed both pro- and anti-tumor properties, but the majority of clinical cancer studies have shown that the presence of a high number of TAM is related to poor prognosis, suggesting that TAM predominantly exert pro-tumoral activity. The prognostic role of TAM in patients with diffuse large B-cell lymphoma (DLBCL), however, is so far unknown. Therefore, TAM were immunohistochemically stained with a CD68 antibody in a retrospective, population-based study including 176 DLBCL patients treated with curative intent. With the exception that patients >60 years of age had a larger number of CD68+ cells (1143 vs 1018 cells/mm2; P = 0.05), no significant differences were found between the number of CD68+ cells and other clinical factors. Similarly, germinal center B-cell (GCB)/non-GCB immunophenotype or low/high Ki-67 percentage were not associated with CD68 expression. Finally, no significant correlation was found between the number of CD68+ cells and progression-free survival (P = 0.34) or overall survival (P = 0.94). These data indicate that the pro-tumor effect of TAM has limited clinical relevance in DLBCL patients, which could imply that therapeutic strategies aimed at enhancing their anti-tumor activity are of continuous clinical interest.

SummaryChemotherapy and rituximab (R) is current standard therapy in diffuse large B-cell lymphoma (DLBCL), but a substantial proportion of patients still fail to reach sustained remission. In vitro studies have indicated that rituximab resistance could be accompanied by dysregulated apoptotic pathways, such as the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway, which can be constitutively activated in DLBCL. In this retrospective, immunohistochemical study on 106 patients treated with R-CHO(E)P (cyclophosphamide, doxorubicin, vincristine, prednisone, rituximab [+etoposide]), we investigated the prognostic role of proteins involved in different apoptotic pathways; phosphorylated AKT (p-AKT), bcl-2, MCL1, bcl-xL, Bax and Bak. High p-AKT expression (>108 cells/mm 2 , highest quartile, n = 27) predicted worse progression-free (PFS) (P = 0AE02) and overall (OS) (P = 0AE01) survival, independent of International Prognostic Index and sex. Also bcl-2+ (cut-off 50%) predicted worse PFS (P = 0AE005) and OS (P = 0AE05) but after adjustment for clinical factors only the influence on PFS (P = 0AE03) remained significant. The prognostic impact of p-AKT overexpression was independent of bcl-2 status. MCL1, bcl-xL, Bax and Bak expression did not add any prognostic information. Our results suggest that high p-AKT expression predicts worse outcome, possibly indicating that inhibition of the activated PI3K/AKT pathway could be of clinical interest in DLBCL patients. In addition, bcl-2 status could have prognostic importance also in the era of immunochemotherapy.

SummaryThe prognostic significance of tumour-infiltrating lymphocytes (TILs) in patients with diffuse large B-cell lymphoma (DLBCL) remains controversial. Furthermore, the possible impact of regulatory T cells (T regs ) on survival in DLBCL is still unknown. We performed a retrospective study on the immunohistochemical expression of cytotoxic cells and T regs , and their correlation with survival in 195 DLBCL patients. Patients with a small number of cytotoxic T-cell intracytoplasmic antigen-1 (TIA-1)+ T cells (£260 cells/mm 2 tumour area; n ¼ 52) had significantly better outcome than patients with a large number (>260 cells/mm 2 ; n ¼ 143); progression-free survival (PFS) at 5 years was 67% vs. 50% (P ¼ 0AE03) and overall survival (OS) was 73% vs. 57% (P ¼ 0AE03). In multivariate analysis, the low TIA-1+ group still had a better PFS (relative risk 0AE75, 95% confidence interval 0AE31-0AE99; P ¼ 0AE05). The number of forkhead box protein 3 (FOXP3)+ T regs had no influence on PFS (P ¼ 0AE89) or OS (P ¼ 0AE75). These results suggest that immunohistochemical analysis of cytotoxic T cells at time of diagnosis could provide additional prognostic information. The lack of correlation between the number of FOXP3+ cells and survival could possibly indicate that tumour-infiltrating T regs are of less clinical importance in DLBCL. However, these findings need to be explored in functional studies.