A practical algorithmic approach to mature aggressive B cell lymphoma diagnosis in the double/triple hit era. Selecting cases, matching clinical benefit. A position paper from the Italian Group of Haematopathology (G.I.E.)

An accurate diagnosis of clinically distinct subgroups of aggressive mature B cell lymphomas is crucial for the choice of proper treatment. Presently, precise recognition of these disorders relies on the combination of morphological, immunophenotypical, and cytogenetic/molecular features. The diagnostic workup in such situations implies the application of costly and time-consuming analyses, which are not always required, since an intensified treatment option is reasonably reserved to fit patients. The Italian Group of Haematopathology proposes herein a practical algorithm for the diagnosis of aggressive mature B cell lymphomas based on a stepwise approach, aimed to select cases deserving molecular analysis, in order to optimize time and resources still assuring the optimal management for any patient

Blastic plasmacytoid dendritic cell neoplasm: Genomics mark epigenetic dysregulation as a primary therapeutic target

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive hematologic malignancy for which there is still no effective B therapy. In order to identify genetic alterations useful for a new treatment design, we used whole-exome sequencing to analyze 14 BPDCN patients and the patient-derived CAL-1 cell line. The functional enrichment analysis of mutational data reported the epigenetic regulatory program to be the most significantly undermined (P<0.0001). In particular, twenty-five epigenetic modifiers were found mutated (e.g. ASXL1, TET2, SUZ12, ARID1A, PHF2, CHD8); ASXL1 was the most frequently affected (28.6% of cases). To evaluate the impact of the identified epigenetic mutations at the gene-expression and Histone H3 lysine 27 trimethylation/acetylation levels, we performed additional RNA and pathology tissue-chromatin immunoprecipitation sequencing experiments. The patients displayed enrichment in gene signatures regulated by methylation and modifiable by decitabine administration, shared common H3K27-acetylated regions, and had a set of cell-cycle genes aberrantly up-regulated and marked by promoter acetylation. Collectively, the integration of sequencing data showed the potential of a therapy based on epigenetic agents. Through the adoption of a preclinical BPDCN mouse model, established by CAL-1 cell line xenografting, we demonstrated the efficacy of the combination of the epigenetic drugs 5’-azacytidine and decitabine in controlling disease progression in vivo

Bone marrow histology in marginal zone B-cell lymphomas: correlation with clinical parameters and flow cytometry in 120 patients

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What factors influence training opportunities for older workers? Three factorial surveys exploring the attitudes of HR professionals

The core research questions addressed in this paper are: what factors influence HR professionals in deciding whether to approve training proposals for older workers? What kind of training are they more likely to recommend for older employees and in which organizational contexts? We administered three factorial surveys to 66 HR professionals in Italy. Participants made specific training decisions based on profiles of hypothetical older workers. Multilevel analyses indicated that access to training decreases strongly with age, while highly-skilled older employees with low absenteeism rates are more likely to enjoy training opportunities. In addition, older workers displaying positive performance are more likely to receive training than older workers who perform poorly, suggesting that training late in working life may serve as a reward for good performance rather than as a means of enhancing productivity. The older the HR professional evaluating training proposals, the higher the probability that older workers will be recommended for training. keywords: training; older workers; HR professionals; factorial survey; multilevel model

Splenic marginal zone lymphoma: a prognostic model for clinical use.

The Integruppo Italiano Linfomi (IIL) carried out a study to assess the outcomes of splenic marginal zone lymphoma and to identify prognostic factors in 309 patients. The 5-year cause-specific survival (CSS) rate was 76%. In univariate analysis, the parameters predictive of shorter CSS were hemoglobin levels below 12 g/dL (P < .001), albumin levels below 3.5 g/dL (P = .001), International Prognostic Index (IPI) scores of 2 to 3 (P < .001), lactate dehydrogenase (LDH) levels above normal (P < .001), age older than 60 years (P = .01), platelet counts below 100 000/μL (P = .04), HbsAg-positivity (P = .01), and no splenectomy at diagnosis (P = .006). Values that maintained a negative influence on CSS in multivariate analysis were hemoglobin level less than 12 g/dL, LDH level greater than normal, and albumin level less than 3.5 g/dL. Using these 3 variables, we grouped patients into 3 prognostic categories: low-risk group (41%) with no adverse factors, intermediate-risk group (34%) with one adverse factor, and high-risk group (25%) with 2 or 3 adverse factors. The 5-year CSS rate was 88% for the low-risk group, 73% for the intermediate-risk group, and 50% for the high-risk group. The cause-specific mortality rate (x 1000 person-years) was 20 for the low-risk group, 47 for the intermediate-risk group, and 174 for the high-risk group. This latter group accounted for 54% of all lymphoma-related deaths. In conclusion, with the use of readily available factors, this prognostic index may be an effective tool for evaluating the need for treatment and the intensity of therapy in an individual patient. © 2006 by The American Society of Hematology

Prognostic relevance and putative histogenetic role of cytokeratin 7 and MUC5AC expression in Crohn\u2019s disease-associated small bowel carcinoma

Most Crohn\u2019s disease-associated small bowel carcinomas (CrD-SBCs) are diagnosed in advanced stage and have poor prognosis. To improve diagnosis and therapy, a better knowledge of tumour precancerous lesions, histotypes and prognostic factors is needed. We investigated histologically and immunohistochemically 52 CrD-SBCs and 51 small bowel carcinomas unrelated to inflammatory disease, together with their tumour-associated mucosa, looking for Crohn-selective changes. Histologic patterns and phenotypic markers potentially predictive of CrD-SBC histogenesis and prognosis were analysed. Cytokeratin 7 or MUC5AC-positive metaplastic changes were found in about half of investigated CrD-SBCs, significantly more frequently than in CrD-unrelated SBCs. They correlated with metaplastic changes of their associated mucosa, while being absent in normal ileal mucosa. Histologic patterns suggestive for progression of some cytokeratin 7 and/or MUC5AC-positive metaplastic lesions into cancer of the same phenotype were also observed. Patient survival analyses showed that tumour cytokeratin 7 or MUC5AC expression and non-cohesive histotype were adverse prognostic factors at univariable analysis, while cytokeratin 7 and non-cohesive histotype were also found to predict worse survival in stage- and age-inclusive multivariable analyses. Besides conventional dysplasia, hyperplasia-like non-conventional lesions were observed in CrD-SBC-associated mucosa, with patterns suggestive for a histogenetic link with adjacent cancer. In conclusion the cytokeratin 7 and/or MUC5AC-positive metaplastic foci and the non-conventional growths may have a role in cancer histogenesis, while tumour cytokeratin 7 and non-cohesive histotype may also predict poor patient survival. Present findings are worth being considered in future prospective histogenetic and clinical studies

Array-based comparative genomic hybridization analysis of aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma (AECD8+L), extranodal NK/T nasal type lymphoma (ENK/T-NT) and blastic plasmocytoid dendritic cell neoplasia (BPDCN)

To better define molecular alterations involved in these proliferations, we performed an arraybased high resolution comparative genomic hybridization (aCGH) analysis on DNA extracted from skin lesions of 13 patients affected from AECD8+L, 5 patients from ENK/T-NT and 21 patients from BPDCN. In AECD8+ lymphoma, our results showed recurrent alterations of chromosomal regions found also in other CTCL, such as amplification of 3p21 (46% of patients), 7q (54%), 8q24 (54%), 16p(77%), 17q (92%), and the deletion of 9p21 (69%), and several alterations seemingly typical for AECD8+L: i.e. amplification of 11q12-q13 (69%), 22q (69%) and trisomy of 19 (69%). Within these amplified regions, the combination of duplication of JAK3 (chr. 19p13.11) and STAT3/STAT5B (chr. 17q21) might explain the hyper-activation of JAK / STAT signaling pathway, with an increased proliferation and an increased anti apoptotic activity. Interestingly, constitutive Jak3 signaling in murine lymphopoiesis, in a bone marrow transplantation model, induces an aggressive lymphoproliferative disorder characterized by the expansion of CD8+, TCR\u3b1\u3b2+ T cells. In addition chromosome 19 contains several genes that can lead to uncontrolled proliferation of cells if overexpressed, such as JUNB, JUND, KIR3DL2, AKT2, LYL1, BCL3 and RELB, alone or in combination with the proto-oncogene RELA, present in the amplified region 11q12-q13. A retrospective case study of 5 white patients affected by ENK/T lymphoma (4 PC-ENK/T-NT and 1 ENK/T-N with cutaneous involvement) was also performed. Genomic alterations were detected by aCGH hybridization that showed gains of 1q, 7q and loss of 17p in the cases of PC-ENK/T-NT lymphomas and gain of 7q and loss of 9p, 12p, 12q in the case of ENK/T-N lymphoma. In our cases, the exclusively cutaneous presentation was not associated with a better prognosis. BPDCN is a rare, often fatal disease: all patients had skin lesions, 12 with extracutaneous disease at diagnosis. By aCGH there were chromosomal imbalances in all biopsies, with an average of 7 copy number alterations/case and losses more frequent than gains (141 vs 18); large interstitial/telomeric imbalances prevailing over the entire chromosome losses/gains (127 vs 32). Common deleted regions (CDR) were found on chromosomes 5, 7, 9, 12, 13 and 14. A CDR at 9p21.3, hosting CDKN2A suppressor gene (P16INK4a, p14ARF), was present in 15 cases; 6 in biallelic status. Chromosome 13 monosomy was found in 11 cases and we identified a minimal CDR on 13q13.1-q14.3, including RB1, CCNA1 and KPNAP3. In 12 cases a monoallelic CDR encompassed 12p13.2-p13.1, hosting CDKN1B (p27/KIP1). Additionally, 4 patients had del(7)(p12), a region harbouring IKZF/Ikaros, defective in cases of acute lymphoblastic leukaemia with poor prognosis. In conclusion, AECD8+L, PC_ENK/T-NT and BPDCN are aggressive neoplastic diseases showing complex genetic alterations, involving activation, proliferations and apoptosis, that may explain the poor response to therapy. These data, complemented with gene expression analysis and immunohistochemical evaluation should help us in deciphering biologic and molecular mechanisms of these disease entities and may become important tools in diagnosis and classification or to find new therapeutic approaches

Gray zones around diffuse large B cell lymphoma. Conclusions based on the workshop of the XIV meeting of the European Association for Hematopathology and the Society of Hematopathology in Bordeaux, France

The term “gray-zone” lymphoma has been used to denote a group of lymphomas with overlapping histological, biological, and clinical features between various types of lymphomas. It has been used in the context of Hodgkin lymphomas (HL) and non-Hodgkin lymphomas (NHL), including classical HL (CHL), and primary mediastinal large B cell lymphoma, cases with overlapping features between nodular lymphocyte predominant Hodgkin lymphoma and T-cell/histiocyte-rich large B cell lymphoma, CHL, and Epstein–Barr-virus-positive lymphoproliferative disorders, and peripheral T cell lymphomas simulating CHL. A second group of gray-zone lymphomas includes B cell NHL with intermediate features between diffuse large B cell lymphoma and classical Burkitt lymphoma. In order to review controversial issues in gray-zone lymphomas, a joint Workshop of the European Association for Hematopathology and the Society for Hematopathology was held in Bordeaux, France, in September 2008. The panel members reviewed and discussed 145 submitted cases and reached consensus diagnoses. This Workshop summary is focused on the most controversial aspects of gray-zone lymphomas and describes the panel’s proposals regarding diagnostic criteria, terminology, and new prognostic and diagnostic parameters