Cutaneous extranodal NK/T-cell lymphoma: a clinicopathologic study of 5 patients with array-based comparative genomic hybridization

Extranodal natural killer/T-cell (ENK/T) lymphoma is a rare neoplasm, subcategorized into ENKITnasal ENK/T-N) and ENK/T-nasal type (ENK/T-NT) lymphomas. ENK/T-NT lymphoma with initial presentation in the skin is known as primary cutaneous (PC) ENK/T-NT lymphoma. Patients and methods: The aim ofthis study was to investigate pathogenesis, genomic alterations, and prognosis ofcutaneous ENK/T lymphomas to provide further insights into clinicopathologic features and genetic mechanism of lymphomagenesis. A retrospective case study of 5 white patients affected by ENK/T lymphoma (4 PC-ENK/T-NT and l ENKIT-N with cutaneous involvement) was performed. Results: Most ofthe cases presented with multiple nodular and ulcerated lesions localized on the extremities. A considerable percentage had disease in advanced stage at diagnosis with a 12-month survival rate of 40%. Genomic alterations were detected by array-based comparative genomic hybridization that showed gains of 1q, 7q and loss of 17p in the cases of PC-ENK/T-NT Iymphomas and gain of 7q and 10ss of 9p, 12p, 12q in the case of ENK/T-N lymphoma. Conclusion: ENK/T lymphoma is a very aggressive entity, and, in our cases, tbe exc1usively cutaneous presentation was not associated with a better prognosis. The results of our array comparative genomic hybridization analysis could be useful to better define the diffcrent ENK/T lymphoma subgroups with cutaneous involvement and new protocols of treatment

Cutaneous T-cell lymphomas CD8+

Recently the expression ofcytotoxic CD8+ immunophenotype in several cutaneous T-cell lymphomas entities was identified. Around 5% of mycosis fungoides (MF) may express a CD8+, CD45RA+, TIA-1+, CD5-(intraepitelial-pagetoid variant) or a CD8+, CD45RO+, CD5+, TIA-1 (dermal, band-like lichenoid variant) immunophenotype and usually present large erythemato-squamous, hycthyosiform plaques in the gluteal area or arms, showing a very indolent course as classical MF. Annular or erythemato-squamous psoriasiform lesions in the abdominal area or arms, with an hypochromic evolution and an indolent course, was characteristic of MF in children and adolescent. In the group of CD30+ lymphoproliferative disorders CD8+ lymphomatoid papulosis cases were associated witb a PLEVA type clinical presentation, with papulo-necrotic or papulo-haemorragic blistering skin lesions and strong epidermotropism. Cases of CD30+, CD8+ cutaneous anaplastic large cell lymphoma were also observed with frequent systemic involvement and fatal outcome in 50% of our cases. Subcutaneous panniculitis-like T-cell lymphoma in the classical cytotoxic (CD45RO+, TIA-1+) alpha-beta (BF-1+) variant showed an intermediate prognosis characterized by cutaneous relapses and possible haemophagocytic syndrome. Aggressive epidermotropic cytotoxic CD8+ T-cell lymphoma (AeCxCD8+L) showed multiple hyperkeratotic or ulcerated nodules and plaques, with a typical CD8+, TIA-1, CD45RA+, CD5-/+, CD2+/-phenotype and a very aggressive fatal course. Cases of pleomorphic small-medium or medium-large lymphoma with an aggressive course (4 cases) or with a benign evolutions may be also CD8+, interestingly three of these aggressive cases were CD8- at presentation and positive in subsequent biopsies. Finally, very rare cases of NK/T nasal type extranodal lymphomas or cases of hydroa vacciniforme-like T ce1l lymphoma showing a very aggressive course may express CD8+, but in association with EBV strong positivity. Cytomorphology, immunohistochemistry and genomics must be used for the diagnosis and in the future they should be useful to better classify CD8+ CTCLs variants

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

Antipsychotic drug exposure and risk of pulmonary embolism: a population-based, nested case–control study

Only three observational studies investigated whether exposure to antipsychotics is associated with an increased risk of pulmonary embolism, with conflicting results. This study was therefore carried out to establish the risk of pulmonary embolism associated with antipsychotic drugs, and to ascertain the risk associated with first- and second-generation antipsychotic drugs, and with exposure to individual drugs

Focus Farmacovigilanza: il nuovo sistema di informazione dei centri regionali di Farmacovigilanza

L'abstract presenta Focus Farmacovigilanza, il bollettino interregionale di Farmacovigilanza