Sinus histiocytosis with massive lymphadenopathy (SHML), or Rosai-Dorfman disease, is rare histiocytic disorder of known origin which shares several cell markers with Langerhans' cell histiocytosis (LCH). Although Rosai-Dorfman cells exhibit an aberrant immunophenotype, the indolent clinical course of SHML suggests a reactive disorder rather than a neoplastic process. Until recently this was prevailing opinion concerning LCH also, but recent studies have detected clonal histiocytes in all forms of this latter condition, which is therefore considered a clonal neoplastic disorder with highly variable biological behaviour. To determine whether the histiocytic proliferation in SHML is polyclonal or clonal we used X-linked polymorphic loci to assess clonality in lesional tissues in two women. Polymorphic regions of the human androgen receptor (HUMARA) locus were amplified by polymerase chain reaction (PCR) analysis. The HUMARA locus was informative in both cases and, following digestion with methylation-sensitive enzymes, typical polyclonal X-inactivation patterns were observed. Since abnormal cells accounted for > 90% lesional tissue cells, we conclude that Rosai-Dorfman histiocytic proliferation was polyclonal in the women studied.

Patients with HCV-positive DLBCL share distinctive clinical features. Future studies should prospectively evaluate the association between HCV and aggressive lymphomas.

Summary. Aberrant promoter hypermethylation is a mechanism of tumour suppressor gene inactivation. We explored aberrant promoter hypermethylation of multiple genes in 88 human immunodeficiency virus (HIV)-non Hodgkin lymphomas (NHL), 25 post-transplant lymphoproliferative disorders (PTLD) and five common variable immunodeficiency (CVI)-related NHL. Twenty-six of 79 (32AE9%) HIV-NHL, eight of 14 (57AE1%) PTLD and two of five (40AE0%) CVI-NHL showed aberrant hypermethylation of O 6 -methylguanine-DNA methyltransferase (MGMT). Aberrant hypermethylation of death-associated protein-kinase (DAP-K) occurred in 70 of 84 (83AE3%) HIV-NHL, 19 of 25 (72AE0%) PTLD and three of five (60AE0%) CVI-NHL. These data implicate MGMT and DAP-K hypermethylation in lymphomagenesis of immunodeficient hosts. In particular, promoter hypermethylation of DAP-K represents the most frequent molecular alteration yet identified in immunodeficiency-related lymphomas.

Fludarabine is effective in chronic lymphocytic leukaemia (CLL) and low-grade non-Hodgkin's lymphoma (NHL). A major side-effect of this purine analogue is immunosuppression which may favour opportunistic infections. Additionally, impairment of immunosurveillance might promote Epstein-Barr virus (EBV) reactivation and possibly favour transformation to high-grade malignancy. The aim of this study was to evaluate the immunosuppression-related effects of the fludarabine-based combination Flucyd in advanced low-grade NHL or CLL by serially monitoring T-lymphocyte subsets, opportunistic infections, EBV-reactivation, and histologic transformation. 24 patients with advanced NHL (n = 21) or CLL (n = 3) received fludarabine 25 mg/m2/d + cyclophosphamide 350 mg/m2/d + dexamethasone 20 mg/d in 3 d courses for a maximum of six courses. The overall response rate was 79% (eight CR, 11 PR, five failures); 11 patients relapsed or progressed between 3 and 19 months from response, and eight are in CR or PR at 3-27 months. The CD4+ lymphocyte counts decreased significantly during therapy from a median of 484/microliter pre-treatment (range 142-1865) to a median of 198/microliter (71-367). In 19 responders monitored off therapy every 3 months until relapse/progression, CD4+ counts were persistently low with minimal recovery over time. During treatment, 16 infections occurred in 11/24 patients. No delayed opportunistic infections occurred in responders while off therapy. The circulating EBV DNA load serially measured in 19 patients by a quantitative PCR assay showed an increase in four patients during treatment. A lymph node biopsy performed in two of these was PCR positive for EBV DNA, whereas LMP1 and EBERs were negative. Six NHL patients evolved into high-grade B-cell NHL. In conclusion, fludarabine combined with cyclophosphamide and dexamethasone is an effective therapy for recurrent indolent lymphoma. This combination produces prolonged T-lymphocytopenia and has the potential to reactivate a latent EBV infection. T-cell dysfunction, however, is not associated with higher incidence of clinical opportunistic infections and does not adversely influence clinical outcome.