Mycosis fungoides: disease evolution of the "lion queen" revisited.

Mycosis fungoides (MF), which represents the most common subtype of primary cutaneous T-cell lymphoma (CTCL), is an epidermotropic lymphoma included as an indolent form in the recent WHO/EORTC classification. From a clinical point of view, the classic disease progression usually is slow and takes over years or even decades, and characterized by the evolution from patches to more infiltrated plaques and eventually to tumours or erythroderma. However, the analysis of the MF disease course has been greatly impaired by the rarity of the disease, thus data about the time course of disease progression and pattern of relapse during time are not well known. In this review, a summary of published data on MF large patients cohorts will be presented, together with the results obtained by a retrospective analysis of clinical features and follow-up data of 1,422 MF patients diagnosed and followed-up from 1975 to 2010 in 27 Italian Centres (Italian Study Group for Cutaneous Lymphoma). From a clinical perspective, the amount of data support the relevance of a stage-tailored, differentiated follow-up strategy, in as much as the TNMB staging appears not only to be associated with different progression rates, but also shows as a new finding a relationship with different patterns of disease progression. From a biological point of view, there is the need to understand the molecular basis of the different clinical pathways of disease progression, to be able to potentially identify at an earlier phase of disease evolution, the patients who are more likely to develop erythroderma or tumour-stage progression. In conclusion, if MF is indeed a true "lion queen", as dermatologists we need to be expert and wise tamers to keep it under control.

Primary cutaneous B-cell lymphoma is associated with somatically hypermutated immunoglobulin variable genes and frequent use of VH1-69 and VH4-59 segments.

BACKGROUND: Accurate assessment of the somatic mutational status of clonal immunoglobulin variable region (IgV) genes is relevant in elucidating tumour cell origin in B-cell lymphoma; virgin B cells bear unmutated IgV genes, while germinal centre and postfollicular B cells carry mutated IgV genes. Furthermore, biases in the IgV repertoire and distribution pattern of somatic mutations indicate a possible antigen role in the pathogenesis of B-cell malignancies. OBJECTIVES: This work investigates the cellular origin and antigenic selection in primary cutaneous B-cell lymphoma (PCBCL). METHODS: We analysed the nucleotide sequence of clonal IgV heavy-chain gene (IgVH) rearrangements in 51 cases of PCBCL (25 follicle centre, 19 marginal zone and seven diffuse large B-cell lymphoma, leg-type) and compared IgVH sequences with their closest germline segment in the GenBank database. Molecular data were then correlated with histopathological features. RESULTS: We showed that all but one of the 51 IgVH sequences analysed exhibited extensive somatic hypermutations. The detected mutation rate ranged from 1.6% to 21%, with a median rate of 9.8% and was independent of PCBCL histotype. Calculation of antigen-selection pressure showed that 39% of the mutated IgVH genes displayed a number of replacement mutations and silent mutations in a pattern consistent with antigenic selection. Furthermore, two segments, VH1-69 (12%) and VH4-59 (14%), were preferentially used in our case series. CONCLUSIONS: Data indicate that neoplastic B cells of PBCBL have experienced germinal centre reaction and also suggest that the involvement of IgVH genes is not entirely random in PCBCL and that common antigen epitopes could be pathologically relevant in cutaneous lymphomagenesis.

Quality of life and psychological distress in patients with cutaneous lymphoma.

BACKGROUND: Cutaneous lymphomas may have a profound impact on patients' health-related quality of life (HRQoL) and psychological well-being. OBJECTIVES: To evaluate HRQoL and psychological distress in patients with cutaneous lymphoma, and to evaluate them in relation to personal and clinical characteristics. METHODS: Patients with cutaneous T-cell lymphoma or cutaneous B-cell lymphoma (CBCL) were consecutively recruited in a dermatological hospital. Data on HRQoL were collected using a dermatology-specific questionnaire, the Skindex-29, and an oncology-specific questionnaire, the EORTC QLQ-C30. RESULTS: Of 95 patients, there were 24 with CBCL, 59 with mycosis fungoides (MF) and 12 with Sézary syndrome (SS). The most frequent items reported in Skindex-29 were itching and sensitive skin, being annoyed by the disease, worry that it could get worse, affected interactions, and impairment in sexual life. The most frequent problems appearing from the EORTC QLQ-C30 analysis were fatigue, pain and insomnia. A worse HRQoL was observed for all the scales in patients with SS, followed by MF, and CBCL. HRQoL impairment in all histotypes was higher in women than in men, in patients with probable anxiety or depression, and when the disease worsened. The highest prevalence of probable anxiety or depression was observed in patients treated with systemic steroids (60%) and interferon (50%). CONCLUSIONS: The detailed evaluation of HRQoL and psychological problems in patients with cutaneous lymphomas, and their relationship with clinical variables, may give important information on the burden of the disease for patients, and thus improve communication and satisfaction with care.

Therapy-induced Ph1 suppression in chronic myeloid leukemia: molecular and cytogenetic studies in patients treated with alpha-2b IFN, high-dose chemotherapy and autologous stem cell infusion.

In this study, cytogenetic and molecular analyses were employed to assess the response to therapy in 29 chronic myeloid leukemia patients undergoing high dose chemotherapy followed by autologous stem cell infusion. Of these, 11 had previously achieved hematologic remission and cytogenetic improvement after alpha-2b interferon (IFN) treatment, whereas 18 underwent autografting in an early phase of the disease. In each case bone marrow samples were examined pre-treatment and at +2, +6 and +12 months in order to verify the degree of Ph1 suppression. In addition, the position of the breakpoint within the BCR region was mapped with multiple restriction enzymes. In 17 cases (59%) a significant Ph1 reduction was observed at +60 days (0-57% residual Ph1+ cells). In three of these cases, a complete cytogenetic response was confirmed at the DNA level by Southern blotting, but specific amplification of the BCR/ABL junction by the polymerase chain reaction (PCR), performed in two cases, still showed residual disease. The remaining 12 patients (41%) revealed a substantial persistence of Ph1+ metaphases (90-100%). Nine of 17 responding patients (53%) showed an increase of Ph1+ cells at 6 months, and five of 20 evaluated had a further increase at 12 months. With the exception of the results seen by PCR, comparison of molecular and cytogenetic techniques did not show significant differences. The variable degrees of Ph1 suppression observed did not appear to be associated with the position of BCR breakpoints. The factors predicting cytogenetic response to IFN and stem cell autograft and long-term durability of cytoconversion should be elucidated in further studies and with longer follow-up.

MicroRNA profiling reveals that miR-21, miR486 and miR-214 are upregulated and involved in cell survival in Sézary syndrome.

Sézary syndrome (SS) is an incurable leukemic variant of cutaneous T-cell lymphoma and its pathogenesis is still unknown. Diagnosis/prognosis may strongly ameliorate the management of SS individuals. Here, we profiled the expression of 470 microRNAs (miRNAs) in a cohort of 22 SS patients, and we identified 45 miRNAs differentially expressed between SS and controls. Using predictive analysis, a list of 19 miRNAs, including miR-21, miR-214, miR-486, miR-18a, miR-342, miR-31 and let-7 members were also found. Moreover, we defined a signature of 14 miRNAs including again miR-21, potentially able to discriminate patients with unfavorable and favorable outcome. We validated our data for miR-21, miR-214 and miR-486 by qRT-PCR, including an additional set of array-independent SS cases. In addition, we also provide an in vitro evidence for a contribution of miR-214, miR-486 and miR-21 to apoptotic resistance of CTCL cell line.

Circulating CD8+ lymphocytes, white blood cells, and survival in patients with mycosis fungoides.

BACKGROUND: There is a need for reliable, easily measurable laboratory markers that may help dermatologists to predict the course of mycosis fungoides (MF) when they first evaluate their patients. OBJECTIVES: Our objective was to identify clinical, haematological or immunological parameters as predictors of mortality in patients with MF. METHODS: We conducted a retrospective study on a prevalent cohort of 124 patients with MF hospitalized at IDI-IRCCS, Rome, Italy, from 1983 to 2001. We calculated the proportion of patients surviving (Kaplan-Meier product-limit estimates) 5 and 10 years after first hospital admission, and hazard ratios (HR) from the Cox proportional hazards model. RESULTS: Patients' survival was linked to age and staging (lower survival in older patients and in patients with staging IIB-IV). Higher numbers of white blood cells (WBC) and neutrophils, lower numbers of CD8+ lymphocytes, low haematocrit and lower levels of albumin were significantly associated with a lower survival probability. When simultaneously accounting for age and staging, CD8+ [HR = 3.02, 95% confidence interval (CI) 1.01-9.07 for CD8+ < 250 vs. > or = 600 cells microL(-1)] and WBC (HR = 2.59, 95% CI 0.96-6.96 for WBC > or = 9000 vs. < 6000 cells microL(-1)) were associated with survival. In addition, we observed an exceedingly high risk of death (HR = 12.40, 95% CI 3.11-49.43) for patients with a combination of WBC > or = 9000 and CD8+ < 600 cells microL(-1) vs. WBC < 9000 and CD8+ > or = 600 cells microL(-1)). CONCLUSIONS: The measurement of CD8+ cells and WBC in MF seems to be a promising criterion to predict survival, and possibly to support treatment decisions and inclusion of patients in randomized controlled trials.

Chronic myeloid leukaemia lymphoid blast crisis. Relevance of molecular analysis at the bcr and immunoglobulin heavy chain gene level in monitoring response to therapy and residual disease.

Southern blot analyses were performed in sequential DNA samples from 4 patients with Ph' + chronic myeloid leukaemia (CML) who underwent lymphoid or mixed blast crisis (BC). Genomic rearrangements at the breakpoint cluster region (bcr) and immunoglobulin heavy chain (IgH) gene level provided, in these cases, a sensitive and specific evaluation of response to therapy both in terms of blasts and Ph' + cell suppression. Recurrent BC was molecularly characterized in the 4 patients, showing each time identical individual specific DNA rearrangement patterns. Residual blasts were detected in 2 cases during intervening chronic phases by IgH rearrangements. Such findings highlight the specificity of these molecular markers, clearly indicating the failure of ablative therapy in eradicating the neoplastic clone. Finally, molecular and phenotypic identity in individual recurrent BC also suggested, in our cases, a lack of clonal evolution during disease progression.

Immunoglobulin heavy chain and T-cell receptor beta chain gene rearrangements in acute non lymphoid leukemia.

The occurrence of immunoglobulin heavy chain (IgH) and/or T-cell receptor (TcR) gene rearrangements has been reported in some cases of acute non lymphoid leukemia (ANLL), and variously interpreted as reflecting "aberrant gene expression" or "lineage promiscuity" of the leukemic cell. In an attempt to verify the incidence, FAB distribution and immunophenotypic correlates of gene rearrangements in ANLL, we analyzed the configuration of IgH and TcR beta chain genes in 70 patients with ANLL. In all cases myeloid (CD13, CD33, CD14, CD15) and lymphoid (CD7, CD2, CD10, CD19, TdT) antigenic determinants were analyzed in conjunction with conventional morpho-cytochemical characterization. Clonal rearrangements of the IgH gene were identified in 6/70 ANLL patients (8.6%), whereas in only 2/48 (4.2%) were T beta rearrangements documented. Concerning FAB subtypes, IgH or T beta rearrangements were detected in the less differentiated forms MO and M1 (3 cases), as well as in 2 M4 and 1 M5a cases. With the exception of a higher incidence of gene rearrangements in TdT+ ANLL, no significant correlation was found with other immunophenotypic markers.