Angiogenin levels are increased in lesional skin and sera in patients with erythrodermic cutaneous T cell lymphoma

Angiogenin is a member of the ribonuclease superfamily that is associated with the angiogenic process. Angiogenesis is regarded as an important step to support primary and metastatic tumor growth. In cutaneous T cell lymphoma (CTCL), angiogenesis in lesional skin is increased, suggesting that interaction between tumor cells and their microvasculature are likely to occur during progression of CTCL. Patients with hematological malignancies show increased serum angiogenin levels, which are related with poor overall survival. To investigate possible roles of angiogenin in development of CTCL, we measured serum angiogenin levels in 36 patients with CTCL and 21 healthy controls by enzyme-linked immunosorbent assay. We also investigated angiogenin mRNA and protein expression in lesional skin of CTCL by quantitative RT-PCR and immunohistochemistry. Serum angiogenin levels in patients with CTCL were significantly higher than those in healthy controls. When classified with types of skin lesions, serum angiogenin levels were elevated only in erythrodermic CTCL patients. Angiogenin mRNA expression levels in lesional skin were significantly elevated in erythrodermic CTCL compared to normal skin. Immunohistochemical study revealed that angiogenin was expressed by keratinocytes, endothelial cells, and infiltrating lymphocytes in CTCL. Our results suggest that enhanced angiogenin expression may be related with a poor prognosis of erythrodermic CTCL. As angiogenin acts as an inhibitor of polymorphonuclear leukocyte degranulation, angiogenin may also be linked to impaired host defense in erythrodermic CTCL.     

No detection of HTLV-I proviral DNA in lesional skin biopsies from Swiss and German patients with cutaneous T-cell lymphoma

Summary The search for an infective agent linked to cutaneous T-cell lymphoma (CTCL) has also included the human T-cell lymphotropic virus type I (HTLV-I). Using sensitive techniques such as Southern blotting under low stringency conditions of hybridization and polymerase chain reaction (PCR) with primer sets designed to match pol, env and pX sequences of HTLV-I, we have screened lesional skin biopsies of 50 Swiss and German patients suffering from CTCL. No evidence of proviral integration of HTLV-I could be demonstrated in any of our patients. Our results, as well as a review of the literature, indicate that at least for European patients, HTLV-I does not seem to play a role in the aetiology of CTCL.     

Epidermal interleukin 1 alpha functional activity and interleukin 8 immunoreactivity are increased in patients with cutaneous T-cell lymphoma

Previous studies have suggested that epidermal-derived interleukin-1 is involved in the pathogenesis of cutaneous T-cell lymphoma (CTCL); however, the findings are conflicting and studies that combine immunohistochemistry and functional activity have not been performed. We investigated the interleukin-1 level in epidermis of patients with cutaneous T-cell lymphoma using both immunohistochemistry, enzyme-linked immunosorbent assays, and the thymocyte co-stimulation assay. Using supernatants obtained from epidermal cell cultures, we found a significant but small increase of interleukin 1 alpha protein release from involved CTCL epidermis compared to normal epidermis from healthy individuals. Both keratinocytes and leukocytes could release interleukin-1 alpha, but the majority was derived from the keratinocytes. Interleukin-1 beta protein was not detectable. In the thymocyte assay, interleukin-1 alpha was found to be biologically active. When lymphokines derived from a T-cell clone obtained from involved CTCL skin were co-cultured with epidermal cells, an enhanced release of epidermal interleukin-1 alpha could be demonstrated. Because interleukin 1 alpha was increased, we investigated the presence of interleukin 1-inducible keratinocyte-derived interleukin 8 and found it increased in CTCL epidermis compared to normal epidermis from healthy individuals. This study demonstrated an elevated epidermal IL-1 alpha level and IL-8 immunoreactivity in CTCL epidermis, which suggests that this elevated level is induced by lymphokines released from activated T cells.     

Neurological complications in patients with cutaneous T-cell lymphoma

Five patients with a cutaneous T-cell lymphoma (four with mycosis fungoides and one with a primary cutaneous T-immunoblastic lymphoma) who developed neurological sequelae are reported. In four of them, central nervous system involvement could be demonstrated at autopsy. The importance of early cerebrospinal fluid examination in these patients is stressed.     

Epidermal interleukin-1 is increased in cutaneous T-cell lymphoma

Interleukin-1 (IL-1) is a monocyte-derived polypeptide with immunoregulatory and proinflammatory functions. Although monocytes are the principle source of IL-1, other cells, such as keratinocytes, endothelial cells, renal mesangial cells, and neutrophils, produce a factor with IL-1 activity. The IL-1-like polypeptide produced by keratinocytes, epidermal-derived thymocyte-activating factor (ETAF), is similar on biological, biochemical, and molecular levels to monocyte-derived IL-1. Studies of IL-1 or ETAF have for the most part been undertaken using cell culture supernatants or cell lysates, and in situ localization of ETAF has not been demonstrated. Previous studies have suggested that ETAF is involved in the pathogenesis of cutaneous T-cell lymphoma (CTCL). To gain insights into the role of these cytokines in disease states, we investigated whether IL-1 could be localized in tissue sections using a direct immunofluorescence technique with a monoclonal antibody directed against IL-1. This monoclonal antibody partially inhibited ETAF activity and totally inhibited IL-1 activity in the co-stimulator assay and so could be used to detect IL-1 or ETAF. We studied skin biopsies from 10 healthy individuals, 10 patients with CTCL, and 11 patients with various inflammatory dermatoses. Intense epidermal fluorescence was demonstrated in all cases of CTCL, whereas minimal reactivity was visible in normal biopsies and the inflammatory dermatoses. Most patients with CTCL showed an intercellular pattern, while none of the normal controls or those with inflammatory dermatoses showed this pattern. An irrelevant IgM monoclonal antibody, used as a negative control, did not demonstrate epidermal staining. To further demonstrate specificity, we incubated the anti-IL-1 antibody with recombinant beta IL-1:Epidermal reactivity was completely blocked. In a separate experiment, COLO 16 cells, a squamous cell carcinoma cell line that constitutively produces ETAF, stained positively for the IL-1 antibody. We conclude that epidermal IL-1 is elevated in CTCL.     

Menus for managing patients with cutaneous T-cell lymphoma

In the management of patients with cutaneous T-cell lymphoma (CTCL), there are numerous distinct therapy options. Each of these therapies is discussed in terms of when to use it, what factors limit the success of the treatment, and what to expect. A menu is defined as a list of items from which to choose. The treatments for CTCL are presented in various menus where they are options for a particular goal in a particular setting of CTCL. The best recognized clinical scenarios of CTCL are those recognized by the staging system: limited patch plaque (T1), disseminated patch plaque (T2), erythroderma (T4), and tumor (T3). Each phase of the disease will have the menu of therapy options presented for a given goal of management.     

Health-related quality-of-life assessment in patients with cutaneous T-cell lymphoma

OBJECTIVE: To measure and evaluate the health-related quality of life (HRQOL) in patients with cutaneous T-cell lymphoma (CTCL), a visible cutaneous malignancy that may have a profound effect on patients' lives. DESIGN: Monocenter, cross-sectional study. SETTING: The Skin Oncology Program, Department of Dermatology, and the Photopheresis Unit of Boston Medical Center. PATIENTS: A total of 22 adult patients with confirmed CTCL. MAIN OUTCOME MEASURES: (1) Evaluation of general oncologic and skin disease-specific HRQOL using, respectively, the Functional Assessment of Cancer Therapy-General (FACT-G) and Skindex-29 profiles; (2) assessment of HRQOL association with disease stage (early stage, IA-IIA; late stage, IIB-IVB). RESULTS: Patients with more advanced CTCL stages reported more effects on general health (FACT-G), particularly in the physical, emotional, and functional domains (P < .05). Patients with early-stage CTCL reported better skin-specific HRQOL overall (Skindex-29; P = .002) and for each specific domain than did patients with late-stage disease. The Skindex-29 scales had high internal consistency, and the confirmatory factor structure was similar to that of previous studies. CONCLUSIONS: The HRQOL of patients with CTCL can be evaluated using the Skindex-29 and FACT-G instruments. Patients with more advanced stages of CTCL had lower HRQOL scores.     

Lupus erythematosus-like features in patients with cutaneous T-cell lymphoma

Background The development of lupus erythematosus-like (LE-like) features in patients with cutaneous T-cell lymphoma (CTCL) has not been reported previously in the literature. Both diseases, however, have been etiologically linked to retroviruses. Objective Our purpose was to report four cases of patients with CTCL who developed LE-like features during the course of their disease, and to evaluate for evidence of antibodies to retroviruses in the sera of these patients. Patients Four patients with biopsy-proven CTCL with clinical or histologic features of systemic lupus erythematosus (SLE) were evaluated for clinical and laboratory criteria for SLE. Only one patient demonstrated four American Rheumatism Association (ARA) criteria sufficient for the diagnosis of SLE. The remaining three patients demonstrated one or two criteria for SLE. In addition, the sera of these patients were examined by Western blot analysis for evidence of human immunodeficiency virus type I (HIV-I), human T-cell lymphotrophic virus type I (HTLV-I), or human intracisternal A-type particle type I (HIAP-I) retroviral proteins. Each patient demonstrated antibodies to some of the retroviral proteins examined. The sera of two patients reacted to proteins for HIAP-I, and the sera of two patients reacted to p24 gag proteins of HIV-I. No patient reacted to HTLV-I proteins. Conclusions Our report identifies four patients with CTCL who developed LE-like features during the course of their disease. Although the etiology of CTCL and SLE has not been well established, each has been linked to retroviruses. Evidence of antibodies to retroviral proteins was identified in each of our patients by Western blot analysis. Although the clinical and laboratory findings in these cases do not resolve the etiologic role of retroviruses in CTCL or SLE, they suggest that retroviruses may have a role in the pathogenesis of the clinical phenomenon reported in these four patients.     

Prognosis in cutaneous T-cell lymphoma by skin stage: long-term survival in 489 patients

BACKGROUND: Although a number of studies have documented the long-term survival of patients with cutaneous T-cell lymphoma (CTCL), none have provided data as to the relative survival of all 4 skin stages. OBJECTIVE: We document survival of CTCL patients by T stage relative to that of an age-, sex-, and race-matched population. METHODS: The survival of 489 patients with CTCL registered since 1957 was compared with that of a California control population. RESULTS: For stage T1 (< 10% skin involved) there was no significant difference between the observed and expected survivals. For the other 3 stages the observed survival was significantly inferior to that of the expected survival (P = .002). At 10 years the relative survivals were: T2 (10% or more skin involved) 67.4%, T3 (tumor stage) 39.2%, T4 (generalized erythroderma) 41.0%. T2 plaque stage patients had an inferior relative survival (P = .001), whereas T2 patch stage patients did not. Lymphadenopathy had an unfavorable impact on prognosis. There was a strong trend toward diagnosing CTCL at an earlier stage in more recent years. We estimate that from 15% to 20% of our patients died of CTCL or related complications. CONCLUSION: The relative survival of CTCL patients worsens with increasing skin stage, although stages T3 and T4 had closely similar survivals. The great majority of patients with CTCL do not die of their disease.     

Endostatin and Thrombospondin-1 levels are increased in the sera of patients with chronic spontaneous urticaria

Chronic urticaria (CU) is a common disease characterized by recurrent itchy wheals and/or angioedema for more than 6 weeks. Increased levels of the pro-angiogenic mediator vascular endothelial growth factor (VEGF) have been described in skin disorders, such as chronic urticaria (CU), psoriasis and atopic dermatitis. Up to now, no data on the role of VEGF endogenous inhibitors Endostatin (ES) and Thrombospondin-1 (TSP-1) in CU are available. The aim of our study is to investigate the potential involvement of ES and TSP-1 in patients with chronic spontaneous urticaria (CSU). The levels of ES and TSP-1 were measured in the sera of 106 adult patients with CSU and 98 healthy subjects by enzyme immunoassays. The serum levels of the anti-angiogenic mediators ES and TSP-1 resulted significantly higher in CSU than in control subjects. Analysis of these mediators in CSU sub-groups, defined by the results of the autologous serum skin test (ASST), identified a significant increase of ES and TSP-1 in both ASST-positive and ASST-negative sub-groups as compared to the controls. Levels of ES and TSP-1 do not parallel the disease severity in CSU. Our study suggests that the extracellular matrix (ECM) fragments ES and TSP-1 with anti-angiogenic activity play a potential role in the pathogenesis of CSU but do not parallel disease activity.     

Substance P levels are decreased in lesional skin of atopic dermatitis

There is increasing evidence that neuropeptides (NP) such as substance P (SP) and vasoactive intestinal polypeptide (VIP) are involved in the pathogenesis of atopic dermatitis (AD). Vasoactive intestinal polypeptide levels were found to be significantly elevated in lesional skin of AD as compared to controls. We evaluated by radioimmunoassay the SP content in whole skin homogenates from chronic lichenified lesions of patients with AD. The levels of SP were significantly decreased in lesional skin from AD patients as compared to control skin (0.25 +/- 0.03 vs. 0.97 +/- 0.24 pmol/g tissue, p < 0.01). The diminished SP levels as opposed to increased VIP concentrations could be consistent with different roles of these NP as modulatory agents in the mechanisms associated with AD.     

Aneuploidy in cutaneous T-cell lymphoma

A new method is described which makes it possible using skin specimens to perform flow cytometric analysis of DNA content. DNA content analysis was performed on 28 skin specimens and 9 blood samples from 18 patients with mycosis fungoides and Sézary syndrome. The reproducibility was fair, with almost identical results in 6 cases (mycosis fungoides and Sézary syndrome) where two samples (skin specimens or blood samples) were taken 6 hours to 10 days apart. Hyperdiploidy was found in 7 of 11 skin specimens from patients with mycosis fungoides stage I with negative histology. In 13 skin specimens and 3 blood samples from patients with mycosis fungoides stages II and IV, abnormalities including hyperdiploidy, near-tetraploidy and near-hexaploidy were found in 8 of 13 skin specimens and in 2 of 3 blood samples. Four patients with Sézary syndrome were studied: 2 patients in remission showed normal DNA histograms (2 skin specimens, 3 blood samples) and 2 patients with active disease showed aneuploidy in the 2 skin specimens examined and in 1 of 3 blood samples. These studies demonstrate: 1) the importance of flow cytometry as a diagnostic tool for use on skin specimens in the early stages of mycosis fungoides where routine histology is non-diagnostic; 2) the diagnostic and prognostic aid of flow cytometry during the course of mycosis fungoides and Sézary syndrome in addition to the probability of measuring the effect of treatment.     

皮肤T细胞淋巴瘤表观遗传学研究进展

表观遗传学主要是研究在不改变DNA序列的情况下,发生的基因表达水平可遗传的变化,主要包括DNA甲基化、组蛋白修饰和非编码RNA调控.皮肤T细胞淋巴瘤是一组原发于皮肤的T淋巴细胞恶性增殖性疾病,蕈样肉芽肿和Sezary综合征是最常见的皮肤T细胞淋巴瘤.近年来研究表明,表观遗传学不仅在皮肤T细胞淋巴瘤的发生发展中起重要作用,而且可以通过改变表观遗传达到治疗皮肤T细胞淋巴瘤目的.     

Overall survival in erythrodermic cutaneous T-cell lymphoma: an analysis of prognostic factors in a cohort of patients with erythrodermic cutaneous T-cell lymphoma

Background The most common cutaneous T‐cell lymphomas (CTCLs) are mycosis fungoides and Sézary syndrome. Aim To determine whether blood stage and other prognostic variables affect overall survival (OS) in CTCL. Methods We studied retrospectively 1197 CTCL patients seen at the M.D. Anderson Cancer Center since 1987. Results We identified 124 (10.3%) patients with erythrodermic CTCL (E‐CTCL), 63% of whom had positive gene rearrangements in skin and 19 of whom had no evidence of hematologic involvement. The median age at diagnosis was 63 years (range, 26–90 years); the male to female ratio was 1.3 : 1. OS curves were estimated by the Kaplan–Meier method and compared using log‐rank tests. The median OS in all 124 E‐CTCL patients was 5.1 years (range, 0.4–18.6 years) regardless of the cause of death or blood involvement. Patients were stratified by the H0–H4 staging system with manual or flow cytometric determination of Sézary cell counts (Russell‐Jones R, Whittaker SJ. Sézary syndrome: diagnostic criteria and therapeutic options. Semin Cutan Med Surg 2000; 19 : 100–108). The median OS was 7.6 years for H0–H2 (< 1000 Sézary cells/L) (n = 23), 5.4 years for H3 (≥ 1000 to ≤ 10,000 Sézary cells/L) (n = 79), and 2.4 years for H4 (≥ 10,000 Sézary cells/L) (n = 22) (P = 0.011). Treatment with systemic steroids, age, serum lactate dehydrogenase, and white blood cell count ≥ 20,000 µL were significant prognostic factors, but large cell transformation, T‐cell receptor gene rearrangement, tumor–node–metastasis stage, treatments, and CD4 : CD8 ratio were not. In multivariate analysis, advanced age and elevated lactate dehydrogenase were the strongest predictors of a poor prognosis. Conclusions Serum LDH and age were the strongest predictive factors for OS in E‐CTCL.