Mechanisms of itching in mycosis fungoides: grade of itching correlates with eosinophil infiltration and kallikrein 5 expression.

BACKGROUND: Mycosis fungoides (MF) is the most common variant of cutaneous T-cell lymphomas (CTCL). Itching can be a major symptom for patients with CTCL, however, itching associated with MF is not relieved by conventional therapy using anti-histamines, suggesting that histamine is not the main pruritogen. Therefore, the underlying mechanisms of itching in MF patients remain unclear. OBJECTIVES: To investigate the clinical and histopathological features associated with MF-related itching. MATERIALS AND METHODS: Skin sections from MF patients and healthy subjects were used for pathophysiological analysis and evaluation of protease activity. These results were compared with the degree of itching. RESULTS: Of the MF patients, 40% did not report itching and 60% reported itching (moderate itching: 40%; strong itching: 20%). The number of eosinophils, but not mast cells, that infiltrated into skin was increased in the group with strong itching. In the skin of patients, both serine protease activity and immunoreactivity to kallikrein 5 (KLK5), a known itch mediator, increased relative to the grade of itching. CONCLUSION: These results suggest that KLK5 and eosinophil infiltration may be involved in itching in patients with MF.

Cutaneous T-Cell Lymphoma. A hypothesis on disease pathophysiology involving deficiency in DNA repair.

Cutaneous T-cell lymphoma (CTCL) is a rare disease occurring in Europe among two persons per million per year. It affects men more often than women (2:1). It is primarily a skin disease. In about 20% of patients, it becomes fatal with tumours in the skin and spreading to lymph glands. Approximately 3% of patients show a leukemic form called Sezary's syndrome, where malignant cells are present in blood with accompanying erythrodermia. CTCL is a T-lymphocyte disease occurring late in life as the average age of patients is around 66 years in Europe, Japan and the US. This article focuses on cell lines and immune surveillance in CTCL, and especially the pronounced chromosomal instability. It leads to the hypothesis that chromosomal changes is the key event linked to DNA repair deficiencies, which in a subpopulation of T cells leads to CTCL development over years.

Global Patterns of Methylation in Sézary Syndrome Provide Insight into the Role of Epigenetics in Cutaneous T-Cell Lymphoma.

van Doorn et al. have defined the DNA methylomes of Sézary cells based on a genome-wide methylation analysis using the Illumina 450K array platform (Illumina, San Diego, CA). Their results show aberrant DNA methylation patterns in CD4-enriched T cells from peripheral blood samples, patterns that are distinct from those of patients with inflammatory erythroderma and from healthy volunteers. Whereas 7.8% of 473,921 5'-cytosine-phosphate-guanine-3' (CpG) sites were hypomethylated, 3.2% showed marked enrichment and selection for hypermethylated CpG sites within the proximal region of gene promoters, including some genes that have previously been shown to be hypermethylated in cutaneous T-cell lymphomas (CTCLs), using standard bisulfite modification techniques.

Pralatrexate Monitoring Using a Commercially Available Methotrexate Assay to Avoid Potential Drug Interactions.

Pralatrexate (PDX) is a folate antagonist structurally similar to methotrexate (MTX). Unlike MTX, it is currently not known whether PDX exhibits delayed clearance and heightened toxicity in the setting of fluid overload. A specific serum assay for PDX is not commercially available. To our knowledge, we report the first case using an MTX serum assay as a surrogate for PDX concentrations to avoid a potential drug-drug interaction with pralatrexate. We describe a 76-year-old man with refractory cutaneous T-cell lymphoma who began therapy with weekly PDX 15 mg/m(2) intravenous infusions on days 1, 8, and 15 of a 28-day cycle. He subsequently developed mucositis, a moderate right-sided pleural effusion, and peripheral edema over the next 5 weeks. Aggressive diuresis with furosemide was initiated, which was then withheld the day before his next PDX dose to avoid a potential drug-drug interaction between PDX and furosemide. His baseline MTX/PDX concentration (measured prior to administration of the cycle 2, week 2 PDX dose) was less than 0.20 µmol/L (i.e., undetectable). After PDX administration, his 1-hour peak MTX/PDX concentration increased to 0.58 µmol/L. Aggressive diuresis was withheld until his MTX/PDX concentration was undetectable, 43.5 hours later. PDX is more potent than MTX and displays similar pharmacokinetic properties. PDX concentrations using the serum MTX assay reflect lower values than those reported from PDX-specific assays in clinical studies. Because PDX is approved by the U.S. Food and Drug Administration for the treatment of uncommon malignancies, it is unlikely that a specific assay will be commercially developed. We propose that the MTX serum assay has merit for use in determining when to reinstate possible interacting drug therapies such as loop diuretics.

Correlations between clinical and pathological features in 17 cases of mycosis fungoides before and after transformation.

BACKGROUND: Mycosis fungoides (MF) may progress to transformed MF (T-MF), a condition with aggressive behavior. OBJECTIVES: This study was designed to compare the clinical and pathological features of biopsies in 17 cases of MF before and after transformation. METHODS: During a revision of primary cutaneous T cell lymphomas, 53 cases of MF were identified, including 17 cases of T-MF. Clinical, pathological, and immunohistochemical data for the MF patients were evaluated. Cases of T-MF and intermediate transformed (IT) MF were diagnosed according to previous criteria. The histological and immunohistochemical features of T-MF biopsies were compared with those of MF/IT-MF biopsies taken before or concomitant with transformation. RESULTS: At the initial diagnosis, three patients were found to have more advanced stages of disease: two had MF and T-MF simultaneously, and another had only oral T-MF. Four patients considered to show histological transformation maintained disease stages Ia and Ib and all remain alive. Of five patients with IT-MF at first diagnosis, all progressed to complete histological transformation, three developed tumors, and two died of disease. Four patients progressed to CD30+ large cell lymphoma, and three of these died of disease. In one of these patients, the MF biopsy showed a high level of expression of CD30 in the epidermis and dermis. CONCLUSIONS: No correlation between advanced MF and expression of CD25 and CD30, or frequency of Ki-67+ cells was found. The frequency of transformation among patients with initially non-transformed MF was high. Our findings support the emphasis given by other authors to IT-MF, a pattern of MF which is generally not considered in many studies.

Tratamiento con aprepitant del prurito refractario secundario a linfoma cutáneo de células T / Aprepitant in the Treatment of Refractory Pruritus Secondary to Cutaneous T-Cell Lymphoma

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Elastophagocytosis: underlying mechanisms and associated cutaneous entities.

Elastophagocytosis is the phagocytosis of elastic fibers that can microscopically be seen in the cytoplasm of histiocytes, multinucleated giant cells, or both. Generally believed to be a characteristic feature of certain granulomatous disorders such as annular elastolytic giant cell granuloma or elastolytic disorders such as mid-dermal elastolysis, this feature has also been described in other cutaneous inflammatory conditions, cutaneous malignancies, infectious entities, and secondary to certain medications. The list of diseases that can exhibit this peculiar finding on histopathology is long. In this review we attempt to shed light on the available literature concerning the pathogenesis of this phenomenon and the plethora of skin conditions that exhibit elastophagocytosis.

Serum soluble CD26 levels: diagnostic efficiency for atopic dermatitis, cutaneous T-cell lymphoma and psoriasis in combination with serum thymus and activation-regulated chemokine levels.

BACKGROUND: CD26 is a multifunctional type II transmembrane glycoprotein, which also exists as a secreted isoform, soluble CD26 (sCD26). The CD26 expression on circulating T cells is decreased in some skin diseases such as cutaneous T-cell lymphoma (CTCL) and psoriasis. It remains to be determined whether sCD26 can be used as a marker of skin diseases or not. OBJECTIVE: To investigate utility of sCD26 as a diagnostic marker of skin diseases in combination with thymus and activation-regulated chemokine (TARC). METHODS: Serum sCD26 levels were measured using enzyme-linked immunosorbent assay in 130 participants including 32 patients with atopic dermatitis (AD); 45 patients with CTCL; 26 patients with psoriasis; and 27 healthy controls. RESULTS: Serum sCD26 levels in patients with CTCL and psoriasis (162.1 ± 80.2 ng/mL and 125.4 ± 82.1 ng/mL respectively) were significantly lower than those of healthy controls (392.6 ± 198.7 ng/mL; P < 0.01 and 0.01 respectively). In patients with CTCL, serum sCD26 levels of patients with advanced stage were 135.0 ± 51.5 ng/mL and they were significantly lower than those with early stage (193.1 ± 96.0 ng/mL; P < 0.05). When we used serum sCD26 and TARC levels for diagnostic criteria, sensitivity, specificity, positive predictive value and negative predictive value for AD, CTCL and psoriasis were 65.2-73.7%, 81.4-97.6%, 65.2-94.4%, and 81.4-88.9% respectively. CONCLUSION: Serum sCD26 levels, combined with serum TARC levels, are helpful in diagnosis of AD, CTCL and psoriasis.

Increased CCL18 expression in patients with cutaneous T-cell lymphoma: association with disease severity and prognosis.

BACKGROUND: CC chemokine ligand (CCL) 18 is expressed by monocytes and dendritic cells (DCs), and has potent chemotactic activity for T cells, B cells and DCs. CCL18 expression is up-regulated in lesional skin of atopic dermatitis and bullous pemphigoid, suggesting its important roles in the development of these skin diseases. OBJECTIVE: To investigate roles of CCL18 in cutaneous T-cell lymphoma (CTCL). METHODS: The CCL18 messenger RNA (mRNA) expression in CTCL skin (n = 21) and in normal skin (n = 7) was examined by quantitative RT-PCR. CCL18 expression was also examined by immunohistochemistry. Serum CCL18 levels were measured in 38 patients with CTCL and 20 healthy controls by enzyme-linked immunosorbent assay. We also analysed correlation between serum CCL18 levels and other clinical and laboratory data. RESULTS: The CTCL lesional skin contained higher levels of CCL18 mRNA than normal skin. CCL18 was expressed by dermal macrophages and DCs in CTCL skin. Serum CCL18 levels in patients with CTCL were significantly higher than those of healthy controls and correlated with types of skin lesions. They also significantly correlated with modified severity-weighted assessment scores, serum sIL-2R, LDH, IL-4, IL-10, IL-31, CCL17 and CCL26 levels. Patients with high serum levels of CCL18 showed significantly poor prognosis compared with those with low CCL18 levels. CONCLUSION: CCL18 mRNA is up-regulated in CTCL lesional skin, and serum CCL18 levels are significantly increased and correlated with the severity of CTCL. These results suggest that CCL18 may be associated with the development of CTCL.

Actualización terapéutica en linfomas cutáneos / Treatment of Cutaneous Lymphomas: an Update

Los linfomas cutáneos primarios (LCP) constituyen un grupo heterogéneo de neoplasias linfoides que se originan primariamente en la piel. La mayoría (75%) son linfomas de células T y solo un 20-25% se originan a partir de los linfocitos B. Es importante diferenciar los LCP de sus equivalentes ganglionares, dado que presentan características clínicas, histopatológicas, inmunofenotípicas y de biología molecular diferentes con un pronóstico en la mayoría de los casos más indolente y tratamientos diferentes. Existen múltiples opciones terapéuticas en el manejo de los LCP. La elección del tratamiento debe basarse principalmente en el estadio clínico del paciente, pero deben considerarse también otros factores, como la accesibilidad a los tratamientos, la edad y el estado general del paciente o el coste-beneficio. Además es importante el abordaje multidisciplinar de estos pacientes, formando un equipo experto entre dermatólogos, hematooncólogos y radioterapeutas que conozcan bien esta infrecuente patología. En los últimos años asistimos a la aparición de múltiples terapias nuevas, especialmente para el tratamiento de los estadios avanzados o de pacientes refractarios a tratamientos previos. El motivo de este artículo es revisar todas las alternativas terapéuticas a nuestro alcance (AU)

Primary cutaneous lymphomas (PCLs) are a heterogeneous group of lymphoid tumors that originate primarily in the skin. Most PCLs (75%) are T-cell lymphomas and only 20% to25% involve B cells. It is important to differentiate between cutaneous lymphomas and lymphnode tumors given the differences in their molecular biology and clinical, histopathologic, and immunophenotypic features. Moreover, PCLs generally follow a more indolent course and require different treatments. Many treatment options are available for managing PLC’s. The choice should be based primarily on the clinical stage of disease but must also take into consideration other factors, such as the patient’s age and general health, the availability and accessibility of the treatment, and the cost-benefit ratio. It will be important to use a multidisciplinary approach, involving a team of expert dermatologists, hematologist-oncologists, and radiotherapists who are familiar with this rare disease. Recent years have seen the emergence of many new therapies, particularly for advanced stages of the disease and for patients whose tumors have proven refractory to treatment. The objective of this article is to review all the treatment options available to us (AU)

Romidepsin: in the treatment of T-cell lymphoma.

Romidepsin is a histone deacetylase inhibitor with high inhibitory activity for class I histone deacetylases. Intravenous romidepsin is indicated in the US for the treatment of adult patients with cutaneous T-cell lymphoma (CTCL) or peripheral T-cell lymphoma (PTCL) who have received at least one prior systemic therapy. The clinical efficacy of romidepsin has been demonstrated in two noncomparative, multicentre, phase II trials in patients with relapsed, refractory or advanced CTCL. In both trials, therapy with intravenous romidepsin was associated with an overall response (i.e. both complete response and partial response) rate of 34% and a complete response rate of 6%. The efficacy of romidepsin was also evaluated in patients with relapsed or refractory PTCL in two noncomparative, multicentre, phase II trials. Intravenous romidepsin therapy was associated with overall response rates of 38% and 26% and a complete response rate of 18% and 13% in these trials. Romidepsin had an acceptable tolerability profile in clinical trials in patients with CTCL or PTCL. The most common adverse events of grade 3 or 4 severity considered at least possibly related to romidepsin were haematological or asthenic in nature, and included leukopenia, lymphopenia, granulocytopenia, thrombocytopenia, fatigue and anaemia.

Cutaneous malignancy in adolescents.

There is compelling epidemiologic evidence that cutaneous malignancies, most notably malignant melanoma and cutaneous T-cell lymphoma, are increasing in incidence. The adolescent population is also affected by this rise in incidence, but can represent both a unique diagnostic and therapeutic challenge. Herein we present up-to-date epidemiology, clinical presentation, risk factors for development, and management options for malignant melanoma, basal cell carcinoma, squamous cell carcinoma, and cutaneous T-cell lymphoma as each pertains to the adolescent population. Prevention in this age group is particularly addressed. One unifying theme that emerges is that a high degree of clinical suspicion and vigilance must be maintained to recognize these entities early on in their presentations.

Emerging role of the histone deacetylase inhibitor romidepsin in hematologic malignancies.

IMPORTANCE OF THE FIELD: Histone acetylation plays a crucial role in chromatin modification and the regulation of gene expression. Histone deacetylase inhibitors (HDACi) are a novel class of antitumor agents with pleiotropic effects; they are under active clinical investigation. The HDACi romidepsin is being evaluated in a variety of tumors and was recently approved for the treatment of cutaneous T-cell lymphomas (CTCL). AREAS COVERED IN THIS REVIEW: This review focuses on the findings from early Phase trials involving romidepsin, and the Phase II trial results that led to the approval of romidepsin in CTCL. WHAT THE READER WILL GAIN: Mechanisms of action of HDACi, including romidepsin, are described in this review and the pharmacodynamic and pharmacokinetic properties of romidepsin are summarized. The efficacy and safety profile of romidepsin in clinical trials in T-cell lymphoma is reviewed, and emerging data on single-agent and combination strategies in myeloid and B-lymphoid malignancies is outlined. TAKE HOME MESSAGE: Romidepsin has significant activity and an acceptable safety profile in CTCL and peripheral T-cell lymphomas. Its use in rationally designed combination approaches is under active investigation in B-lymphoid malignancies.

Subcutaneous lymphoma and related conditions.

A variety of lymphoma entities can involve the subcutaneous tissue. The term subcutaneous panniculitis-like T cell lymphoma is now solely utilized for primary cutaneous CD8+ lymphomas expressing the alphabeta T cell receptor heterodimer. This condition is generally responsive to treatment; however, the development of the hemophagocytic syndrome is a poor prognostic indicator. Overlapping features with lupus panniculitis has been observed, and cases with ambiguous pathology may be classified as atypical lobular lymphocytic panniculitis. These ambiguous cases often respond to systemic steroids or methotrexate. Overall, this condition follows an indolent course; however, evolution into frank lymphomas in some cases reflects the diagnostic difficulties of these conditions. Gamma-delta lymphomas have a poor prognosis regardless of the presence or absence of a hemophagocytic syndrome. Treatment options are limited because of lack of large studies and the rarity of this condition. Prolonged remission may be achieved with allogeneic stem cell transplantation.