Clinicopathological analysis of 17 primary cutaneous T-cell lymphoma of the ?? phenotype from Japan.
ABSTRACT: Primary cutaneous ?? T-cell lymphoma (PCGD-TCL) is an aggressive lymphoma consisting of clonal proliferation of mature activated ?? T-cells of a cytotoxic phenotype. Because primary cutaneous ?? T-cell lymphoma is a rare disease, there are few clinicopathological studies. In addition, T-cell receptor (TCR) ?? cells are typically immunostained in frozen sections or determined by TCR? negativity. We retrospectively analyzed 17 primary cutaneous T-cell lymphomas of the ?? phenotype (CTCL-??) in a clinicopathological and molecular study using paraffin-embedded sections. Among 17 patients, 11 had CTCL-?? without subcutaneous panniculitis-like T-cell lymphoma (SPTCL) features and six had CTCL-?? with SPTCL features. Immunophenotypically, some significant differences were found in CD8 and CD56 positivity between our patient series of CTCL-?? patients with SPTCL features and SPTCL-?? patients described in the previous literature. A univariate analysis of 17 CTCL-?? patients showed that being more than 60 years old, presence of visceral organ involvement, and small-to-medium cell size were poor prognostic factors. In addition, the 5-year overall survival rate was 42.4% for the CTCL-?? patients without SPTCL features and 80.0% for those with SPTCL features. Consequently, there was a strikingly significant difference in overall survival among SPTCL, CTCL-?? with SPTCL features and CTCL-?? without SPTCL features (P = 0.0005). Our data suggests that an indolent subgroup may exist in CTCL-??. Studies on more cases, including those from other countries, are warranted to delineate the clinicopathological features and the significance in these rare lymphomas.
Project description:Cutaneous T-cell lymphomas (CTCL) are a heterogenous group of rare diseases. Many studies have reported on local epidemiology or geographic clustering, however we lack information from a global perspective. A systematic review and meta-analysis was conducted in Medline and the Cochrane Library based on a previously registered protocol and according to the preferred reporting of items for systematic reviews and meta-analyses (PRISMA). We selected publications that enrolled at least 100 patients with primary cutaneous lymphomas according to the current classifications. The relative frequencies (proportions) of subtypes were compared between studies and geographic regions in a meta-analysis. In total, 26 studies met our inclusion criteria, reporting on altogether 16,953 patients. Within primary cutaneous lymphomas, CTCL appeared to be 15% more frequent in Asian populations. Mycosis fungoides (MF) accounted for 62% of CTCL, with an important heterogeneity in frequencies between studies and continents. The proportion of Sézary syndrome (SS) was 3%, stable worldwide. Rare CTCL, such as NK/T-cell lymphoma or subcutaneous panniculitis-like lymphoma, were more frequent in Asian studies. This global meta-analysis of CTCL confirmed the predominance of CTCL among primary cutaneous lymphomas (83% on average) in the three analyzed continents, most of which were MF cases. It revealed the same proportions of SS across continents, and the heterogeneity of MF frequencies, suggesting the possible role of environmental factors in the pathophysiology of the latter. Registration number: CRD42020148295 (PROSPERO).
Project description:Early diagnosis of cutaneous T cell lymphoma (CTCL) is difficult and takes on average 6 years after presentation, in part because the clinical appearance and histopathology of CTCL can resemble that of benign inflammatory skin diseases. Detection of a malignant T cell clone is critical in making the diagnosis of CTCL, but the T cell receptor ? (TCR?) polymerase chain reaction (PCR) analysis in current clinical use detects clones in only a subset of patients. High-throughput TCR sequencing (HTS) detected T cell clones in 46 of 46 CTCL patients, was more sensitive and specific than TCR? PCR, and successfully discriminated CTCL from benign inflammatory diseases. HTS also accurately assessed responses to therapy and facilitated diagnosis of disease recurrence. In patients with new skin lesions and no involvement of blood by flow cytometry, HTS demonstrated hematogenous spread of small numbers of malignant T cells. Analysis of CTCL TCR? genes demonstrated that CTCL is a malignancy derived from mature T cells. There was a maximal T cell density in skin in benign inflammatory diseases that was exceeded in CTCL, suggesting that a niche of finite size may exist for benign T cells in skin. Last, immunostaining demonstrated that the malignant T cell clones in mycosis fungoides and leukemic CTCL localized to different anatomic compartments in the skin. In summary, HTS accurately diagnosed CTCL in all stages, discriminated CTCL from benign inflammatory skin diseases, and provided insights into the cell of origin and location of malignant CTCL cells in skin.
Project description:Hypopigmented mycosis fungoides (HMF) is a form of cutaneous T-cell lymphoma (CTCL), a heterogeneous group of extranodal non-Hodgkin's lymphomas. HMF has a unique set of defining features that include light colored to achromic lesions, a predilection for darker skin phototypes, an early onset of disease, and predominance of CD8+ T-cells, among others. In the current review, we detail the known pathways of molecular pathogenesis for this lymphoma and posit that an active Th1/cytotoxic antitumor immune response in part explains why this variant is primarily seen in children/adolescents and young adults, who do not exhibit signs of immunosenescence. As a result of this potent cytotoxic response, HMF patients experience mostly favorable overall prognosis, while hypopigmentation may in fact represent a useful surrogate marker of cytotoxic immunity targeting the malignant cells. Understanding the molecular processes behind the specific features that define HMF may lead to improved diagnostic accuracy, personalized prognosis by risk stratification, and improved management of HMF. Moreover, improving our knowledge of HMF may aid our further understanding of other cutaneous lymphomas.
Project description:Papuloerythroderma of Ofuji (PEO) is an erythroderma-like eruption with flat-topped papules that spare the skin folds (a "deck-chair sign" finding). Many infections, medications, and systemic diseases have been associated with PEO, including cutaneous T-cell lymphomas (CTCL). The relationship between the clinical presentation of PEO and CTCL remains poorly elucidated. Clinical, laboratory, and histopathological data were obtained from the Lymphoma Clinic at the Ottawa Hospital, Canada. We report 5 patients with deck-chair-sign-positive CTCL, mycosis fungoides, and Sézary syndrome variants. We contend that PEO should be viewed as a diagnosis of exclusion and that these patients should be monitored carefully for possible emergence of CTCL. Skin biopsy alone is not sufficient to exclude CTCL in these patients. A skin eruption demonstrating a positive deck-chair sign may signify systemic/leukemic CTCL and, therefore, warrants a thorough investigation, including skin biopsy, flow cytometry, and T-cell receptor clonality studies.
Project description:Cutaneous T-cell lymphomas (CTCLs) are the most frequent primary skin lymphomas. Nevertheless, diagnosis of early disease has proven difficult because of a clinical and histologic resemblance to benign inflammatory skin diseases. To address whether microRNA (miRNA) profiling can discriminate CTCL from benign inflammation, we studied miRNA expression levels in 198 patients with CTCL, peripheral T-cell lymphoma (PTL), and benign skin diseases (psoriasis and dermatitis). Using microarrays, we show that the most induced (miR-326, miR-663b, and miR-711) and repressed (miR-203 and miR-205) miRNAs distinguish CTCL from benign skin diseases with > 90% accuracy in a training set of 90 samples and a test set of 58 blinded samples. These miRNAs also distinguish malignant and benign lesions in an independent set of 50 patients with PTL and skin inflammation and in experimental human xenograft mouse models of psoriasis and CTCL. Quantitative (q)RT-PCR analysis of 103 patients with CTCL and benign skin disorders validates differential expression of 4 of the 5 miRNAs and confirms previous reports on miR-155 in CTCL. A qRT-PCR-based classifier consisting of miR-155, miR-203, and miR-205 distinguishes CTCL from benign disorders with high specificity and sensitivity, and with a classification accuracy of 95%, indicating that miRNAs have a high diagnostic potential in CTCL.
Project description:BACKGROUND:Primary cutaneous T-cell lymphomas (CTCL) belong to the group of non-Hodgkin lymphomas and usually run an indolent course. However, some patients progress to advanced tumour or leukaemic stages. To date, there is no cure for those cases. In the last few years, several publications reported durable responses in some patients following allogeneic stem cell transplantation (alloSCT). This is an update of a Cochrane review first published in 2011 and updated in 2013. OBJECTIVES:To compare the efficacy and safety of conventional therapies with allogeneic stem cell transplantation in patients with advanced primary cutaneous T-cell lymphomas. SEARCH METHODS:We searched the Cochrane Central Register of Controlled Trials (CENTRAL, Issue 1), MEDLINE (1950 to January 2013), Internet-databases of ongoing trials, conference proceedings of the American Society of Clinical Oncology (ASCO, 2009 to July 2013) and the American Society of Hematology (ASH, 2009 to July 2013). We also contacted members of the European Organisation for Research and Treatment of Cancer (EORTC) Cutaneous Lymphoma Task Force to check for ongoing study activities. We handsearched citations from identified trials and relevant review articles. In addition, we handsearched randomised controlled trials from the European Group for Blood and Marrow Transplantation (EBMT) and International Conference on Cutaneous T-cell Lymphoma, ASCO and ASH up to July 2013. SELECTION CRITERIA:Trials eligible for inclusion were genetically randomised controlled trials (RCTs) comparing alloSCT plus conditioning therapy (regardless of agents) with conventional therapy as treatment for advanced CTCL. DATA COLLECTION AND ANALYSIS:Two review authors would have extracted data from eligible studies and assessed their quality. The primary outcome measure was overall survival; secondary outcomes were time to progression, response rate, treatment-related mortality, adverse events and quality of life. MAIN RESULTS:We did not identify any randomised controlled trials from the updated search in January 2013. In 2011, we found 2077 citations but none were relevant genetically or non-genetically randomised controlled trials. All 41 studies that were thought to be potentially suitable were excluded after full text screening for being non-randomised, not including CTCL or being review articles. AUTHORS' CONCLUSIONS:We planned to report evidence from genetically or non-genetically randomised controlled trials comparing conventional therapy and allogeneic stem cell transplantation. However, we did not identify any randomised controlled trials addressing this question. Nevertheless, prospective genetically randomised controlled trials need to be initiated to evaluate the precise role of alloSCT in advanced CTCL.
Project description:Mycosis fungoides and Sézary syndrome are two major forms of cutaneous T-cell lymphoma (CTCL) characterized by resistance to apoptosis. A central pathway for T-cell apoptosis is activation-induced cell death, which is triggered through the T-cell receptor (TCR). This results in upregulation of FAS ligand (FASL) and subsequent apoptosis through the FAS death receptor pathway. It has been known for more than a decade that TCR signaling is defective in CTCL; however, the underlying mechanism has not been apparent. In this report, we show that the E3 ubiquitin ligase, c-CBL, is overexpressed in CTCL and that its knockdown overcomes defective TCR signaling, resulting in phosphorylation of PLC-g1, calcium influx, ROS generation, upregulation of FASL, and extrinsic pathway apoptosis in CTCL cells expressing adequate FAS. In CTCL cells with suboptimal FAS expression, FAS can be upregulated epigenetically by derepression of the FAS promoter using methotrexate, which we showed previously has activity as a DNA methylation inhibitor. Using these combined strategies, FAS-low as well as FAS-high CTCL cells can be killed effectively.
Project description:Cutaneous T-cell lymphoma (CTCL) is a rare heterogeneous group of non-Hodgkin lymphomas that arises in the skin but can progress to systemic disease (lymph nodes, blood, viscera). Historically, in clinical trials of CTCL there has been little consistency in how responses were defined in each disease "compartment"; some studies only assessed responses in the skin. The histone deacetylase inhibitor romidepsin is approved by the US Food and Drug Administration for the treatment of CTCL in patients who have received at least one prior systemic therapy. Phase II studies that led to approval used rigorous composite end points that incorporated disease assessments in all compartments. The objective of this analysis was to thoroughly examine the activity of romidepsin within each disease compartment in patients with CTCL. Romidepsin was shown to have clinical activity across disease compartments and is suitable for use in patients with CTCL having skin involvement only, erythroderma, lymphadenopathy and/or blood involvement.
Project description:B-lymphoid kinase (Blk) is exclusively expressed in B cells and thymocytes. Interestingly, transgenic expression of a constitutively active form of Blk in the T-cell lineage of mice results in the development of T-lymphoid lymphomas. Here, we demonstrate nuclear factor-kappa B (NF-kappaB)-mediated ectopic expression of Blk in malignant T-cell lines established from patients with cutaneous T-cell lymphoma (CTCL). Importantly, Blk is also expressed in situ in lesional tissue specimens from 26 of 31 patients with CTCL. Already in early disease the majority of epidermotropic T cells express Blk, whereas Blk expression is not observed in patients with benign inflammatory skin disorders. In a longitudinal study of an additional 24 patients biopsied for suspected CTCL, Blk expression significantly correlated with a subsequently confirmed diagnosis of CTCL. Blk is constitutively tyrosine phosphorylated in malignant CTCL cell lines and spontaneously active in kinase assays. Furthermore, targeting Blk activity and expression by Src kinase inhibitors and small interfering RNA (siRNA) inhibit the proliferation of the malignant T cells. In conclusion, this is the first report of Blk expression in CTCL, thereby providing new clues to the pathogenesis of the disease.
Project description:Cutaneous T-cell lymphoma (CTCL) is a heterogeneous non-Hodgkin's lymphoma that may variably involve the skin, lymph nodes, and peripheral blood. Malignant burden ranges from cutaneous patches and plaques with little evidence of blood involvement to erythroderma often in association with frank leukemia, as in Sézary syndrome. Toward a better understanding of the pathogenesis of this CD4+ T-cell malignancy, we conducted a high-resolution genomic analysis combining DNA (23 samples) and mRNA (12 samples) data of peripheral blood isolates from CTCL patients across a spectrum of stages. Strikingly, even patients with limited involvement, e.g., normal CD4 counts, contained significant copy-number alterations. Defining genomic characteristics of CTCL blood involvement included gains on 8q and 17q, and deletions on 17p and chromosome 10. A consensus analysis of 108 leukemic CTCL samples demonstrated global similarities among patients with varied blood involvement, narrowing 38 of 62 loci. Toward an annotated framework for in vitro testing, we also characterized genomic alterations in five CTCL cell lines (HH, HUT78, PNO, SeAx, and Sez4), revealing intact core features of leukemic CTCL. Together, these studies produce the most comprehensive view of the leukemic CTCL genome to date, with implications for pathogenesis, molecular classification, and potential future therapeutic developments.