Array-CGH Analysis of Cutaneous Anaplastic Large Cell Lymphoma.

2013

Szuhai K, van Doorn R, Tensen CP, Van Kester.

Source

Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands.

Abstract

This chapter describes a study in which the pattern of numerical chromosomal alterations in cutaneous anaplastic large cell lymphoma (C-ALCL) tumor samples was defined using array-based comparative genomic hybridization (CGH). First, the array-based CGH technique applied is outlined in detail. Next, its application in the analysis of C-ALCL tumor specimens is described. This approach resulted in the identification of highly recurrent chromosomal alterations in C-ALCL that include gain of 7q31 and loss on 6q16-6q21 and 13q34, each affecting 45% of the patients. The pattern characteristic of C-ALCL differs markedly from chromosomal alterations observed in other CTCL such as mycosis fungoides and Sézary syndrome and yielded several candidate genes with potential relevance in the pathogenesis of C-ALCL.

PubMed

The antihistamines clemastine and desloratadine inhibit STAT3 and c-Myc activities and induce apoptosis in cutaneous T-cell lymphoma cell lines.

Feb 2013

Döbbeling U, Waeckerle-Men Y, Zabel F, Graf N, Kündig TM, Johansen P.

Source

Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.

Abstract

Mycosis fungoides and its leukaemic counterpart Sézary syndrome are the most frequent cutaneous T-cell lymphomas (CTCL), and there is no cure for these diseases. We evaluated the effect of clinically approved antihistamines on the growth of CTCL cell lines. CTCL cell lines as well as blood lymphocytes from patients with Sézary syndrome were cultured with antihistamines, and the cell were analysed for proliferation, apoptosis and expression of programmed death molecules and transcription factors. The two antihistamines clemastine and desloratadine, currently used for symptom alleviation in allergy, induced potent reduction of the activities of the constitutively active transcription factors c-Myc, STAT3, STAT5a and STAT5b in mycosis fungoides and Sézary syndrome cell lines. This inhibition was followed by apoptosis and cell death, especially in the Sézary syndrome-derived cell line Hut78 that also showed increased expression of the programmed death-1 (PD-1) after clemastine treatment. In lymphocytes isolated from Sézary syndrome patients, the CD4-positive fraction underwent apoptosis after clemastine treatment, while CD4-negative lymphocytes were little affected. Because both c-Myc and STAT transcription factors are highly expressed in proliferating tumours, their inhibition by clemastine, desloratadine and other inhibitors could complement established chemotherapies not only for cutaneous T-cell lymphomas but perhaps also other cancers.

PubMed

Composite lymphoma of mycosis fungoides and cutaneous small B-cell lymphoma in a 73-year-old male patient.

Jan  2013

Whitling NA, Shanesmith RP, Jacob L, McBurney E, Sebastian S, Wang E, Wang AR.

Source

Department of Pathology, Tulane University, New Orleans, LA, USA 70112.

Abstract

Composite lymphoma of T-cell and B-cell type is uncommon, and the one occurring primarily on skin is extremely rare. Herein, we report a unique case of composite lymphoma of mycosis fungoides and cutaneous small B-cell lymphoma in a 73-year-old male patient. The patient presented with multiple erythematous patches, plaques, and nodules on the upper arms, scalp, and trunk. Four punch biopsies of arm and scalp lesions demonstrated lymphoid infiltrate in superficial to deep dermis with a characteristic zone distribution of T-cell and B-cell components. T cells were distributed in papillary and perifollicular dermis and displayed a larger size with convoluted nuclei, whereas B cells were small sized, assuming nodular infiltrate in mid-deep dermis with coexpression of CD5. Molecular test detected clonal rearrangement of both TCRG and IGH/K genes with identical amplicons for each gene in all 4 biopsies. Clinical staging revealed no extracutaneous lesions. A multidisplinary approach is emphasized to establish a definitive diagnosis.

PubMed

New Insights into Associated Co-morbidities in Patients with Cutaneous T-cell Lymphoma (Mycosis Fungoides).

Jan 2013

Hodak E, Lessin S, Friedland R, Freud T, David M, Pavlovsky L, Shapiro J, Cohen AD.

Source

Department of Dermatology, Rabin Medical Center, Petah Tiqva, 49100, Peath Tiqva, Israel. hodake@post.tau.ac.il.

Abstract

Studies of associated cancer in patients with mycosis fungoides (MF) have focused primarily on secondary cancers in North American and European populations. This study investigated the association between MF and malignancies, anxiety and depression in the Israeli population. Data on Israeli patients with MF and age- and gender-matched controls were collected from a database of population- based cohort (683 patients; 1,700 controls) and an institution- based cohort (343 patients; 846 controls) and analysed by univariate and multivariate methods. MF was significantly associated with Hodgkin's lymphoma in both cohorts (multivariate odds ratio (OR) 7.83, univariate OR ∞, respectively); acute leukaemia (multivariate OR 10.1, first cohort) and lung cancer (multivariate OR 10.15, second cohort). MF was significantly associated with anxiety and depression (multivariate OR 1.59, OR 1.51, respectively in first cohort). The current study provides support to the associations between MF and other cancers: Hodgkin's lymphoma, acute leukaemia and lung cancer. The study also em-phasizes the association between MF and anxiety and depression.

Medical Journals

Integrated Positron-Emission Tomography and Computed Tomography Manifestations of Cutaneous T-Cell Lymphoma

Dec 2012

Research letters

Mycosis fungoides (MF) and Sézary syndrome (SS) represent the most common types of primary cutaneous T-cell lymphomas (CTCLs). Current guidelines recommend [18F]-fluorodeoxyglucose positron-emission tomography (FDG-PET) plus computed tomography (CT) scan for staging purposes in all patients except in cases of early-stage disease (IA-IB). However, the application of FDG-PET in CTCL has not been widely documented. In this study, we retrospectively evaluated the findings of FDG-PET/CT scans in 41 patients with CTCL.

Complete text

Archives of Dermatology

Mycosis fungoides palmaris et plantaris.

Nov 2012

[Article in German]

Pfaff S, Megahed M.

Source

Klinik für Dermatologie und Allergologie, RWTH Aachen University, Pauwelsstr. 30, 52074, Aachen, Deutschland, spfaff@ukaachen.de.

Abstract

Mycosis fungoides (MF) is a low-grade cutaneous T-cell lymphoma characterized by skin-homing CD4- positive helper T cells. Mycosis fungoides palmaris et plantaris is an uncommon variant primarily involving the palms and soles. An 80-year old man presented with hyperkeratotic erythematous palmoplantar changes. Clinical and histopathologic criteria led to the diagnosis mycosis fungoides palmaris et plantaris. Tumor staging using sonography of the abdomen and lymph nodes, chest x-ray and blood examination is recommended, because extracutaneous manifestations may be present.

Springerlink

Topical Chemotherapy in Cutaneous T-cell Lymphoma: Positive Results of a Randomized, Controlled, Multicenter Trial Testing the Efficacy and Safety of a Novel Mechlorethamine, 0.02%, Gel in Mycosis Fungoides.

Lessin SR, Duvic M, Guitart J, Pandya AG, Strober BE, Olsen EA, Hull CM, Knobler EH, Rook AH, Kim EJ, Naylor MF,Adelson DM, Kimball AB, Wood GS, Sundram U, Wu H, Kim YH.

Abstract

OBJECTIVE To evaluate the efficacy and safety of a novel mechlorethamine hydrochloride, 0.02%, gel in mycosis fungoides. 

DESIGN Randomized, controlled, observer-blinded, multicenter trial comparing mechlorethamine, 0.02%, gel with mechlorethamine, 0.02%, compounded ointment. Mechlorethamine was applied once daily for up to 12 months. Tumor response and adverse events were assessed every month between months 1 and 6 and every 2 months between months 7 and 12. Serum drug levels were evaluated in a subset of patients. 

SETTING Academic medical or cancer centers. 

PATIENTS In total, 260 patients with stage IA to IIA mycosis fungoides who had not used topical mechlorethamine within 2 years and were naive to prior use of topical carmustine therapy. 

MAIN OUTCOME MEASURES Response rates of all the patients based on a primary clinical end point (Composite Assessment of Index Lesion Severity) and secondary clinical end points (Modified Severity-Weighted Assessment Tool and time-to-response analyses). 

RESULTS Response rates for mechlorethamine gel vs ointment were 58.5% vs 47.7% by the Composite Assessment of Index Lesion Severity and 46.9% vs 46.2% by the Modified Severity-Weighted Assessment Tool. By the Composite Assessment of Index Lesion Severity, the ratio of gel response rate to ointment response rate was 1.23 (95% CI, 0.97-1.55), which met the prespecified criterion for noninferiority. Time-to-response analyses demonstrated superiority of mechlorethamine gel to ointment (P < .01). No drug-related serious adverse events were seen. Approximately 20.3% of enrolled patients in the gel treatment arm and 17.3% of enrolled patients in the ointment treatment arm withdrew because of drug-related skin irritation. No systemic absorption of the study medication was detected. 

CONCLUSION The use of a novel mechlorethamine, 0.02%, gel in the treatment of patients with mycosis fungoides is effective and safe. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00168064.

Archives Dermatology

IRF4 Gene Rearrangements Define a Subgroup of CD30-Positive Cutaneous T-Cell Lymphoma

IRF4 Gene Rearrangements Define a Subgroup of CD30-Positive Cutaneous T-Cell Lymphoma:

A Study of 54 Cases

J Invest Dermatol. 2009 Oct

Pham-Ledard A, Prochazkova-Carlotti M, Laharanne E, Vergier B, Jouary T, Beylot-Barry M, Merlio JP.

Department of Histology and Molecular Pathology of Tumors, University Bordeaux 2, Bordeaux, France.

Correspondence: Professor Jean-Philippe Merlio, Department of Histology and Molecular Pathology, University Bordeaux 2, 146 rue Leo Saignat, Bordeaux 33076, France. E-mail:jp.merlio@u-bordeaux2.fr

The identification of IFN regulatory factor 4 gene (IRF4) translocation in 8 out of 14 cases of cutaneous anaplastic large cell lymphomas (C-ALCLs) (Leukemia, 2009; 23(3):574-80) prompted us to study IRF4 locus status in different cutaneous T-cell lymphoma (CTCL) subtypes. Fluorescence in situ hybridization (FISH) was used with break-apart dual-color probes. Sixty samples from 54 patients were analyzed with 23 C-ALCL, 11 transformed mycosis fungoides (T-MF), 7 lymphomatoid papulosis (LyP), and 13 Sézary syndrome (SS) cases. IRF4 immunostaining was performed in 32 cases. We observed a split FISH signal pattern indicating a translocation at the IRF4 locus in 6 out of 23 C-ALCL (26%) and 2 out of 11 T-MF (18.2%) cases. Extra copies of the IRF4 locus were found in 4 out of 13 SS, 1 out of 11 T-MF, and 1 out of 23 C-ALCL cases, corresponding to either aneuploidy, chromosome 6 trisomy, or 6p partial gain. The IRF4 expression was not correlated with the presence of IRF4 alteration in C-ALCL or T-MF. Interestingly, IRF4 rearrangements define a subgroup of CD30-positive C-ALCL and T-MF cases. Conversely, T-MF cases with IRF4 rearrangements may correspond to the development of C-ALCL in MF patients and not to large cell transformation. Investigation of the biological pathways triggered by IRF4 rearrangements and/or expression in CTCL will provide a biological basis for IRF4-directed therapy.Journal of Investigative Dermatology advance online publication, 8 October 2009; doi:10.1038/jid.2009.314.

Nature

Abbreviations:

ALCL, anaplastic large cell lymphoma; ALK, anaplastic lymphoma kinase; C-ALCL, cutaneous anaplastic large cell lymphoma; CTCL, cutaneous T-cell lymphoma; FISH, fluorescencein situ hybridization; IRF4, IFN regulatory factor 4; LyP, lymphomatoid papulosis; MF, mycosis fungoides; MM, multiple myeloma; MUM1, multiple myeloma antigen 1; PTCL, peripheral T-cell lymphoma; T-MF, transformed mycosis fungoides