Variant Of Cutaneous T-cell Lymphoma Research Articles

Primary Cutaneous Peripheral T-Cell Lymphoma Not Otherwise Specified: A Rapidly Progressive Variant of Cutaneous T-Cell Lymphoma.

Primary Cutaneous Peripheral T-Cell Lymphoma NOS (PTL-NOS) is a rare, progressive, fatal dermatologic disease that presents with features similar to many common benign plaque-like skin conditions, making recognition of its distinguishing features critical for early diagnosis and treatment (Bolognia et al., 2008). A 78-year-old woman presented to ambulatory care with a single 5 cm nodule on her shoulder that had developed rapidly over 1-2 weeks. Examination was suspicious for malignancy and a biopsy was performed. Biopsy results demonstrated CD4 positivity, consistent with Mycosis Fungoides with coexpression of CD5, CD47, and CD7. Within three months her cancer had progressed into diffuse lesions spanning her entire body. As rapid progression is usually uncharacteristic of Mycosis Fungoides, her diagnosis was amended to PTL-NOS. Cutaneous T-Cell Lymphoma (CTCL) should be suspected in patients with patches, plaques, erythroderma, or papules that persist or multiply despite conservative treatment. Singular biopsies are often nondiagnostic, requiring a high degree of suspicion if there is deviation from the anticipated clinical course. Multiple biopsies are often necessary to make the diagnosis. Physicians caring for patients with rapidly progressive, nonspecific dermatoses with features described above should keep more uncommon forms of CTCL in mind and refer for early biopsy.

Single-Fraction Radiotherapy for CD30(+) Lymphoproliferative Disorders.

Objectives. CD30+ lymphoproliferative disorder is a rare variant of cutaneous T-cell lymphoma. Sustained complete response following first-line treatments is rare. This retrospective review evaluates the response of refractory or recurrent lesions to palliative radiation therapy. Methods. The records of 6 patients with 12 lesions, treated with radiation therapy, were reviewed. All patients received previous first-line treatments. Patients with clinical and pathological evidence of symptomatic CD30+ lymphoproliferative disorder, with no history of other cutaneous T-cell lymphoma variants, and with no prior radiation therapy to the index site were included. Results. The median age of patients was 50.5 years (range, 15–83 years). Median size of the treated lesions was 2.5 cm (range, 2–7 cm). Four sites were treated with a single fraction of 750–800 cGy (n = 3) and 8 sites were treated with 4000–4500 cGy in 200–250 cGy fractions (n = 3). Radiation therapy was administered with electrons and bolus. Median follow-up was 113 months (range, 16–147 months). For all sites, there was 100% complete response with acute grade 1-2 dermatitis. Conclusions. For recurrent and symptomatic radiation-naïve CD30+ lymphoproliferative disorder lesions, palliative radiation therapy shows excellent response. A single fraction of 750–800 cGy is as effective as a multifractionated course and more convenient.

Evidence of an Oncogenic Role for Aberrant Tox Activation in Cutaneous T Cell Lymphoma

Cutaneous T cell lymphoma (CTCL) consists of two main subtypes: mycosis fungoides (MF), which primarily affects the skin; and Sézary syndrome (SS), which is characterized by the presence of circulating malignant Sézary cells. Although defective apoptosis and cell cycle progression have been implicated in CTCL disease development, the precise molecular mechanism underlying these abnormalities is only partially understood. Recently our group showed that TOX, a transcription factor transiently expressed during thymocyte development, was ectopically expressed in the malignant CD4+ T cells in MF skin lesions. Normally in mature CD4+ T cells, TOX is expressed at very low levels. Not only is TOX highly expressed in the infiltrating CD4+ T cells in MF skin lesions, but its expression levels also inversely correlate with the clinical outcome of CTCL patients. However, its involvement in other types of CTCL remains unknown and its biological effects on CTCL pathogenesis have not been explored. In this study, we sought to examine if aberrant TOX expression occurs in SS (a leukemic variant of CTCL), and whether it contributes to CTCL pathogenesis. We found that TOX expression is also enhanced significantly in primary CD4+CD7- cells from SS patients (n=12), and its enhanced transcript levels correlate with higher disease-specific mortality (P=0.039). To investigate the role of TOX in CTCL, we corrected the ectopic TOX expression by lentiviral-shRNA-mediated TOX gene knock-down in CTCL cell lines (Hut78, HH, and SZ4). In all three cell lines, this resulted in markedly increased apoptosis (measured using Annexin V apoptosis assay, 2-3 fold, P<0.05) and reduced cellular proliferation (assessed by BrdU incorporation assay and colony formation in 3D cultures, 1.5-12 fold, P<0.05). In line with these phenotypes, TOX knock-down led to an increase in cleaved caspases (3, 9) and enhanced expression of multiple cell cycle inhibitors (CDKN1B, CDKN1C). Moreover, to test the effect of TOX suppression on the tumor-inducing ability of CTCL cells in vivo, we injected TOX-suppressed cells or control CTCL cells (1x106 per injection site) subcutaneously into NOD-SCID IL2rγ null (NSG) mice and monitored local tumor formation. Control CTCL cells (Hut78, HH) induced local tumor growth in six out of six mice within 2 weeks of injection, with enlargement progressively to 1.5cm in diameter within 4 weeks of injection. In contrast, TOX silencing effectively reduced the tumor volume induced by HH cells (n=6) and abolished the tumor-forming ability of Hut78 cells (n=6). Since TOX is a DNA-binding nuclear protein, we next sought to explore the potential downstream molecular partners of TOX by performing comparative transcriptome analysis between TOX-suppressed cells and control CTCL cells (Hut78, HH). The expression of several tumor suppressor genes, including SMAD3 and FOXO3, was increased upon TOX knock-down in both Hut78 and HH cell lines. Pathway analyses of the differentially-expressed genes uncovered activation of apoptotic pathways and cell cycle arrest processes upon TOX suppression. These findings were validated using quantitative RT-PCR. In conclusion, our results indicate that ectopic expression of TOX in CTCL cells causes the proliferation/apoptosis balance to shift toward proliferation through suppression of the transcription of multiple tumor suppressors. Therefore abolishing TOX activity may be a promising treatment strategy for CTCL. DisclosuresNo relevant conflicts of interest to declare.

Personalized treatment of Sézary syndrome by targeting a novel CTLA4:CD28 fusion.

Matching molecularly targeted therapies with cancer subtype-specific gene mutations is revolutionizing oncology care. However, for rare cancers this approach is problematic due to the often poor understanding of the disease's natural history and phenotypic heterogeneity, making treatment of these cancers a particularly unmet medical need in clinical oncology. Advanced Sézary syndrome (SS), an aggressive, exceedingly rare variant of cutaneous T-cell lymphoma (CTCL) is a prototypical example of a rare cancer. Through whole genome and RNA sequencing (RNA-seq) of a SS patient's tumor we discovered a highly expressed gene fusion between CTLA4 (cytotoxic T lymphocyte antigen 4) and CD28 (cluster of differentiation 28), predicting a novel stimulatory molecule on the surface of tumor T cells. Treatment with the CTLA4 inhibitor ipilimumab resulted in a rapid clinical response. Our findings suggest a novel driver mechanism for SS, and cancer in general, and exemplify an emerging model of cancer treatment using exploratory genomic analysis to identify a personally targeted treatment option when conventional therapies are exhausted.

Chronic actinic dermatitis/actinic reticuloid: a clinicopathologic and immunohistochemical analysis of 37 cases.

Chronic actinic dermatitis/actinic reticuloid (CAD/AR) is an eczematous hypersensitivity reaction to ultraviolet rays that can vary from mild eczematous cases to AR, the most severe cases which may resemble cutaneous T-cell lymphoma. Diagnosis is based on clinical, histopathologic, and photobiologic features. In this study, we characterize the histopathologic and immunohistochemical features of 40 biopsies from 37 patients with established CAD. The cohort included 30 men and 7 women, ranging in age from 38 to 84 years (median, 62 years) and with a median duration of symptoms at presentation of 3 years (range, 1 to 40 years). All patients presented with erythematous lichenified plaques on sun-exposed areas. Severe cases (12/37) had extension to non-exposed areas. Positive photo-testing (20/20) and patch-testing (10/10) results, and cases with a high peripheral blood eosinophila (7/24) and HIV positivity (4/37) were noted. Skin biopsies demonstrated eczematous features including parakeratosis, acanthosis, spongiosis, and prominent dermal fibroplasia. Dermal dendrocytes were prominent in all cases with frequent multinucleated giant cells positive for factor XIIIa and S100 protein. Most cases displayed a brisk lymphocytic infiltrate with subtle exocytosis, atypical lymphocytes, and increased numbers of Langerhans cells, eosinophils, and plasma cells. There was a predominance of CD8 T cells within the epidermis (20/25) and a low CD4:CD8 ratio was noted in 20 of 25 cases. T-cell clonality studies were negative in 10 of 10 cases. CAD/AR may be difficult to distinguish from eczematous variants of cutaneous T-cell lymphoma. Important clues to differentiate both conditions include the identification of prominent dermal dendrocytes with multinucleated giant cells, eosinophils, plasma cells, and a low CD4:CD8 ratio.

Depletion of M2-Like Tumor-Associated Macrophages Delays Cutaneous T-Cell Lymphoma Development In Vivo

Macrophages have key roles in tumor development and invasion in several human cancers, but little is known about their pathogenic role in cutaneous T-cell lymphoma (CTCL). Herein, we used PCR arrays to profile the expression of inflammatory cytokines in 12 patients with mycosis fungoides (MF), the most common variant of CTCL. Compared with normal controls, MF skin displayed increased mRNA levels of macrophage-related cytokines. Moreover, we detected CD163, a reliable marker of tumor-associated macrophages, in the tumor microenvironment of MF biopsies. To demonstrate that macrophages had a role in CTCL tumorigenesis, we xenografted human CTCL tumor cells in immunocompromised mice and compared tumor development using clodronate-containing liposomes to deplete macrophages in mice. Mice treated with clodronate-containing liposomes show markedly less tumor growth compared with mice treated with phosphate-buffered saline-containing liposomes (P<0.001). We also noted a strong correlation between macrophage depletion and decreased expression of vascular marker, CD31, and lymphatic marker, podoplanin, suggesting a role for macrophages in angiogenesis. In vitro, clodronate-containing liposomes killed activated murine M2 macrophages, but not Hut78 cells, demonstrating selective ability to induce apoptosis in macrophages. Our data indicate that macrophages have a critical role in the progression of Hut78 cell tumor formation in skin, thus providing a new therapeutic strategy for CTCL.

Long-Term Complete Responses to Combination Therapies and Allogeneic Stem Cell Transplants in Patients With Sézary Syndrome.

Sézary syndrome (SS) is a rare leukemic variant of cutaneous T-cell lymphoma (CTCL). It presents with 80% erythroderma of the body, the presence of > 1000 Sézary cells in the peripheral blood, lymphadenopathy, and pruritus. Complete remission or response (CR) is rare in patients with SS. An analysis of a prospective database identified 217 patients with SS (14%), whose long-term CRs (> 1 years) are reported. Of 217 patients with SS, 18 (8.3%) achieved a CR (14 Caucasians, 2 African Americans, and 2 Hispanics; 9 women and 9 men). The median age at diagnosis was 53.5 years (range, 21-80 years). The stage at the initial diagnosis was IB in 1, III in 2, IVA in 4, and IVB in 11. The median duration of CR was 6.25 years (range, 1-13 years). The average interval between the diagnosis and CR was 2 years (range, 1-11 years). Three CRs were achieved with immunomodulatory therapy (extracorporeal photopheresis, interferon-α, and/or retinoids), antibiotics, and topical steroids. One CR was achieved with alemtuzumab and another with mogamulizumab. The other 13 CRs were achieved after allogeneic stem cell transplantation (SCT). Seven patients achieved a durable response (DR) with a 5.1-year disease-free interval. Three patients with a DR after SCT died of sepsis after 2 years with relapse. Of the remaining 4 patients, 3 achieved a DR from medical therapy alone and were alive with stable disease at the last follow-up visit. The fourth patient died of sepsis 1 year after relapse. SS is a rare and aggressive type of CTCL that is refractory to current therapies. We report that CRs can be achieved in 3 methods: combined immunomodulatory therapy, targeted biologic agents, or total skin electron beams followed by nonablative allogeneic SCT.

Subcutaneous Panniculitis- like T-Cell Lymphoma: Report of two cases

Subcutaneous panniculitis-like T-cell lymphoma is a distinct variant of cutaneous T-cell lymphoma, characterized by primary involvement of the subcutaneous fat in a manner mimicking panniculitis. It accounts for less than one percent of all non Hodgkin lymphoma. We describe two such patients who presented with cutaneous nodules. A 28 year old male presented with a one and a half month history of multiple subcutaneous nodules over the thighs, abdominal wall and chest. A clinical diagnosis of panniculitis was made. An excision biopsy of one the nodules was performed and the histopathology revealed subcutaneous panniculitis-like T-cell lymphoma. The other patient was a 44 year old male who underwent excision of a subcutaneous mass in the right thigh and on histopathological examination a diagnosis of subcutaneous panniculitis-like T-cell lymphoma was made. The patients received one cycle of CHOP (cyclophoshamide, vincristine, doxorubicin and prednisolone) regimen, followed by systemic steroids and were advised follow up.

Novel TBL1XR1, EPHA7 and SLFN12 mutations in a Sezary syndrome patient discovered by whole exome sequencing

Sezary syndrome (SS) is an aggressive leukaemic variant of cutaneous T-cell lymphoma. Recurrent chromosomal aberrations have been found in SS, but the whole genetic mutation spectrum is unknown. To better understand the molecular pathogenesis of SS, we performed exome sequencing, copy number variation (CNV) and gene expression analysis of primary SS cells. In our index patient with typical SS, we found novel somatic missense mutations in TBL1XR1, EPHA7 and SLFN12 genes in addition to larger chromosomal changes. The mutations are located in biologically relevant genes affecting apoptosis and T-cell maturation. They may play a role in the pathobiology of the disease, but no recurrent mutations were discovered in nine additional patients with SS studied. Thus, screening of larger patient cohorts is needed to confirm their prevalence and biological significance in SS.

IL-15 and IL-17F are differentially regulated and expressed in mycosis fungoides (MF)

Skin lesions from mycosis fungoides (MF) patients display an increased expression of interleukin-15 (IL-15), IL-17F, and other cytokines implicated in inflammation and malignant cell proliferation in cutaneous T-cell lymphoma (CTCL). In the leukemic variant of CTCL, Sézary syndrome (SS), IL-2 and IL-15 trigger activation of the Jak-3/STAT3 pathway and transcription of IL17A gene, whereas it is unknown what causes IL-15 expression, Jak3/STAT3 activation, and production of IL-17F in MF. Here, we studied the expression and regulation of IL-15 and its relation to IL-17F in MF cell lines and skin lesions from 60 MF patients. We show that: (1) the spontaneous IL-15 mRNA expression is resistant to Jak3 and STAT3 inhibitors at concentrations that profoundly inhibit STAT3 activation and IL-17F mRNA expression; (2) anti-IL-15 antibody blocks STAT3 activation induced by exogenous IL-15 in non-malignant MF T cells, whereas the spontaneous STAT3 activation and IL-17F expression in malignant T cells is not inhibited; (3) patients display heterogeneous IL-15/IL-17F mRNA expression patterns in skin lesions; and (4) IL-15 expression (in contrast to IL-17F) is not associated with progressive disease. Taken together, these findings indicate that IL-15 and IL-17F are differentially regulated and expressed in MF. We propose that IL-15 and IL-17F are markers for different inflammatory environments and play distinct roles in the development and progression of MF.

Cutaneous Lymphomas

Primary cutaneous T-cell lymphomas (CTCL) represent the majority of cutaneous lymphomas (CLs) and are a spectrum of diseases with a wide variety of clinical, histological, and phenotypic features and diverse biologic behavior. This review focuses on the observations on new variants of CTCL and recent developments in deciphering the pathogenetic mechanisms, which have implication for the nosologic concepts and future classification of CLs. Variants of mycosis fungoides (MF) such as the unilesional and the papular form have been characterized in more detail. Studies analyzed the expression of CD30 and PD-1 in MF and other forms of CTCL. New variants in the group of cutaneous CD30⁺ lymphoproliferative disorders include the epidermotropic CD8⁺ variant of lymphomatoid papulosis (type D) and angiocentric lymphomatoid papulosis (type E), which histologically mimic aggressive lymphomas, and therefore may be diagnostically challenging. Cutaneous proliferations of T cell-expressing markers of follicular helper T cells (PD-1, CXCL-13, and bcl-6) display a prognostically heterogeneous group. There is an increasing spectrum of CTCL with the expression of CD8 by tumor cells, including CD8⁺ MF, CD8⁺ forms of cutaneous CD30⁺ lymphoproliferative disorders, and CD8⁺ small/medium-sized lymphoproliferations, which are not included as distinct entities in the World Health Organization-European Organization for Research and Treatment of Cancer for CLs and the World Health Organization classification. Unusual presentations and incomplete phenotypes of blastic neoplasm of plasmacytoid dendritic cells are discussed. Clinicopathologic correlation is mandatory for the diagnosis of primary CLs. Analysis of genetic and epigenetic alterations in CLs revealed new diagnostic markers and putative targets for therapy of aggressive forms of CLs.

Subcutaneous panniculitis-like T-cell lymphoma

Panniculitis like T-cell lymphoma is a rare, aggressive variant of cutaneous T-cell lymphoma. The main dilemma lies in differentiating these lesions from simple panniculitis which is a benign lesion. We present the case of a 73 -year-old female patient, who presented with complaints of swelling in left axilla since 15 days, associated with throbbing pain and swelling of one arm. The initial diagnosis was paniculitis, but no clinical improvement was seen despite systemic antibiotic therapy. After two skin biopsies, the patient was diagnosed with panniculitis cutaneous T-cell lymphoma (PTCL). SPTCL can be a challenge to diagnose and can be misdiagnosed as benign panniculitis due to similarities in clinical and histological features between the two entities and for which immunohistochemical stains are required for confirmation of diagnosis.

Mycosis fungoides palmaris et plantaris successfully treated with radiotherapy: Case report and mini‐review of the published work

Mycosis fungoides palmaris et plantaris (MFPP) is a rare variant of cutaneous T-cell lymphoma limited to the palms and soles that is not widely recognized because of its uncommon occurrence. We report a 73-year-old Japanese man who presented with an erosion on the left dorsal hand, a reddish tumor on the right palm, and hyperkeratotic erythematous plaques on the right sole. Skin biopsy showed histological features of mycosis fungoides (MF) with invasion into the deeper layers of skin. There was no visceral or lymph node invasion. We diagnosed this case as MFPP. External beam radiotherapy (EBRT) was performed to treat the hand lesions. Combination treatment with topical steroids and topical psoralen plus ultraviolet light therapy was performed to treat the right sole lesion, but was ineffective. Therefore, sequential EBRT was performed. Complete remission of all lesions was obtained. This is the first report of MFPP with a locally advanced tumor for which the efficacy of radiotherapy is described in detail. MFPP lesions occur on the dorsal aspect of hand or foot, and here we propose a classification of MFPP as hand and foot MF. The pathogenesis of MFPP is still unclear and further accumulation of data is required.

Treatment of pagetoid reticulosis with intensity modulated radiation therapy

Pagetoid reticulosis, also known as Woringer-Kolopp disease, is a rare variant of cutaneous T-cell lymphoma usually presenting as an isolated patch or plaque on the extremities. Immunohistochemical staining of T-cell markers can be variable, but as the name implies the epidermotropic lymphocytes consistently display a "pagetoid" appearance. The following case demonstrates clearance of this condition with intensity modulated radiation therapy, whereas most cases are managed with electron beam therapy if radiation therapy is implemented.

Response Of Rare Variants Of Cutaneous T Cell Lymphoma (CTCL) To Treatment With Bexarotene. A Prospective German DeCOG Trial

▪The Retinoid-X-Receptor specific retinoid bexarotene is approved for treatment of cutaneous T-cell lymphoma (CTCL) in the United States and Europe. CTCL is a heterogeneous group of peripheral non-Hodgkin lymphomas with different prognosis and different response to treatment and the current WHO classification contains nine different entities with Mycosis fungoides (MF) as the most common subtype. Since most data on efficacy and tolerability are available from studies with MF, this Dermatologic Cooperative Oncology Group (DeCOG) trial (ADO-CTCL-3) evaluates treatment response to bexarotene in patients with non-MF CTCL, encompassing CD30+ primary cutaneous ALCL and severe lymphomatoid papulosis (LyP), CD-30 negative pleomorphic TCL, Sezary's syndrome (SS), subcutaneous panniculitis-like TCL, and other defined variants. Additionally, patients with different rare variants of MF, including folliculotropic (fMF), granulomatous, erythrodermic, and CD30+ transformed MF were included.200 patients with CTCL stage IB or higher and at least one prior treatment failure were registered in this trial with bexarotene at an initial daily dose of 150mg/m² orally und prophylactic fenofibrate medication. Bexatrotene was increased to a target dosage of 300 mg/m² in patients with tolarable serum lipids under these conditions. Patients were evaluated according to a standardized evaluation tool (tumor burden index; TBI) up to 24 weeks of of treatment or until progression occured. In responding patients, treatment could be continued until progression.After a central pathology board review process 2 patients needed to be excluded from evaluation because of misdiagnoses. Additional 11 patients could not be evaluated for response due to early withdrawal. Among the remaining patients there were 18 patients with SS, 8 cutaneous CD30+ ALCL, 10 Lyp, 9 other rare entities. In addition MF cases with folliculotropic subtype (18), CD30+ transformation (11), CD30- transformation (4), and a variety of other MF subtypes could be compared to the response in classical MF.Response to bexarotene could be confirmed in classical MF with an objective response (OR) rate of 37 percent (5% CR; 32% PR). Response rates for the other entities were as follows: CD30+ ALCL 50% OR, LyP 60% OR, SS 33% OR, other forms of CTCL together 33% OR. In MF with CD30+ transformation 46% responded, in contrast to only 11% of cases with folliculotropic MF.Tolerability was as expected with most grade III/IV toxicities limited to hyperlipidemia. Side effect management anf the incidence of serious adverse events could be substantially improved using standard algorithms for lipid control.In conclusion, this is one of the largest CTCL cohorts with exact pathological review worldwide evaluated for treatment response with bexarotene. Bexarotene appears to be a safe and effective treatment option also in non-classical MF and CTCL variants. Folliculotropic MF proved to be a difficult-to-treat entity and CD30 expression seems to be a favourable prognostic marker for treatment response. Disclosures:Weichenthal:Cephalon GmbH: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; TEVA GmbH: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Goldinger:Cephalon: Travel costs Other; TEVA: Travel costs, Travel costs Other. Wehkamp:TEVA GmbH: Travel costs Other. Beyer:TEVA GmbH: Honoraria, Research Funding; Cephalon GmbH: Honoraria, Research Funding. Stein:Cephalon: Travel costs Other; TEVA: Travel costs, Travel costs Other. Tsianakas:Cephalon: Travel costs Other; TEVA: Travel costs, Travel costs Other. Koch:Cephalon: Travel costs Other. Yazdi:Cephalon: Travel costs Other; TEVA: Travel costs, Travel costs Other. Wobser:Cephalon: Travel costs Other; TEVA: Travel costs, Travel costs Other. Frambach:Cephalon: Travel costs Other; TEVA: Travel costs, Travel costs Other. Dippel:Cephalon GmbH: Honoraria, Travel costs Other; TEVA GmbH: Honoraria, Travel costs, Travel costs Other. Geißler:Cephalon GmbH: Travel costs Other; TEVA GmbH: Travel costs, Travel costs Other. Loquai:TEVA GmbH: Travel costs Other. Kurschat:Cephalon: Travel costs Other; TEVA GmbH: Honoraria, Travel costs, Travel costs Other. Pföhler:Cephalon: Travel costs Other. Hartmann:Cephalon GmbH: Travel costs Other; TEVA GmbH: Travel costs, Travel costs Other. Coors:Cephalon GmbH: Travel costs Other; TEVA GmbH: Honoraria, Travel costs, Travel costs Other. Hallermann:TEVA GmbH: Travel costs Other. Mohr:TEVA: Honoraria, Travel costs Other. Hillen:TEVA: Travel costs Other. Belloni:Cephalon GmbH: Travel costs Other. Mitteldorf:Cephalon: Travel costs Other. Assaf:TEVA: Honoraria, Research Funding, Travel costs Other. Klemke:TEVA GmbH: Consultancy, Honoraria; Cephalon GmbH: Honoraria. Becker:Cephalon GmbH: Honoraria, Research Funding; TEVA GmbH: Honoraria. Dummer:Cephalon GmbH: Honoraria, Research Funding; TEVA GmbH: Honoraria. Nicolay:TEVA: Travel costs Other.

Comprehensive analysis of PTEN status in Sézary syndrome

AbstractSézary syndrome (SS) is an incurable leukemic variant of cutaneous T-cell lymphoma characterized by recurrent chromosomal alterations, among which, chromosome 10q deletion is very frequent. In this study, we investigated the PTEN status, on locus 10q23, in 44 SS patients; our findings show that PTEN is deleted in 36% of SS cases, whereas PTEN downregulation is observed in almost all of the samples evaluated by quantitative reverse-transcriptase polymerase chain reaction and Western blotting analysis. Neither DNA sequence mutation nor promoter hypermethylation were found at the PTEN locus, but we demonstrate that PTEN level can be also reduced by a group of miRs previously found upregulated and of prognostic relevance in SS; particularly, miR-21, miR-106b, and miR-486 were able to control PTEN abundance either in vitro or in vivo. Finally, because reduced PTEN activates the PI3/AKT-mediated pathway of cell growth and survival, we demonstrate that PTEN deficiency is associated with activated AKT in skin resident but not circulating SS cells, suggesting that the cutaneous milieu may strongly contribute to the SS cell growth. To our knowledge, this is the first study fully exploring the PTEN status in a large cohort of SS patients, unveiling potential elements of clinical utility in this malignancy.

MiRNA in mycosis fungoides and skin inflammation

In this mini-review, progress in our understanding of the link between miRNAs and cytokines in inflammatory skin diseases is highlighted with focus on miR-155 in mycosis fungoides (MF). MF is the most common variant of cutaneous T-cell lymphoma (CTCL) and is characterized by malignant T-cell proliferation in a chronic inflammatory environment in affected skin. Recent data show that miR-155 is expressed in situ by both malignant and non-malignant T cells, induced via the STAT5 signal pathway and IL-2Rbeta/gamma cytokines, and thus suggest the importance of miR-155 in malignant proliferation, clinical diagnosis, and prognosis in CTCL.

Mycosis Fungoides Misdiagnosed As Squamous Cell Carcinoma

Mycosis Fungoides Misdiagnosed As Squamous Cell Carcinoma

Clinical and Histopathological Features of Folliculotropic Mycosis Fungoides: A Norwegian Patient Series

Folliculotropic mycosis fungoides is a variant of cutaneous T-cell lymphoma with distinct clinicopathological features. We describe here the clinical presentation, pathology findings and treatment outcome in 15 Norwegian patients. All patients were diagnosed between 1997 and 2010 at Oslo University Hospital. A spectrum of skin lesions, both typical and atypical, such as leonine facies, acneiform lesions, psoriasiform plaques, purulent ulcerations and cystic milia-like lesions for mycosis fungoides, were seen. Histological examination revealed characteristic infiltration of hair follicles with neoplastic T cells associated with partial destruction of the former. A CD4+ immunophenotype of the neoplastic T cells with loss of one or more T-cell markers was demonstrated. In general, the patients were given more aggressive therapeutic regimens than those with conventional mycosis fungoides, and showed a trend towards more rapid disease progression. In conclusion, this case series confirms the distinct clinical and histological features of folliculotropic mycosis fungoides.

CD25+ folliculotropic Sézary syndrome with CD30+ large cell transformation

Folliculotropic Sézary syndrome is a rare and unique variant of cutaneous T-cell lymphoma (CTCL) characterised by both follicular and leukaemic involvement of mycosis fungoides (MF). It is associated with a more aggressive clinical course and fatal outcomes. Large cell transformation (LCT) of mycosis fungoides/Sézary syndrome is also associated with an aggressive disease course and shortened survival, requiring an intensive therapeutic approach. This report describes a case of folliculotropic Sézary syndrome with CD30+ LCT. Most of the larger lymphocytes in the lesions were positive for CD25, the expression of which is associated with advanced CTCL. In addition, we review the literature on this unusual CTCL and provide evidence that this entity represents a distinct clinicopathological entity occasionally associated with extracutaneous involvement and LCT.