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Cutaneous T-cell lymphoma

Cutaneous T-cell lymphoma (CTCL) is a type of non-Hodgkin lymphoma of the skin in which T-cells (part of the immune system) grow in an uncontrolled way. Mycosis fungoides is the most common type of CTCL and tends to be slow growing and usually only affects the skin. Sezary syndrome is a less common but more advanced type of CTCL characterised by redness (erythroderma) in large areas of the skin, swollen lymph nodes, and abnormal lymphocytes circulating in the blood.

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    MeSH term: Lymphoma, T-Cell, Cutaneous
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Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Rieger KE, Kim J, Kim YH
Zosteriform Mycosis Fungoides: A New Clinical Presentation With a Dermatomal Distribution.
Am J Dermatopathol. 2017; 39(2):e17-e18 [PubMed] Related Publications
Classic mycosis fungoides (MF) presents with patches and plaques on the trunk and proximal extremities. However, numerous clinicopathologic variants have been described, making diagnosis challenging. Here, the authors report a 21-year-old woman with immunophenotypically and molecularly confirmed MF occurring in a dermatomal distribution. Awareness of this and other rare variants of MF is critical to avoid misdiagnosis.

Shamsuyarova A, Kamil Z, Delabie J, et al.
Primary Cutaneous Follicular Helper T-cell Lymphoma in a Patient With Neurofibromatosis Type 1: Case Report and Review of the Literature.
Am J Dermatopathol. 2017; 39(2):134-139 [PubMed] Related Publications
Patients with neurofibromatosis type 1 (NF-1) have a well-known predisposition for certain types of malignancies, including lymphoproliferative disorders. Cutaneous T-cell lymphoma (CTCL) has been reported in patients with NF-1, although it is considered a rare entity in this subset of patients. Cutaneous follicular helper T-cell lymphoma (CTFHCL) is a recently emerged rare subtype of CTCL with peculiar clinical and histopathological features and represents a diagnostic and therapeutic challenge. Only a few cases of CTFHCL have been reported in the literature. We report a case of CTFHCL in a patient with NF-1 and compare our findings with previously reported cases. We aim to raise awareness among pathologists regarding this rare subtype of CTCL and emphasize characteristic histological features of CTFHCL, which can be confused with B-cell lymphomas and lead to mismanagement.

Xu L, Pang H, Zhu J, et al.
Mycosis fungoides staged by 18F-flurodeoxyglucose positron emission tomography/computed tomography: Case report and review of literature.
Medicine (Baltimore). 2016; 95(45):e5044 [PubMed] Free Access to Full Article Related Publications
INTRODUCTION: Mycosis fungoides is a kind of malignant lymphoma arising from T cells, but primarily occurs in skin, and it is the most common type of cutaneous lymphoma. Mycosis fungoides (MF) is a rare non-Hodgkin lymphoma but the most common type of primary cutaneous T-cell lymphomas. Because of unknown etiology and mechanism, and lack of typical clinical and histophysiological manifestations, the final diagnosis of MF is currently dependent on pathology and immunohistochemistry. Subsequently, tumor staging is very important. Different approaches would be taken according to varying degrees of cutaneous and extracutaneous lesions. Computed tomography (CT) scan has been chosen to stage tumors customarily. However, CT could only provide morphological information and analyze lymphadenopathy by the size criteria. F-flurodeoxyglucose positron emission tomography/computed tomography (PET/CT) could provide morphological information and metabolic conditions simultaneously, which is helpful to locate and stage lesion.
CONCLUSION: F-flurodeoxyglucose PET/CT could identify cutaneous and extracutaneous lesions in patients with MF. It could provide the range of lesions and biopsy target.

Ion A, Popa IM, Papagheorghe LM, et al.
Proteomic Approaches to Biomarker Discovery in Cutaneous T-Cell Lymphoma.
Dis Markers. 2016; 2016:9602472 [PubMed] Free Access to Full Article Related Publications
Cutaneous T-cell lymphoma (CTCL) is the most frequently encountered type of skin lymphoma in humans. CTCL encompasses multiple variants, but the most common types are mycosis fungoides (MF) and Sezary syndrome (SS). While most cases of MF run a mild course over a period of many years, other subtypes of CTCL are very aggressive. The rapidly expanding fields of proteomics and genomics have not only helped increase knowledge concerning the carcinogenesis and tumor biology of CTCL but also led to the discovery of novel markers for targeted therapy. Although multiple biomarkers linked to CTCL have been known for a relatively long time (e.g., CD25, CD45, CD45RA, and CD45R0), compared to other cancers (lymphoma, melanoma, colon carcinoma, head and neck cancer, renal cancer, and cutaneous B-cell lymphoma), information about the antigenicity of CTCL remains relatively limited and no dependable protein marker for CTCL has been discovered. Considering the aggressive nature of some types of CTCL, it is necessary to identify circulating molecules that can help in the early diagnosis, differentiation from inflammatory skin diseases (psoriasis, nummular eczema), and aid in predicting the prognosis and evolution of this pathology. This review aims to bring together some of the information concerning protein markers linked to CTCL, in an effort to further the understanding of the convolute processes involved in this complex pathology.

Benoit BM, Jariwala N, O'Connor G, et al.
CD164 identifies CD4(+) T cells highly expressing genes associated with malignancy in Sézary syndrome: the Sézary signature genes, FCRL3, Tox, and miR-214.
Arch Dermatol Res. 2017; 309(1):11-19 [PubMed] Related Publications
Sézary syndrome (SS), a leukemic variant of cutaneous T-cell lymphoma (CTCL), is associated with a significantly shorter life expectancy compared to skin-restricted mycosis fungoides. Early diagnosis of SS is, therefore, key to achieving enhanced therapeutic responses. However, the lack of a biomarker(s) highly specific for malignant CD4(+) T cells in SS patients has been a serious obstacle in making an early diagnosis. We recently demonstrated the high expression of CD164 on CD4(+) T cells from Sézary syndrome patients with a wide range of circulating tumor burdens. To further characterize CD164 as a potential biomarker for malignant CD4(+) T cells, CD164(+) and CD164(-)CD4(+) T cells isolated from patients with high-circulating tumor burden, B2 stage, and medium/low tumor burden, B1-B0 stage, were assessed for the expression of genes reported to differentiate SS from normal controls, and associated with malignancy and poor prognosis. The expression of Sézary signature genes: T plastin, GATA-3, along with FCRL3, Tox, and miR-214, was significantly higher, whereas STAT-4 was lower, in CD164(+) compared with CD164(-)CD4(+) T cells. While Tox was highly expressed in both B2 and B1-B0 patients, the expression of Sézary signature genes, FCRL3, and miR-214 was associated predominantly with advanced B2 disease. High expression of CD164 mRNA and protein was also detected in skin from CTCL patients. CD164 was co-expressed with KIR3DL2 on circulating CD4(+) T cells from high tumor burden SS patients, further providing strong support for CD164 as a disease relevant surface biomarker.

Nguyen GH, Wang JY, Hymes KB, Magro CM
An Index Case of Concomitant Tumoral and Ichthyosiform Mycosis Fungoides-Like Presentation of Chronic Adult T-cell Leukemia/Lymphoma Associated With Upregulation of TOX.
Am J Dermatopathol. 2017; 39(1):28-32 [PubMed] Related Publications
Adult T-cell leukemia/lymphoma (ATLL) is a rare and often aggressive lymphoid malignancy known to be associated with human T-cell lymphotropic virus type 1. There are 2 broad categories: acute and chronic. In the acute category, there is a leukemic and a lymphomatous variant, whereas in the designated "chronic" form, there is mild peripheral blood lymphocytosis. The intermediate "smoldering" category is without peripheral blood lymphocytosis with only discernible skin involvement. We present a 68-year-old human T-cell lymphotropic virus type 1 seropositive female with a mild peripheral blood atypical lymphocytosis who had indurated nodules on her hands of 2 years duration and a new scaly ichthyosiform eruption on her lower extremities. Histopathologic examination of the hand biopsy revealed coalescing nodules of large atypical noncerebriform lymphocytes with focal areas of epidermotropism. Phenotypically, the infiltrate was positive for β-F1, CD2, CD4, CD5, CD7, Foxp3, and CD25. In both biopsies, there was striking upregulation of TOX (thymocyte selection-associated high mobility group box factor) in the nuclei of neoplastic cells. The second biopsy taken from the ichthyotic patch on the patient's left leg showed a subtle pattern of epidermal infiltration by atypical noncerebriform lymphocytes and a distinct compact scale consistent with the clinical picture of ichthyosis. The histopathologic appearance was that of a yet undescribed ichthyosiform mycosis fungoides-like presentation of chronic ATLL. In addition, the observed upregulation of nuclear TOX may play an oncogenic role in ATLL. The course to date in this patient has been relatively indolent, although the patients believe that large cell transformation could portend more aggressive disease.

Johnson WT, Leeman-Neill RJ, Patel P, et al.
Fatal Case of Primary Cutaneous Aggressive T-Cell Lymphoma Switching From a CD4+ to a CD8+ Phenotype: Progressive Disease With Bexarotene and Romidepsin Treatment.
Am J Dermatopathol. 2016; 38(11):832-837 [PubMed] Related Publications
A 77-year-old white male presented to the clinic with two isolated cutaneous tumors on his forehead. A cutaneous biopsy showed a focally folliculotropic CD4 cutaneous lymphoma. The tumors were irradiated with a complete response, and he was started on oral bexarotene. He experienced localized cutaneous relapse 3 months into treatment. These new tumors now revealed a surprisingly CD8 cytotoxic phenotype, but with the same clone. A systemic workup was negative. His regimen was switched to romidepsin, and he was treated with local radiation again. Another 3.5 months passed in remission until he developed widespread cutaneous tumors. Positron emission tomography/computed tomography revealed multifocal systemic disease involving his diaphragm, liver, distal duodenum, proximal jejunum, anterior chest wall including pectoral muscles, and lungs without significant adenopathy. He died a few days later. Given his full clinical and pathological course, he was given the diagnosis of an aggressive primary cutaneous T-cell lymphoma, unspecified.

Zhao MJ, Abdul-Fattah B, Qu XY, et al.
Mycosis fungoides patient accompanied actinic keratosis, actinic keratosis with squamous cell carcinoma transformation, and porokeratosis after NBUVB therapy - 1st case report and review of the literature.
Medicine (Baltimore). 2016; 95(41):e5043 [PubMed] Free Access to Full Article Related Publications
INTRODUCTION: Mycosis fungoides (MF) is the most common form of primary cutaneous T cell lymphoma. Narrowband ultraviolet B light (NBUVB) is used increasingly in treating MF because of its good toleration and well-established management.
CONCERNS: To discuss the risk factors and underlying pathogenic factors in the patients with secondary skin diseases after NBUVB therapy.
METHODS: We report in details the first case of a patient with MF accompanied with actinic keratosis (AK), AK with squamous cell carcinoma (SCC) transformation and porokeratosis after NBUVB therapy. Meanwhile, Sequence variants in tumor suppressor p53 gene in the patient's specimens were detected. A literature search of the key word "narrowband ultraviolet B light "and "side effects" was performed on PubMed, 14 cases of this entity were found. A total of 15 patients including our case were reviewed in this study and meaningful conclusion could be drawn.
OUTCOMES: The mean age at diagnosis of secondary skin dermatoses after NBUVB therapy was 62.08 years with a male to female ratio of 2:1. The cases were reported more in Europeans than in Asians (2.75:1), and the Fitzpatrick skin type was mainly Ito III (12/15). The mean cumulative number and cumulative dose of UVB treatments were 43.71 and 42, 400 (mJ/cm), respectively. There was a positive relationship between Fitzpatrick skin type and cumulative dose of UVB treatments. Among the secondary skin diseases after NBUVB treatment, 12 were tumors, 2 were non-tumorous dermatoses. Only our patient presented with both. By polymerase chain reaction-single nucleotide polymorphism (PCR-SNP) analysis, C-G mutation of exon 4 of p53 was found in AK and MF specimens in our patient.
CONCLUSION: To our knowledge, our case is the first MF patient accompanied with AK, AK with SCC transformation and Porokeratosis after NBUVB treatment. Lower Fitzpatrick skin type may be the risk factor of secondary skin diseases after NBUVB treatment.

Reddy SA
Romidepsin for the treatment of relapsed/refractory cutaneous T-cell lymphoma (mycosis fungoides/Sézary syndrome): Use in a community setting.
Crit Rev Oncol Hematol. 2016; 106:99-107 [PubMed] Related Publications
Cutaneous T-cell lymphoma (CTCL) is a heterogeneous group of rare non-Hodgkin lymphomas that arise in the skin. In advanced stages, CTCL becomes systemic and is associated with poor prognosis. Diagnosis of CTCL and treatment of early-stage disease with topical therapies often occurs under the care of a dermatologist. Community oncologists see few patients with CTCL due to direct referrals from dermatologists to academic or lymphoma specialty centers. However, some patients will continue to be managed in a community setting. Currently there is no evidence-based stepwise algorithm for treatment of patients with CTCL, and guidelines suggest a wide range of systemic therapies, including biologics, targeted agents, and more traditional chemotherapies. To provide optimal care in a community setting, oncologists must become familiar with newer nonchemotherapeutic treatment options. This review highlights romidepsin, a histone deacetylase inhibitor approved for the treatment of patients with CTCL who have received ≥1 prior systemic therapy.

Jankowska-Konsur A, Kobierzycki C, Grzegrzolka J, et al.
Expression of CD31 in Mycosis Fungoides.
Anticancer Res. 2016; 36(9):4575-82 [PubMed] Related Publications
BACKGROUND/AIM: Mycosis fungoides (MF) is the most common primary cutaneous T-cell lymphoma (CTCL) characterized by malignant proliferation of mature T lymphocytes and primary skin involvement. Recent reports suggest that angiogenesis may play a role in the growth and spread of this malignancy. Cluster of differentiation 31 (CD31) is a protein classified into the Ig-superfamily of cell adhesion molecules, expressed on endothelial cells and majority of hematopoietic non-erythroid cells. The aim of our study was to explore the role of angiogenesis in MF.
MATERIALS AND METHODS: We evaluated the expression of CD31 in relation to clinicopathological data and potential impact on patients' outcome in MF utilizing immunohistochemistry (IHC) and western blot (WB) techniques in 73 and 19 MF and 21 and 4 control samples, respectively.
RESULTS: In the IHC study, statistical analysis revealed significantly higher CD31 expression in MF compared to the controls (p<0.0001) with highest expression in advanced stages vs. early ones and controls (p<0.0001 for both). In regard to skin involvement, expression was also elevated in more infiltrative (T3, tumors) and in more extensive (T4, erythroderma) cutaneous lesions compared to less infiltrative and limited skin lesions (T1, T2, patches and/or plaques) (p<0.01 for both). Regarding the extracutaneous spread, higher CD31 expression correlated with nodal involvement (N1-3 vs. N0; p<0.0001). In the WB study, statistical analysis revealed significantly higher CD31 expression only in advanced vs. early stage of MF (p<0.05). In regard to skin involvement, expression was also elevated in T3 and T4 as compared T1+T2 (p=0.08, p<0.05; respectively). Higher CD31 expression correlated with nodal involvement (N1-3 vs. N0; p<0.01). A strong significant correlation between CD31 expression at the protein level analyzed by IHC and WB was noticed (r=0.802, p<0.0001). Moreover, strong positive correlations between IHC expression of CD31 and podoplanin (PDPN; r=0.582, p<0.0001), vascular endothelial growth factor C (VEGFC; r=0.332, p<0.01) and Ki-67 (r=0.330, p<0.01) were disclosed.
CONCLUSION: Expression of CD31 in MF skin biopsies provides new evidence for the role of angiogenesis in the progression of MF. Additionally, the new data revealed prompts for further research on potential use of CD31 as a new marker of the disease advancement, as well as the target of new therapeutic strategies.

Papadavid E, Braoudaki M, Bourdakou M, et al.
Aberrant microRNA expression in tumor mycosis fungoides.
Tumour Biol. 2016; 37(11):14667-14675 [PubMed] Related Publications
Herein, miRNA candidates relevant to mycosis fungoides were investigated to provide data on the molecular mechanisms underlying the pathogenesis of the disease. The miRNA expression profile of skin biopsies from patients with tumor stage MF (tMF) and normal donors was compared using miRNA microarrays. Overall, 154 miRNAs were found differentially expressed between tMF and the control cohort with the majority of them being up-regulated (57 %). Among the upregulated miRNAs, miR-3177, miR-514b-3p, miR-1267, and miR-1282 were exclusively detected in 70 % of tMF. Additional upregulated miRNAs included miR-34a, miR-29a, let-7a*, and miR-210, while miR-200c* was identified among the downregulated ones. Quantitative real-time polymerase chain reaction was used to further investigate the expression profiles of miR-34a and miR-29a and validated the overexpression of miR-34a. Enrichment studies revealed that the target genes of the differentially expressed miRNAs were important in several cancer-related signaling pathways. The overlapping relationship of the target genes among tMF, Sezary syndrome, and atopic dermatitis revealed several common and disease-specific genes. Collectively, our study modulated miR-34a as a candidate oncogenic molecule and miR-29a as a putative tumor suppressor highlighting their promising potential in the molecular pathogenesis of tMF.

Boursi B, Haynes K, Mamtani R, Yang YX
An association between newly diagnosed cutaneous T cell lymphoma and prior impetigo: a nested case-control study.
Arch Dermatol Res. 2016; 308(9):661-664 [PubMed] Related Publications
Colonization with staphylococcus aureus (SA) is associated with disease activity and progression in patients with cutaneous T-cell lymphoma (CTCL) secondary to T-cell activation by bacterial superantigens. The aim of the current study was to evaluate the possible role of SA as an etiologic factor affecting CTCL initiation. We conducted a nested case-control study in a large population-representative database from the UK. Cases were defined as all patients with an incident diagnosis of mycosis fungoides (MF) or Sezary syndrome (SS) between 1995 and 2013. For every case, four eligible controls matched on age, sex, practice-site, and duration of follow-up were selected. Exposure of interest was clinical diagnosis of impetigo prior to CTCL diagnosis. Conditional logistic regression was used to calculate odds-ratio (ORs) and 95 % confidence-interval (CI) for CTCL risk. The results were further stratified according to age, sex and time interval between impetigo and CTCL diagnosis. The study population included 310 cases with MF or SS and 1223 matched controls. Among cases with CTCL 4.8 % (n = 15) had impetigo prior to cancer diagnosis compared to 2 % (n = 24) of controls. The adjusted OR for CTCL diagnosis among patients with prior impetigo was 2.33 (95 % CI 1.12-4.83). The risk was elevated among individuals with impetigo 1-5 years before cancer diagnosis (OR 3.33, 95 % CI 1.00-11.10). There was no change in risk among patients with impetigo more than 5 years before cancer diagnosis (OR 1.09, 95 % CI 0.35-3.37). Our results suggest a possible association between SA colonization and CTCL initiation that might serve as an important etiological factor for the disease.

Jankowska-Konsur A, Kobierzycki C, Grzegrzółka J, et al.
Podoplanin Expression Correlates with Disease Progression in Mycosis Fungoides.
Acta Derm Venereol. 2017; 97(2):235-241 [PubMed] Related Publications
The aim of this study was to investigate the role of lymphangiogenesis in the clinical progression and outcome of mycosis fungoides. Immunohistochemistry and Western blot techniques were used to assess the expression of podoplanin and vascular endothelial growth factor C in mycosis fungoides. Expression of vascular endothelial growth factor C measured by immunohistochemistry was significantly higher in mycosis fungoides samples in comparison with control cases (chronic benign dermatoses) (p = 0.0012). Increased expression of podoplanin was found in advanced vs. early mycosis fungoides (p < 0.0001), and was positively correlated with cutaneous and nodal involvement (p < 0.001, p < 0.0001; respectively). Higher podoplanin expression was also significantly associated with shorter survival (p < 0.001). Strong positive correlation was observed between expression of podoplanin analysed by immunohistochemistry and Western blot (r = 0.75, p < 0.0001). A similar association was shown regarding expression of vascular endothelial growth factor C (r = 0.68, p = 0.0007). In conclusion, these results suggest that increased expression of podoplanin is associated with poor clinical course, as well as shorter survival, of patients with mycosis fungoides.

Ramani NS, Curry JL, Merrill ED, et al.
Primary Cutaneous Gamma-Delta (γ/δ) T-cell Lymphoma: An Unusual Case With Very Subtle Histopathological Findings.
Am J Dermatopathol. 2016; 38(10):e147-9 [PubMed] Related Publications
Primary cutaneous γ/δ T-cell lymphoma (PCGDTCL) accounts for <1% of all primary cutaneous lymphomas. These rare diseases are believed to originate from γ/δ lymphocytes. Clinical presentation may vary, but its clinical behavior is regarded as aggressive and long-term survival is anecdotal. This study describes the case of a 60-year-old man with multiple, rapidly progressing skin plaques on his head, arms, torso, buttocks, and legs. The histopathological changes seen in the skin biopsy were extraordinarily subtle with mild epidermal hyperplasia and a very sparse lymphoid infiltrate involving epidermis and superficial dermis. Immunohistochemical studies revealed the atypical intraepidermal hyperchromatic cells to be mostly positive for CD3 and CD7 and negative for both CD4 and CD8. The intraepidermal atypical lymphocytes were positive for TCR gamma, and negative for betaF1 and CD56. The clinical, morphologic, and immunohistochemical findings supported the diagnosis of PCGDTCL. This case illustrates a case of epidermotropic variant of PCGDTCL that, albeit a bland histopathological presentation, was associated with an aggressive clinical behavior.

Eren R, Nizam N, Doğu MH, et al.
Evaluation of neutrophil-lymphocyte ratio in patients with early-stage mycosis fungoides.
Ann Hematol. 2016; 95(11):1853-7 [PubMed] Related Publications
Neutrophil-lymphocyte ratio (NLR), an indicator of inflammation, has been lately demonstrated as a prognostic factor and an indicator of disease activity in various diseases. However, the effects of NLR have not been investigated in mycosis fungoides (MF) patients yet. The aim of this study is to investigate the relationship between the NLR and treatment demand (systemic PUVA and/or chemotherapy), time to treatment, progression in stage, and time to progression in stage in MF patients. The data of 117 patients, who were followed with the diagnosis of MF at the Department of Dermatology in Istanbul Training and Research Hospital between April 2006 and January 2016, were analyzed retrospectively. The cutoff score for NLR was determined as 2 according to the median NLR level which was 1.96. At the time of diagnosis, the median age of patients was 54 years (range, 21-90) with 62 (53 %) female and 55 (47 %) male. Seventy-seven (65.8 %) patients required treatment during follow-up. Sixty-three (53.8 %) patients showed progression in disease stage. There was no significant difference in treatment demand, time to treatment, progression in stage, and time to progression in stage in patients with a NLR ≥ 2 and NLR < 2 (p = 0.331, 0.987, 0.065, and 0.119, respectively). It seems that there is no association between the NLR and treatment demand, time to treatment, progression in stage, and time to progression in stage in MF patients.

Garaicoa FH, Roisman A, Arias M, et al.
Genomic imbalances and microRNA transcriptional profiles in patients with mycosis fungoides.
Tumour Biol. 2016; 37(10):13637-13647 [PubMed] Related Publications
Mycosis fungoides is the most common type of primary cutaneous T cell lymphoma. We have evaluated CDKN2A losses and MYC gains/amplifications by FISH analysis, as well as expression of miR-155 and members of the oncogenic cluster miR-17-92 (miR17, miR18a, miR19b, and miR92a) in MF patients with advanced disease. Formalin-fixed paraffin-embedded skin biopsies from 36 patients at diagnosis, 16 with tumoral MF (T-MF), 13 in histological transformation to a large T cell lymphoma (TR-MF), and 7 cases with folliculotropic variant (F-MF), were studied. Twenty cases showed genomic alterations (GAs): 8 (40 %) had CDKN2A deletion, 7 (35 %) showed MYC gain, and 5 (25 %) exhibited both alterations. GAs were more frequently observed in F-MF (p = 0.004) and TR-MF (p = 0.0001) than T-MF. GAs were significantly higher in cases presenting lesions in head, neck, and lower extremities compared to those observed in trunk and upper extremities (p = 0.03), when ≥25 % neoplastic cells were CD30 positive (p = 0.016) as well as in cases with higher Ki-67 proliferation index (p = 0.003). Patients with GAs showed bad response to treatment (p = 0.02) and short survival (p = 0.04). Furthermore, MF patients showed higher miRNA expression compared to controls (p ≤ 0.0223). T-MF showed higher miR17 and miR-18a expression compared to F-MF and TR-MF (p ≤ 0.0387) while miR19b, miR92a, and miR-155 showed increased levels in F-MF and TR-MF with respect to T-MF (p ≤ 0.0360). Increased expression of miR17 and miR19b in GA group compared to cases without alterations (p ≥ 0.0307) was also detected. Our results add new information about genomic imbalances in MF patients, particularly in F-MF, and extend the present view of miRNA deregulation in this disease.

Gammon B, Gammon BR, Kim YH, Kim J
Neurotropic Gamma-Delta T-Cell Lymphoma With CD30-Positive Lymphoid Infiltrates.
Am J Dermatopathol. 2016; 38(9):e133-6 [PubMed] Related Publications
Primary cutaneous gamma-delta T-cell lymphoma (PCGD-TCL) is a clonal proliferation of gamma-delta T cells with a cytotoxic phenotype that is typically characterized by an aggressive clinical course with ulcerative plaques or subcutaneous nodules. In this report, the authors describe a patient who developed an ulcerated tumor on the left upper extremity and painful papules and nodules on the right lower extremity. Interestingly, several of the papulonodules on the right lower extremity underwent spontaneous involution. A skin biopsy of the papulonodular lesion demonstrated a superficial and deep perivascular interstitial infiltrate with a population of pleomorphic enlarged CD30-positive T cells. These enlarged lymphocytes lacked expression of TCR beta, CD4, CD8, and the pan T-cell antigen CD7, but were positive for TCR gamma, supporting the diagnosis of PCGD-TCL. The patient rapidly developed pain and severe weakness in the left upper limb and MRI revealed extensive neurolymphomatosis of the left brachial plexus. The patient was treated with chemotherapy with complete remission achieved. Unfortunately, her response was transient and the patient relapsed and ultimately died due to her disease. In this article, the authors describe an extraordinary case of a CD30-positive PCGD-TCL to expand the histopathological spectrum of CD30-positive and gamma-delta-positive lymphoproliferative disorders.

Shen G, Dong L, Zhang S
Subcutaneous Panniculitis-like T Cell Lymphoma Mimicking Early-Onset Nodular Panniculitis.
Am J Case Rep. 2016; 17:429-33 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Subcutaneous panniculitis-like T cell lymphoma is a very uncommon subtype of cutaneous T cell lymphoma. The manifestations of this rare disease are atypical at onset, and may mimic some rheumatic or dermatologic diseases, which causes the delay of diagnosis and treatment.
CASE REPORT: We report a 24-year-old man suffering from intermittent fever and skin nodules on the left anterior chest wall, who was initially misdiagnosed with nodular panniculitis and finally diagnosed with subcutaneous panniculitis-like T cell lymphoma through repeat examination of biopsy of the skin nodule. Positron emission tomography revealed extracutaneous adipose tissue involvement. Subsequently, hemophagocytic syndrome occurred while under a conventional dose of glucocorticoid, but remission was induced by treatment with cyclosporine A and high doses of dexamethasone.
CONCLUSIONS: In order to avoid the delay diagnosis and inappropriate treatment of subcutaneous panniculitis-like T cell lymphoma, in addition to a thorough physical examination, PET-CT and disease-specific pathologic, immunophenotypic, and T cell receptor tests of the skin biopsy should be performed. Extracutaneous involvement, especially hemophagocytic syndrome, indicated worse prognosis. Even so, cyclosporine A plus high-dose corticosteroid could be an option of treatment.

Saulite I, Hoetzenecker W, Weidinger S, et al.
Sézary Syndrome and Atopic Dermatitis: Comparison of Immunological Aspects and Targets.
Biomed Res Int. 2016; 2016:9717530 [PubMed] Free Access to Full Article Related Publications
Sézary syndrome (SS), an aggressive form of erythrodermic pruritic cutaneous T cell lymphoma (CTCL), from an immunological perspective characterized by increased Th2 cytokine levels, elevated serum IgE and impaired cellular immunity. Not only the clinical appearance but also the hallmark immunological characteristics of SS often share striking similarities with acute flares of atopic dermatitis (AD), a common benign chronic inflammatory skin disease. Given the overlap of several immunological features, the application of similar or even identical therapeutic approaches in certain stages of both diseases may come into consideration. The aim of this review is to compare currently accepted immunological aspects and possible therapeutic targets in AD and SS.

Jankowska-Konsur A, Kobierzycki C, Reich A, et al.
Expression of SOX18 in Mycosis Fungoides.
Acta Derm Venereol. 2017; 96(7):17-23 [PubMed] Related Publications
SOX18 is a transcription factor involved in the development of hair follicle, blood and lymphatic vessels, as well as regenerative processes. In addition, accumulated data indicate the role of SOX18 in tumourigenesis. So far, no studies on the role of SOX18 expression in mycosis fungoides (MF), the most common primary cutaneous T-cell lymphoma, have been performed. Therefore, we evaluated SOX18 expression in MF at the mRNA and protein level. SOX18 expression was observed predominantly on the blood and lymphatic vessels, in the intratumoural and peritumoural microenvironment of MF. The intra-tumoural, but not peritumoural, expression of SOX18 correlated positively with the advancement of the disease, cutaneous involvement and extracutaneous meta-stases at the protein level (p < 0.001, p < 0.001, p = 0.004; respectively). Significantly lower SOX18 mRNA expression was correlated with lymph node involvement (p = 0.01). In conclusion, we hypothesize that SOX18, as a marker of neovascularization, may be involved in the progression of MF.

Tebeică T, Andrei R, Zurac S, Stăniceanu F
Practical Aspects Regarding the Histopathological Diagnosis of Early Mycosis Fungoides.
Rom J Intern Med. 2016 Jan-Mar; 54(1):3-10 [PubMed] Related Publications
Mycosis fungoides is the most common primary T-cell lymphoma of skin. The disease has a protean clinical and histological presentation in its early patch and plaque stages, when distinction from mimicking inflammatory dermatoses is difficult. Since no single criterion is specific enough, a reliable diagnosis in early stages requires integration of clinical, histopathological and molecular findings. In skin biopsies, the most helpful histologic features are the detection of atypical lymphocytes in the epidermis with minimal epidermal changes, basal alignment of lymphocytes along dermal-epidermal junction and formation of Pautrier microabscesses. An aberrant immunophenotype of T cells and molecular detection of a clonal T-cell population are factors that could allow a more specific diagnosis. This work recapitulates and discusses these features from a practical perspective.

Wieser I, Wohlmuth C, Nunez CA, Duvic M
Lymphomatoid Papulosis in Children and Adolescents: A Systematic Review.
Am J Clin Dermatol. 2016; 17(4):319-27 [PubMed] Related Publications
BACKGROUND: Lymphomatoid papulosis (LyP) is a lymphoproliferative disorder that is rare among adults and even rarer among children. In adults, LyP is associated with an increased risk of secondary lymphomas.
OBJECTIVE: The aim of this systematic review was to describe the clinical and histopathological features of LyP in children, to assess the risk of associated lymphomas, and to compare the disease to the adult form.
METHODS: A systematic review was conducted using the MEDLINE (PubMed), EMBASE, Scopus, and Cochrane databases from inception to June 2015. Articles were included if data were extractable from studies, case series, and single reports of pediatric LyP patients.
RESULTS: A total of 251 children and adolescents with LyP were identified, with the mean age at diagnosis being 9.3 ± 4.6 years (n = 187). The female to male ratio was 1:1.4, and the majority of children reported on were Caucasian (n = 74, 85.1 %). The predominant histologic subtype was type A (n = 106, 79.1 %). Clinically, LyP lesions presented as erythematous papules or nodules, appearing preferentially on the extremities and the trunk. LyP has to be differentiated from pityriasis lichenoides (PL) and primary cutaneous anaplastic large cell lymphoma (ALCL). PL and associated lymphomas were diagnosed before, with, and after LyP in 19 and 14 cases, respectively. Of the 14 subjects with associated lymphomas, two children developed systemic ALCL.
CONCLUSION: LyP has to be differentiated from ALCL to avoid erroneous treatments. Due to the increased risk of development of non-Hodgkin lymphomas, lifelong follow-up and proper patient counseling are warranted.

Celebi Cherukuri N, Roth CG, Aggarwal N, et al.
Cutaneous Small/Medium CD4+ Pleomorphic T-Cell Lymphoma-Like Nodule in a Patient With Erythema Chronicum Migrans.
Am J Dermatopathol. 2016; 38(6):448-52 [PubMed] Related Publications
CD4+ small/medium pleomorphic T-cell lymphoma is a relatively rare subtype of cutaneous lymphoproliferative disorder with an indolent clinical behavior. The place of this condition among lymphomas is debatable. The authors describe a rare case of the direct association of CD4 small/medium pleomorphic T-cell lymphoma-like solitary nodule with Borrelia burgdorferi infection in a 5-year-old boy, discuss the reactive nature of this condition, and emphasize the importance of clinicopathological correlation.

Magro CM, Momtahen S
Differential NFATc1 Expression in Primary Cutaneous CD4+ Small/Medium-Sized Pleomorphic T-Cell Lymphoma and Other Forms of Cutaneous T-Cell Lymphoma and Pseudolymphoma.
Am J Dermatopathol. 2017; 39(2):95-103 [PubMed] Related Publications
BACKGROUND: Primary cutaneous CD4 small/medium-sized pleomorphic T-cell lymphoma (PCSTCL) has recently emerged as a distinct clinicopathological entity. Because of a considerable degree of overlap with pseudolymphoma, the diagnosis is often challenging. Preliminary studies suggest that nuclear upregulation of calcineurin/nuclear factor of activated T cells (NFAT) may play a role in lymphomagenesis.
DESIGN: 137 cases (70 males and 67 female, mean age = 55) of various forms of cutaneous T-cell and B-cell infiltration were evaluated for NFATc1 expression. The study comprised 18 cases of PCSTCL, 45 cases of mycosis fungoides (MF), 5 cases of lymphomatoid papulosis (LyP), 5 cases of anaplastic large-cell lymphoma (ALCL), 8 cases of other forms of peripheral T-cell lymphoma, not otherwise specified, 12 precursor lesions of MF (ie, cutaneous T-cell dyscrasias), 35 cases of pseudolymphomas, 8 primary cutaneous B-cell lymphoma, and 1 chronic lymphocytic leukemia. The number of cells exhibiting a nuclear stain was counted per 10  high-power field and 2-tailed statistical analysis was used for comparison of nuclear NFATc1 expression between primary PCSTCL and all other groups. A P-value <0.05 was considered to indicate statistical significance.
RESULTS: All cases of PCSTCL showed nuclear staining for NFATc1 (mean = 296 ± 236) with no cases in which an exclusive cytoplasmic stain was observed. The cells exhibiting this staining pattern were oftentimes larger manifesting other features of a follicular helper T-cell phenotype, such as variable positivity for PD1, ICOS, CXCL13, and BCL6. In comparison, an exclusively cytoplasmic stain was observed in 29 cases of MF; in few cases, rare nuclear staining cells were observed averaging less than 10 per high-power field (P = 0.0001). These positive staining cases were not only limited to tumor-stage MF but also encompassed patch- and plaque-stage lesions and follicular variants of MF. The same pattern was observed in cases of T-cell dyscrasia (mean = 3 ± 3, P = 0.0001) and pseudolymphoma (mean = 2 ± 3, P = 0.0001), both revealing a dominant cytoplasmic staining pattern. In pseudolymphomatous folliculitis, a greater extent of nuclear staining for NFATc1 was observed compared with other forms of pseudolymphoma. No significant difference was seen between MF and T-cell dyscrasia or pesudolymphomas excluding pseudolymphotous folliculitis. Anaplastic large-cell lymphoma cases showed an almost exclusive cytoplasmic staining pattern with rare nuclear staining (mean = 55 ± 102, P = 0.0001); similar results were observed in LyP (mean = 17 ± 15, P = 0.004). Cutaneous B-cell lymphomas showed a similar extent of staining as that noted for PCSTCL. The greatest extent of staining was observed in chronic lymphocytic leukemia. A significant difference was noted between the extent of nuclear staining in PCSTCL and other forms of primary cutaneous T-cell lymphoma, type unspecified (mean = 22 ± 43, P = 0.0002), although not between PCSTCL and B-cell lymphoma.
CONCLUSION: NFAT signaling plays a critical role in peripheral T-cell activation after T cell receptor engagement. When assessing T-cell-rich infiltrates where the differential diagnosis is largely between a PCSTCL and pseudolymphoma, a significant degree of nuclear staining of lymphocytes would be more in keeping with a diagnosis of PCSTCL. Upregulation of the NFAT pathway is not a feature of tumor progression in the setting of MF.

Novelli S, García-Muret P, Mozos A, et al.
Total body-surface area as a new prognostic variable in mycosis fungoides and Sézary syndrome.
Leuk Lymphoma. 2016; 57(5):1060-6 [PubMed] Related Publications
Mycosis fungoides and Sézary syndrome (MF/SS) are the most common forms of primary cutaneous T cell lymphomas. We analyzed the applicability of the cutaneous lymphoma international prognostic index (CLIPi) in MF/SS. We introduced the total body-surface area affected (TBSA) and the type of skin lesions at diagnosis as prognostic variables. The overall survival (OS) at median time of follow up (96 months) was 75.6% (CI 95%, 62.0-98.5%). In the univariate analysis, age>60 years, advanced disease, type of skin lesions and TBSA>50 showed poorer OS (p<0.05). In the multivariate analysis there was a significant increased relative risk of death in those patients>60 years, with advanced disease and TBSA>50% (p<0.05). TBSA identified a group of poor prognosis patients with advanced MF/SS that may benefit from novel systemic therapies.

Martinez-Escala ME, Kuzel TM, Kaplan JB, et al.
Durable Responses With Maintenance Dose-Sparing Regimens of Romidepsin in Cutaneous T-Cell Lymphoma.
JAMA Oncol. 2016; 2(6):790-3 [PubMed] Related Publications
IMPORTANCE: Romidepsin is a histone deacetylase inhibitor approved for the treatment of cutaneous T-cell lymphoma (CTCL). Durable responses have been published without establishing a standard recommendation about duration of treatment.
OBJECTIVE: To review the long-term use of romidepsin in responders who received a dose-sparing regimen.
DESIGN, SETTING, AND PARTICIPANTS: Retrospective review of medical records of patients with a diagnosis of CTCL, including mycosis fungoides (MF), Sézary syndrome (SS), or CTCL not otherwise specified seen at a multidisciplinary clinic at Northwestern University from 2009 until December 2014.
EXPOSURES: Doses administered and different regimens of romidepsin were reviewed.
MAIN OUTCOMES AND MEASURES: Duration of treatment, participants receiving dose-sparing regimen.
RESULTS: Of 47 patients identified, 23 had MF, 15 had SS, and 9 had other types of CTCL. None of these 9 (mostly cytotoxic lymphomas) achieved a durable response. Of the remaining 38 patients, 17 were considered long-term responders (>6 months of treatment). Nine of these patients received a dose-sparing regimen. The median (range) duration of treatment was 15 (7-34) months; the frequency of patients with SS (10 of 15) in the long-term group was significantly higher than that of patients with MF (7 of 23; P = .046). Adverse events were reported in 29 (69%) of 42 patients for whom data were available. There was no significant difference in the incidence of AEs between the short-term and long-term groups (12 of 21 vs 12 of 17; P = .50).
CONCLUSIONS AND RELEVANCE: Decreasing the frequency of infusions in patients with MF or SS who achieve a response with romidepsin therapy may provide a practical strategy to prolong response.

Ceriolo P, Fausti V, Cinotti E, et al.
Pancreatic metastasis from mycosis fungoides mimicking primary pancreatic tumor.
World J Gastroenterol. 2016; 22(12):3496-501 [PubMed] Free Access to Full Article Related Publications
Mycosis fungoides (MF) is a cutaneous T-cell lymphoma that can undergo local progression with possible systemic dissemination. We report a case of a patient affected by MF with a pancreatic mass that was a diagnostic challenge between primitive tumor and pancreatic metastasis from MF. Clinical setting findings and imaging studies raised the suspicion of a pancreatic primary neoplasm. A diagnostic clue was provided by the combined histomorphologic/immunohistochemical study of pancreatic and cutaneous biopsies, which revealed a pancreatic localization of MF. Considering the rarity of metastatic localization of MF to the pancreas, we next investigated whether chemokine-chemokine receptor interactions could be involved in the phenomenon to provide new insight into the possible mechanisms underlying metastatic localization of MF to the pancreas. Histological analyses of archival pancreatic tissue demonstrated that glucagon-secreting cells of the pancreatic islets expressed the CCL27 chemokine, which may have attracted in our case metastatic MF cells expressing the complementary receptor CCR10.

Nattkemper LA, Martinez-Escala ME, Gelman AB, et al.
Cutaneous T-cell Lymphoma and Pruritus: The Expression of IL-31 and its Receptors in the Skin.
Acta Derm Venereol. 2016; 96(7):894-898 [PubMed] Related Publications
Approximately 88% of cutaneous T-cell lymphoma (CTCL) patients are affected by pruritus that responds poorly to current antipruritic therapies. Interleukin (IL)-31, a Th2 cytokine, has been found to be increased in the serum of CTCL patients and to correlate with itch severity. This study investigated the role of IL-31 and its receptors (IL-31 receptor-alpha [IL-31RA] and OSMRβ) in the skin of CTCL patients with mild versus moderate/severe pruritus. Expression levels of IL-31, IL-31RA, and OSMRβ in the skin were measured using immunohistochemistry and correlated to pruritus severity and disease stage. In CTCL patients with moderate/severe pruritus, IL-31 was significantly elevated in the epidermis and dermal infiltrate, while IL-31RA and OSMRβ were significantly elevated only in the epidermis. Furthermore, epidermal IL-31 levels correlated to itch severity. These results show that IL-31 may play a role in CTCL pruritus by exerting indirect effects on sensory nerves through epidermal neoplastic T cells and keratinocytes to transmit itch.

Mna AB, Souissi A, Halouani S, et al.
Methotrexate-induced necrolysis in tumoral-stage mycosis fungoides: a challenging diagnosis.
Dermatol Online J. 2016; 22(1) [PubMed] Related Publications
Methotrexate-induced cutaneous ulceration is a rare but potentially serious drug adverse reaction. This adverse reaction of methotrexate therapy has been initially described in psoriasis patients and is unusual in patients with cutaneous T-cell lymphoma. In 1978, Mc Donald et al reported the first three cases of cutaneous ulcerations in patients treated for a mycosis fungoides with intravenous infusions of methotrexate. Since then, few cases of methotrexate-induced skin ulcers in patients with mycosis fungoides have been published. We report an additional patient with erythrodermic mycosis fungoides who developed cutaneous ulcerations as a sole manifestation of methotrexate toxicity.

Romano RC, Cohen DN, Howard MT, Wieland CN
A Primary Cutaneous CD30-Positive T-Cell Lymphoproliferative Disorder Arising in a Patient With Multiple Myeloma and Cutaneous Amyloidosis.
Am J Dermatopathol. 2016; 38(5):388-92 [PubMed] Related Publications
CD30-positive cutaneous lymphoproliferative disorders, a group of T-cell neoplasms, including lymphomatoid papulosis (LyP) and cutaneous anaplastic large cell lymphoma, require careful clinicopathologic correlation for diagnosis. An association between LyP and the development of a second hematolymphoid malignancy has been established in the literature. LyP has also been reported with systemic amyloidosis, but no such reports have documented coexisting cutaneous amyloid deposition with LyP to our knowledge. A 66-year-old woman with cutaneous amyloidosis, secondary to multiple myeloma, in remission, presented with erythematous and dark-brown papules involving the right arm, scalp, and torso. Punch biopsy of the arm showed a dermal infiltrate of intermediate-sized lymphocytes, some of which displayed a plasmacytoid morphology and prominent nodular subepidermal amyloid deposition. Punch biopsy of the scalp similarly showed a nonepidermotropic dense dermal infiltrate of intermediate-sized plasmacytoid lymphocytes and multifocal amyloid deposition. Both infiltrates were immunophenotypically CD30-positive, anaplastic lymphoma kinase-negative T-cell lymphoproliferative processes. Subsequent studies showed no systemic involvement, and clinical correlation suggested a final diagnosis of LyP. We present this case of LyP, which histologically mimics a B-cell proliferation with a plasmacytoid morphology arising in association with cutaneous amyloidosis to highlight the importance of clinicopathologic correlation, a thorough battery of immunohistochemical studies, and consideration for a second hematologic malignancy arising in the setting of LyP.

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