Alexandra C. Hristov

GATA-3 expression identifies a high-risk subset of PTCL, NOS with distinct molecular and clinical features.

The cell of origin and the tumor microenvironments role remain elusive for the most common peripheral T-cell lymphomas (PTCLs). As macrophages promote the growth and survival of malignant T cells and are abundant constituents of the tumor microenvironment, their functional polarization was examined in T-cell lymphoproliferative disorders. Cytokines that are abundant within the tumor microenvironment, particularly interleukin (IL)-10, were observed to promote alternative macrophage polarization. Macrophage polarization was signal transducer and activator of transcription 3 dependent and was impaired by the Janus kinase inhibitor ruxolitinib. In conventional T cells, the production of T helper (Th)2-associated cytokines and IL-10, both of which promote alternative macrophage polarization, is regulated by the T-cell transcription factor GATA-binding protein 3 (GATA-3). Therefore, its role in the T-cell lymphomas was examined. GATA-3 expression was observed in 45% of PTCLs, not otherwise specified (PTCL, NOS) and was associated with distinct molecular features, including the production of Th2-associated cytokines. In addition, GATA-3 expression identified a subset of PTCL, NOS with distinct clinical features, including inferior progression-free and overall survival. Collectively, these data suggest that further understanding the cell of origin and lymphocyte ontogeny among the T-cell lymphomas may improve our understanding of the tumor microenvironments pathogenic role in these aggressive lymphomas.

A novel recurrent NPM1-TYK2 gene fusion in cutaneous CD30-positive lymphoproliferative disorders

The spectrum of cutaneous CD30-positive lymphoproliferative disorders (LPDs) includes lymphomatoid papulosis and primary cutaneous anaplastic large cell lymphoma. Chromosomal translocations targeting tyrosine kinases in CD30-positive LPDs have not been described. Using whole-transcriptome sequencing, we identified a chimeric fusion involving NPM1 (5q35) and TYK2 (19p13) that encodes an NPM1-TYK2 protein containing the oligomerization domain of NPM1 and an intact catalytic domain in TYK2. Fluorescence in situ hybridization revealed NPM1-TYK2 fusions in 2 of 47 (4%) primary cases of CD30-positive LPDs and was absent in other mature T-cell neoplasms (n = 151). Functionally, NPM1-TYK2 induced constitutive TYK2, signal transducer and activator of transcription 1 (STAT1), STAT3, and STAT5 activation. Conversely, a kinase-defective NPM1-TYK2 mutant abrogated STAT1/3/5 signaling. Finally, short hairpin RNA-mediated silencing of TYK2 abrogated lymphoma cell growth. This is the first report of recurrent translocations involving TYK2, and it highlights the novel therapeutic opportunities in the treatment of CD30-positive LPDs with TYK2 translocations.

Primary Cutaneous Diffuse Large B-Cell Lymphoma, Leg Type Diagnostic Considerations

CONTEXT Primary cutaneous diffuse large B-cell lymphoma, leg type, may show features that overlap with other lymphomas. However, timely recognition of this entity can have important clinical and therapeutic implications. OBJECTIVE To review the clinical, morphologic, and immunophenotypic characteristics of primary cutaneous diffuse large B-cell lymphoma, leg type, and juxtapose these features with other diagnostic considerations. In particular, other variants of primary cutaneous diffuse large B-cell lymphoma, as well as primary cutaneous follicle center lymphoma, will be reviewed. Additionally, systemic/extracutaneous lymphomas will be discussed, including diffuse large B-cell lymphoma, not otherwise specified, Epstein-Barr virus-positive diffuse large B-cell lymphoma of the elderly, and lymphomatoid granulomatosis. DATA SOURCES Relevant literature will be reviewed and key differentiating findings will be highlighted. CONCLUSIONS Although primary cutaneous diffuse large B-cell lymphoma, leg type, may show aspects that overlap with other lymphomas, it can be distinguished from other entities in the differential diagnosis.

Selected Inflammatory Imitators of Mycosis Fungoides: Histologic Features and Utility of Ancillary Studies

Mycosis fungoides is the most common primary cutaneous lymphoma; however, it remains a significant diagnostic challenge, in part because of the overlap with several inflammatory dermatoses. Despite advances in immunohistochemistry and molecular diagnostics, false-positive, false-negative, and indeterminate diagnoses are not uncommon. In most cases, the overall balance of morphologic, immunophenotypic, and genetic features must be considered carefully because there are few sensitive and specific clues to the diagnosis. Moreover, an appropriate clinical presentation is essential to the diagnosis and helps to favor or exclude inflammatory/reactive processes. Herein, we discuss 3 important inflammatory dermatoses that may closely simulate mycosis fungoides, and we review the use of ancillary studies in these challenging cases.

A retrospective comparative outcome analysis following systemic therapy in Mycosis Fungoides and Sezary Syndrome

Cutaneous T‐cell lymphomas (CTCL), with few exceptions, remain incurable and treatment is largely palliative. We performed a retrospective analysis of systemic treatment outcomes of patients diagnosed with MF/SS. We identified 223 patients with MF/SS evaluated at a single institution from 1997 to 2013. Disease stage at diagnosis, time of treatment, and treatments received were retrospectively analyzed using our CTCL database. The primary endpoint was time to next treatment (TTNT). Treatment outcomes were analyzed using Kaplan–Meier method and comparisons among groups were made using log‐rank analysis. A superior TTNT was associated with retinoid or interferon therapies when compared with HDAC inhibitors or systemic chemotherapy. Retinoids and interferon were associated with superior TTNT in both limited‐stage and advanced stage disease. Extracorporeal photophoresis (ECP) had a superior TTNT in Sezary Syndrome. HDAC inhibitors and chemotherapy were associated with inferior TTNT in both limited stage disease and advanced stage disease. With the exception of interferon, retinoids, or ECP, durable responses are rarely achieved with systemic therapies in MF/SS patients, particularly those with advanced‐stage disease. Therefore, clinical trial participation with novel agents should be encouraged. Am. J. Hematol. 91:E491–E495, 2016.

Mycosis fungoides with CD20 expression: report of two cases and review of the literature

CD20 expression is exceedingly rare in T‐cell lymphomas. Most published cases have been diagnosed as peripheral T‐cell lymphomas, not otherwise specified. Only 18 cases of CD20‐positive mycosis fungoides (MF) have been previously reported. Here, we describe two cases of CD20‐positive MF. Patient 1 was an 84‐year‐old woman who presented with a 5‐year history of multiple pruritic erythematous papules coalescing into thin plaques over 80% of her body surface area. She expired after developing tumors and large cell transformation. Patient 2 was a 67‐year‐old woman with a long‐standing history of tumor stage MF with large cell transformation. She developed a nodular plaque while receiving topical and systemic therapy. In both cases, the neoplastic T‐cells demonstrated a CD4‐positive immunophenotype with loss of pan‐T‐cell markers and a monoclonal T‐cell receptor gamma gene rearrangement. CD20 was expressed by a significant population of the neoplastic T‐cells, but these T‐cells lacked expression of other B‐cell markers, including CD79a, CD19 and PAX5. This report adds to and summarizes the small body of literature describing CD20‐positive MF, and discusses diagnostic and clinical implications.

T-cell Receptor Signaling Activates an ITK/NF-κB/GATA-3 axis in T-cell Lymphomas Facilitating Resistance to Chemotherapy

Purpose: T-cell lymphomas are a molecularly heterogeneous group of non-Hodgkin lymphomas (NHL) that account for a disproportionate number of NHL disease-related deaths due to their inherent and acquired resistance to standard multiagent chemotherapy regimens. Despite their molecular heterogeneity and frequent loss of various T cell–specific receptors, the T-cell antigen receptor is retained in the majority of these lymphomas. As T-cell receptor (TCR) engagement activates a number of signaling pathways and transcription factors that regulate T-cell growth and survival, we examined the TCRs role in mediating resistance to chemotherapy. Experimental Design: Genetic and pharmacologic strategies were utilized to determine the contribution of tyrosine kinases and transcription factors activated in conventional T cells following TCR engagement in acquired chemotherapy resistance in primary T-cell lymphoma cells and patient-derived cell lines. Results: Here, we report that TCR signaling activates a signaling axis that includes ITK, NF-κB, and GATA-3 and promotes chemotherapy resistance. Conclusions: These observations have significant therapeutic implications, as pharmacologic inhibition of ITK prevented the activation of this signaling axis and overcame chemotherapy resistance. Clin Cancer Res; 23(10); 2506–15. ©2016 AACR.

Acute treatment of generalized pustular psoriasis of von Zumbusch with single-dose infliximab.

REFERENCES 1. Fern andez-Guarino M, Aldanondo I, Gonz alez-Garc ıa C, Garrido P, Marquet A, P erez-Garc ıa B, et al. Dermatosis perforante por gefinitib. Actas Dermosifiliogr 2006;97:208-11. 2. Gilaberte Y, Coscojuela C, V azquez C, Rosell o R, Vera J. Perforating folliculitis associated with tumor necrosis factor alpha inhibitors administered for rheumatoid arthritis. Br J Dermatol 2007;156:368-71. 3. Vano-Galvan S, Moreno C, Medina J, P erez-Garc ıa B, Garc ıaL opez JL, Jaen P. Perforating dermatosis in a patient receiving bevacizumab. J Eur Acad Dermatol 2009;23:972-4. 4. Minami-Hori M, Ishida-Yamamoto A, Komatsu S, Iiduka H. Transient perforating folliculitis induced by sorafenib. J Dermatol 2010;37:833-4. 5. Wolber C, Udvardi A, Tatzreiter G, Schneeberger A, Volc-Platzer B. Perforating folliculitis, angioedema, hand-foot syndrome e multiple cutaneous side effects in a patient treated with sorafenib. J Dtsch Dermatol Ges 2009;7:449-52.

Controversies and considerations in the diagnosis of primary cutaneous CD4⁺ small/medium T-cell lymphoma.

CONTEXT Primary cutaneous CD4⁺ small/medium T-cell lymphoma is a provisional and controversial entity with a broad differential diagnosis. Despite being an uncommon lymphoma, it is a frequent diagnostic consideration in cutaneous biopsies with a dense lymphoid infiltrate because it shows overlapping features with reactive lymphoid hyperplasia (pseudolymphoma) and a variety of other primary cutaneous and systemic lymphomas. However, proper classification of this process is important for determining patient prognosis and treatment options. OBJECTIVE To review the clinical, morphologic, immunophenotypic, and genetic features of primary cutaneous CD4⁺ small/medium T-cell lymphoma and contrast those features with entities in the differential diagnosis. DATA SOURCES Applicable literature will be reviewed with emphasis on current controversies and distinguishing characteristics. CONCLUSIONS Although many consider primary cutaneous CD4⁺ small/medium T-cell lymphoma to be indistinguishable from reactive lymphoid hyperplasia/pseudolymphoma, it can be differentiated from other primary cutaneous and systemic lymphomas. Patients with solitary lesions of primary cutaneous CD4⁺ small/medium T-cell lymphoma generally have an excellent prognosis. Nevertheless, a subset of patients who have been reported to meet criteria for this lymphoma have followed a more-aggressive course; however, those patients show some differing clinical, morphologic, and immunophenotypic features.

Protein gene product 9.5 (PGP9.5) expression in benign cutaneous mesenchymal, histiocytic, and melanocytic lesions: comparison with cellular neurothekeoma

Cellular neurothekeoma (CNTK) frequently enters the differential diagnosis of a benign dermal cellular proliferation. Diagnosis often relies on immunohistochemistry including the use of protein gene product 9.5 (PGP9.5). A previous study demonstrated PGP9.5 expression across a wide variety of soft tissue neoplasms. We explored the utility of this antibody in distinguishing CNTK from other benign dermal-based lesions. A cohort of CNTK (n=7) and benign cutaneous lesions of neural (n=28), fibrohistiocytic (n=23), fibroblastic (n=25), histiocytic (n=18), myofibroblastic (n=7), smooth muscle (n=14), and melanocytic (n=12) differentiations were immunostained with PGP9.5. Staining was graded by H-score and compared with CNTK. A significantly higher H-score was found in CNTK compared with the fibrohistiocytic (p=0.0001), histiocytic (p=0.0016), myofibroblastic (p=0.0003), smooth muscle (p<0.0001), and melanocytic (p=0.0004) groups, with the exceptions of plexiform fibrohistiocytic tumour, xanthoma, and xanthogranuloma. No significant difference was found when comparing CNTK with fibroblastic and neural lesions, with the exceptions of neurofibroma and perineurioma. In conclusion, PGP9.5 is helpful in distinguishing CNTK from most benign cutaneous fibrohistiocytic, histiocytic, myofibroblastic, smooth muscle, and melanocytic lesions. In addition to CNTK and neural lesions, PGP9.5 is also expressed in benign fibroblastic lesions, and therefore distinction of these lesions should not be based on PGP9.5 positivity.