Sluzevich, Jason C.

Background: Subcutaneous lymphomas are a heterogeneous group of diseases with variable clinical behavior that ranges from a lymphoproliferative disorder to an aggressive cytotoxic lymphoma. Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is an uncommon, often indolent cutaneous lymphoma that localizes to the subcutaneous adipose tissue. These tumors exhibit an alpha/beta phenotype (abSPTCL). Primary cutaneous gamma-delta T-cell lymphoma (PCgdTCL) is a rare, highly aggressive lymphoma that frequently involves the subcutaneous adipose tissue. The goal of this study is to identify key inflammatory and oncogenic pathways in SPTCL and PCgdTCL to determine which mutational or expression patterns differentiate abSPTCL and PCgdTCL. A comprehensive catalog of cancer gene expression profiles generated via RNA sequencing on patient samples is essential to understand tumorigenesis and to develop effective therapies. Methods: We performed transcriptomic profiling analysis using RNA sequencing in lesional skin biopsies from patients of abSPTCL (n=10), PCgdTCL (n=9), and controls (n=5). Differential analyses were performed on the entire transcriptomic profiles among the 3 groups. Results: Although the transcriptomic profiles of abSPTCL and PCgdTCL samples had similarities, there were notable differences between these groups that may elucidate unique pathways that propagate each disease. In contrast to abSPTCL, PCgdTCL samples demonstrated upregulation of cell motility and proliferation, and downregulation of pathways involving apoptosis and tumor necrosis factor production. The most significantly upregulated gene pathways in both abSPTCL and PCgdTCL samples were those involving immune and inflammatory response, viral defense, type I interferon signaling, interferon-gamma-mediated signaling, and positive regulation of T cell proliferation. The most significantly downregulated gene pathways in the two groups were those involving cell adhesion, rRNA processing and translation, and extracellular matrix organization. The top 5 upregulated immune response and downregulated cell adhesion hub genes for abSPTCL highlighted by gene interaction network analysis included: TNF, CTLA4, CD86, IL10, CCR5 & ITGB5, ITGA8, VWF, APP, CDH5, respectively. Conclusion: Our transcriptomic profiling pinpoints disease-related enrichment pathways and gene functions in abSPTCL and PCgdTCL patients, which may shed light on molecular mechanisms that drive disease activity. Hub genes in abSPTCL represent potential drug targets for further development of novel therapies. Disclosures Mangold: Kirin:Membership on an entity's Board of Directors or advisory committees;Elorac:Research Funding;Sun Pharma:Research Funding;MiRagen:Research Funding;Solagenix:Research Funding.

PURPOSEMore than 80% of patients who undergo sentinel lymph node (SLN) biopsy have no nodal metastasis. Here, we describe a model that combines clinicopathologic and molecular variables to identify patients with thin- and intermediate-thickness melanomas who may forgo the SLN biopsy procedure because of their low risk of nodal metastasis.PATIENTS AND METHODSGenes with functional roles in melanoma metastasis were discovered by analysis of next-generation sequencing data and case-control studies. We then used polymerase chain reaction to quantify gene expression in diagnostic biopsy tissue across a prospectively designed archival cohort of 754 consecutive thin- and intermediate-thickness primary cutaneous melanomas. Outcome of interest was SLN biopsy metastasis within 90 days of melanoma diagnosis. A penalized maximum likelihood estimation algorithm was used to train logistic regression models in a repeated cross-validation scheme to predict the presence of SLN metastasis from molecular, clinical, and histologic variables.RESULTSExpression of genes with roles in epithelial-to-mesenchymal transition (glia-derived nexin, growth differentiation factor 15, integrin-β3, interleukin 8, lysyl oxidase homolog 4, transforming growth factor-β receptor type 1, and tissue-type plasminogen activator) and melanosome function (melanoma antigen recognized by T cells 1) were associated with SLN metastasis. The predictive ability of a model that only considered clinicopathologic or gene expression variables was outperformed by a model that included molecular variables in combination with the clinicopathologic predictors Breslow thickness and patient age (area under the receiver operating characteristic curve, 0.82; 95% CI, 0.78 to 0.86; SLN biopsy reduction rate, 42%; negative predictive value, 96%).CONCLUSIONA combined model that included clinicopathologic and gene expression variables improved the identification of patients with melanoma who may forgo the SLN biopsy procedure because of their low risk of nodal metastasis.

Pulmonary nocardiosis is a severe and uncommon opportunistic infection caused by Nocardia species. We present a patient with cryptogenic organizing pneumonia who was receiving long-term immunosuppressive therapy, whose treatment course was complicated by cutaneous and pulmonary nocardiosis. Tissue cultures confirmed Nocardia brasiliensis. Nocardiosis should be a diagnostic consideration for patients treated with long-term immunosuppression who have worsening pulmonary symptoms and relapsing pustular skin lesions.

Background/Purpose: To describe the findings and clinical course of a patient with scleromyxedema complicated by retinal vasculitis and macular edema. Methods: Interventional case report. Results: A 64-year old Caucasian woman with recently diagnosed, biopsy proven scleromyxedema presented with decreased visual acuity (20/50 OD; 20/100 OS) due to retinal vasculitis and macular edema. She received intravitreal bevacizumab and subtenon's triamcinolone acetonide for the macular edema, and bilateral pars plana vitrectomies were required for vitreous hemorrhages. Monthly intravenous infusions of immunoglobulins (IVIG) resulted in resolution of the macular edema and vasculitis, and stabilization of the VA (20/40 OD; counting fingers at 6 feet OS). Conclusion: Scleromyxedema may be complicated by retinal vasculitis and macular edema. Treatment with corticosteroids and vascular endothelial growth factor inhibitors may be minimally effective but IVIG should be considered for both the ocular and systemic findings.

Primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL-LT) is a rare diffuse large B-cell lymphoma confined to the skin of the legs. The typical presentation is characterized by solitary or multiple growing plaques, usually confined to one leg. We report a case of PCDLBCL-LT of activated B-cell subtype characterized by multiple local relapses in the legs, initially, and systemic relapses about seven years after the diagnosis. Local relapses were sensitive to radiation therapy. Cutaneous and systemic relapses responded well to immunomodulatory therapy with lenalidomide followed by Bruton's tyrosine kinase inhibition with ibrutinib. Ibrutinib is the only treatment that resulted in long-lasting complete remission. Lenalidomide and especially ibrutinib appear to have a significant activity against this lymphoma and should be incorporated in the treatment of this resistant and aggressive lymphoma. To our knowledge, this is the first case of PCDLBCL-LT reported in the literature exhibiting a complete response to ibrutinib.