Profound loss of T-cell receptor repertoire complexity in cutaneous T-cell lymphoma

Blood ◽  
2003 ◽  
Vol 102 (12) ◽  
pp. 4059-4066 ◽  
Author(s):  
Nikhil Yawalkar ◽  
Katalin Ferenczi ◽  
David A. Jones ◽  
Keiichi Yamanaka ◽  
Ki-Young Suh ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Lymphoma ◽  
Early Stage ◽  
Cell Repertoire ◽  
Early Stage Disease ◽  
Stage Disease ◽  
Beta Variable ◽  
Disease Stages ◽  
Complementarity Determining Region

Abstract Cutaneous T-cell lymphoma (CTCL) is a malignancy of skin-homing T cells. A major feature of CTCL is profound immunosuppression, such that patients with advanced mycosis fungoides or Sézary syndrome have been compared with patients with advanced HIV disease and are susceptible to opportunistic infection. The etiology of this immunosuppression is unclear. We analyzed peripheral blood T cells of patients with CTCL with stage I to IV disease, using a sensitive beta-variable complementarity-determining region 3 spectratyping approach. Our data revealed a profound disruption of the complexity of the T-cell repertoire, which was universally observed in patients with advanced disease (stages III and IV), and present in up to 50% of patients with early-stage disease (stages I and II). In most patients, multiple monoclonal and oligoclonal complementarity-determining region 3 (CDR3) spectratype patterns in many different beta-variable families were seen. Equally striking was a reduction of normal T cells (as judged by absolute CD4 counts) across multiple beta-variable families. In general, CTCL spectratypes were reminiscent of advanced HIV spectratypes published elsewhere. Taken together, these data are most consistent with a global assault on the T-cell repertoire in patients with CTCL, a process that can be observed even in early-stage disease. (Blood. 2003;102:4059-4066)

scholarly journals First-line non–anthracycline-based chemotherapy for extranodal nasal-type NK/T-cell lymphoma: a retrospective analysis from the CLCG

2020 ◽  
Vol 4 (13) ◽  
pp. 3141-3153
Author(s):  
Shu-Nan Qi ◽  
Yong Yang ◽  
Yu-Qin Song ◽  
Ying Wang ◽  
Xia He ◽  
...  
Keyword(s):  
T Cell ◽  
Survival Benefit ◽  
Cell Lymphoma ◽  
Early Stage ◽  
T Cell Lymphoma ◽  
Collaborative Group ◽  
First Line ◽  
Early Stage Disease ◽  
Nasal Type ◽  
Nk T Cell

Abstract The present study investigated the survival benefit of non–anthracycline (ANT)-based vs ANT-based regimens in a large-scale, real-world cohort of patients with extranodal natural killer (NK)/T-cell lymphoma, nasal type (ENKTCL). Within the China Lymphoma Collaborative Group (CLCG) database (2000-2015), we identified 2560 newly diagnosed patients who received chemotherapy with or without radiotherapy. Propensity score matching (PSM) and multivariable analyses were used to compare overall survival (OS) and progression-free survival (PFS) between the 2 chemotherapy regimens. We explored the survival benefit of non–ANT-based regimens in patients with different treatments in early-stage disease and in risk-stratified subgroups. Non–ANT-based regimens significantly improved survivals compared with ANT-based regimens. The 5-year OS and PFS were 68.9% and 59.5% for non–ANT-based regimens compared with 57.5% and 44.5% for ANT-based regimens in the entire cohort. The clinical advantage of non–ANT-based regimens was substantial across the subgroups examined, regardless of stage and risk-stratified subgroup, and remained significant in early-stage patients who received radiotherapy. The survival benefits of non–ANT-based regimens were consistent after adjustment using multivariable and PSM analyses. These findings provide additional evidence supporting non–ANT-based regimens as a first-line treatment of patients with ENKTCL.

Characteristics and outcomes of extranodal NK/t-cell lymphoma (ENKL): A North American (NA) multi-institutional experience.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 8060-8060
Author(s):  
Lauren Shizue Maeda ◽  
Jessica L. Geiger ◽  
Kerry J. Savage ◽  
Jim Rose ◽  
Lauren C. Pinter-Brown ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Lymphoma ◽  
Early Stage ◽  
Combined Modality Therapy ◽  
Progression Free Survival ◽  
T Cell Lymphoma ◽  
Stage I ◽  
Stage Iii ◽  
Cell Transplant ◽  
Early Stage Disease

8060 Background: ENKL is a rare and aggressive subtype of peripheral T-cell lymphoma. Due to its geographic predilection there is a paucity of data on clinical experiences from non-Asian countries. The purpose of this study was to analyze characteristics and outcomes of patients (pts) with ENKL identified from major academic centers in NA. Methods: Pts with newly diagnosed CD56+ ENKL were retrospectively identified. Analyses included disease characteristics, ethnicity, therapy, and outcomes. Results: 115 pts (63.5% Caucasian, 20% Asian, 16.5% other) were identified across 10 centers diagnosed between 5/1990-5/2011 (Era 1: pre-2000, n=16; Era 2: 2000-2005, n=45; Era 3: post-2005, n=54). Median age was 52 years (19-88). 75 (65%) had stage I/II disease and were treated with combined modality therapy (CMT) n=48, chemotherapy (CT) n=14 or radiotherapy (RT) n=14. 40 pts had stage III/IV disease and were treated with CT (n=23), CMT (n=12) or RT (n=5). CT regimens used alone or in CMT were either anthracycline-based (n=68) or other (n=29). 63% of stage I/II pts and 40% with stage III/IV achieved complete remission (CR). 30 pts underwent a stem cell transplant (SCT); 14 in first CR and 16 at progression/relapse (autologous, n=21; allogeneic, n=9). Pts with stage I/II disease had a better progression-free survival (PFS) and overall survival (OS) compared with stage III/IV (12 vs 5.2 months (p=0.003) and 41.5 vs 8.9 months (p<0.0001), respectively). For all stages, treatment with CMT compared with CT or RT alone was also associated with better PFS and OS, 18.0 vs 3.9 months (p<0.0001), and 41.5 vs 10.2 months (p=0.002) respectively. Non-anthracycline-based regimens were associated with better PFS (p=0.001) and OS (p=0.045). No survival differences were seen between Asian and non-Asian pts. Conclusions: This series represents one of the largest experiences of ENKL in NA. Our data are consistent with Asian studies in: 1) majority of pts present with early stage disease; 2) overall poor outcome; 3) superiority of CMT and non-anthracycline regimens. Advances in understanding biology and international collaborative efforts are required to improve outcome in this rare entity.

scholarly journals A Retrospective Analysis of Outcomes of Diffuse Large B Cell Lymphoma (DLBCL) in the Elder Patients in China

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5410-5410
Author(s):  
Peng Liu ◽  
Ying Han ◽  
Jianliang Yang ◽  
Xiaohui He ◽  
Changgong Zhang ◽  
...  
Keyword(s):  
Cell Lymphoma ◽  
Early Stage ◽  
B Cell Lymphoma ◽  
Disease Stage ◽  
Early Stage Disease ◽  
Large B Cell Lymphoma ◽  
Elder Patients ◽  
Stage Disease ◽  
Ann Arbor ◽  
Advanced Disease Stage

Abstract Background: Elderly patients with diffuse large B-cell lymphoma (DLBCL) have a worse prognosis compared to the younger population, since older age is associated with comorbidity and suboptimal performance status leading to intolerance of chemo-immunotherapy. The outcome of DLBCL in the older patients (> 60 years) was well described in clinical trials with reported 5-year overall survival (OS) of 50-80% (Coiffier et al., N Engl J Med 2002). Since this group is often precluded from clinical trials and population-based studies are limited, optimal treatment strategy for the old patients with DLBCL remains controversial. Here, we describe a Chinese real-world experience of management of elderly DLBCL patients treated at National Cancer Hospital, China. Methods: This is a single-center, retrospective analysis of consecutive DLBCL patients aged ≥60 who planned to receive chemotherapy +/- rituximab. The standard regimens included 3-4 cycles (early stage disease) or 6 cycles (advanced) of R-CHOP like regimens (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone) followed by two rituximab doses in fit patients; R-miniCHOP for unfit and R-CE(etoposide)OP for frail elder patients. Patient data including baseline characteristics, histology, clinical parameters, and treatment outcomes were extracted from hospital medical records. The primary endpoint was progression-free survival (PFS); secondary endpoint was OS. Statistical analyses included descriptive statistics and Kaplan Meier estimates. Results: From June 2006 to December 2012, 349 patients aged ≥60 years were included, in which 204 patients were aged <70 years (Table 1). 326 patients received chemotherapy or chemo-immunotherapy with rituximab. Median follow up was 82 months. Five year PFS and OS of the elder patients were 45.8% and 51.9%, respectively. Significant difference was seen between patients < 70 years and those ≥70 years in terms of PFS (51.0% vs 38.6%, p=0.030) and OS (58.3% vs 42.8%, p=0.007) (Figure 1). Patients with early-stage disease (Ann Arbor StageⅠ/Ⅱ) had better 5-year PFS (60.1% vs 23.5%, p<0.001) and OS (65.3% vs 30.9%, p<0.001) than patients with advanced disease stage (Ann Arbor Stage III/IV) (Figure2). In addition, regimen including rituximab significantly improved the survival than chemotherapy alone (5-year PFS: 37.3% vs 64.0%, p<0.001; 5-year OS: 44.5% vs 69.3%, p<0.001), especially in patients ≥70 years, which almost doubled 5-year PFS and OS (5-year PFS: 25.4% vs 50.7%, p<0.001; 5-year OS: 28.8% vs 56.0%, p<0.001) (Figure3). Conclusions: Elder age (≥70 years) and advanced disease stage (Ann Arbor Stage III/IV) are associated with poor PFS and OS in Chinese elder DLBCL patients. The addition of rituximab significantly improves the survival compared to chemotherapy alone, especially in patients aged ≥70 years. These findings underscore the importance of personalized evaluation and treatment in elder patients with DLBCL. Disclosures No relevant conflicts of interest to declare.

scholarly journals Recent advances in understanding and managing cutaneous T-cell lymphomas

F1000Research ◽  
2020 ◽  
Vol 9 ◽  
pp. 331
Author(s):  
Patrick M. Brunner ◽  
Constanze Jonak ◽  
Robert Knobler
Keyword(s):  
T Cell ◽  
Early Stage ◽  
Disease Stage ◽  
Treatment Modalities ◽  
Early Stage Disease ◽  
T Cell Lymphomas ◽  
Stage Disease ◽  
Related Quality ◽  
Health Related ◽  
Stage Ivb

Cutaneous T-cell lymphomas (CTCLs) comprise a heterogeneous group of extranodal non-Hodgkin lymphomas involving primarily the skin and mycosis fungoides is its most frequent entity. Whereas most patients show an indolent course in early disease (clinical stages IA to IIA), some patients progress to advanced disease (stage IIB or higher), and the 5-year survival rate is unfavorable: only 47% (stage IIB) to 18% (stage IVB). Except for allogeneic stem cell transplantation, there is currently no cure for CTCL and thus treatment approaches are palliative, focusing on patients’ health-related quality of life. Our aims were to review the current understanding of the pathogenesis of CTCL, such as the shift in overall immune skewing with progressive disease and the challenges of making a timely diagnosis in early-stage disease because of the lack of reliable positive markers for routine diagnostics, and to discuss established and potential treatment modalities such as immunotherapy and novel targeted therapeutics.

scholarly journals T-cell receptor sequencing of early stage breast cancer tumors identifies altered clonal structure of the T-cell repertoire

2017 ◽  
Author(s):  
John F. Beausang ◽  
Amanda J. Wheeler ◽  
Natalie H. Chan ◽  
Violet R. Hanft ◽  
Frederick M. Dirbas ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
T Cell ◽  
Breast Tissue ◽  
Normal Breast Tissue ◽  
Early Stage ◽  
Normal Breast ◽  
Early Stage Breast Cancer ◽  
Clonal Structure ◽  
Cell Repertoire

Tumor infiltrating T-cells play an important role in many cancers, and can improve prognosis and yield therapeutic targets. We characterized T-cells infiltrating both breast cancer tumors and the surrounding normal breast tissue to identify T-cells specific to each, as well as their abundance in peripheral blood. Using immune profiling of the T-cell beta chain repertoire in 16 patients with early stage breast cancer, we show that the clonal structure of the tumor is significantly different from adjacent breast tissue, with the tumor containing approximately 3-fold more T-cells, but with a lower fraction of unique sequences and higher clonality compared to normal breast. The clonal structure of T-cells in blood and normal breast is more similar than between blood and tumor and can be used to distinguish tumor from normal breast tissue in 14 of 16 patients. Many T-cells overlap between tissues from the same patient, including approximately 50% of T-cells between tumor and normal breast. Both solid tissues contain high-abundance "enriched" sequences that are absent or of low abundance in the other tissue. Many of these T-cells are either not detected or detected with very low frequency in the blood, suggesting the existence of separate compartments of T-cells in both tumor and normal breast. Enriched T-cell sequences are typically unique to each patient, but there is a subset of sequences that are shared between many different patients. We show that most of these are commonly generated sequences and thus unlikely to play an important role in the tumor microenvironment.

Primary Mediastinal B-Cell Lymphoma: The Dilemma of Radiotherapy

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 30-31
Author(s):  
Filipa Saraiva ◽  
Christopher J. Saunders ◽  
Margarida Fevereiro ◽  
Alexandra Monteiro ◽  
Aida B Sousa
Keyword(s):  
B Cell ◽  
Conflicts Of Interest ◽  
Cell Lymphoma ◽  
Early Stage ◽  
Autologous Transplantation ◽  
B Cell Lymphoma ◽  
Molecular Characteristics ◽  
Early Stage Disease ◽  
Free Survival ◽  
Stage Disease

Introduction: According to the WHO classification, primary mediastinal (thymic) large B-cell lymphoma (PMBCL) is a distinct entity, which has a close relationship with nodular sclerosing classical Hodgkin's lymphoma (cHL) in terms of clinical and molecular characteristics and sharing an excellent prognosis. When PMBCL is treated with R-CHOP, the addition of radiotherapy (RT) turns more than 90% of positron emission tomography (PET) positive cases into complete remissions (CR) and increases 5-year overall survival (OS) to 93%. However, the fear of potential late toxicities due to RT, has led an increasing number of centers to favor more intensive regimens like DA-EPOCH-R without RT. This controversy is deepened by the recent comparison between the latter regime with R-CHOP, unfavorable to the DA-EPOCH-R for toxicity reasons. Objective: Evaluate the effectiveness and late toxicities of R-CHOP plus RT in our center and secondarily compare these results with the ones obtained in our cHL patients with bulky and early stage disease. Methods: Retrospective analysis of patients with PMBCL treated between Jan/2007 and Dec/2017 according to clinical characteristics, late toxicities, rate of CR, OS and disease-free survival (DFS) estimated by Kaplan-Meier method. Results: In 32 patients with a median age of 34 years (23-70), 56% were male, 91% had limited stage and 6% had an unfavorable IPI. The rate of CR was 91% (2 patients needed second line therapy to achieve CR) with 2 relapses (at 6 and 11 months, respectively) rescued with autologous transplantation. Three deaths were recorded due to disease progression. With a median follow-up of 86 months, OS and DFS at 10 years were 91% and 93%, respectively. As for late toxicities, besides 2 cases of severe pulmonary fibrosis, there were no other relevant late toxicities registered. These results overlap those obtained in our cHL patients with bulky and early stage disease treated with Stanford V plus RT with an OS and an event free survival of 93% and 84%, respectively. Conclusion: These results support PMBCL's excellent prognosis, parallel to that of cHL. Given the low probability of late toxicities with this regimen our data uphold against the therapeutic strategy of more intensive regimens, that have an increased management complexity and are clinically more toxic. Disclosures No relevant conflicts of interest to declare.

Anti-Tumor TCF1+ CD8 T Cells are Functionally Diverse and Evolve During Tumorigenesis and Progression

2020 ◽  
Vol 154 (Supplement_1) ◽  
pp. S5-S6
Author(s):  
Jason Schenkel ◽  
Rebecca Herbst ◽  
David Canner ◽  
Amy Li ◽  
Michelle Hillman ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Early Stage ◽  
Cd8 T Cell ◽  
Temporal Analysis ◽  
T Cell Response ◽  
Target Cells ◽  
Early Stage Disease ◽  
Longitudinal Response

Abstract CD8+ T cells drive protective responses against infection and cancer. In the context of chronic antigen stimulation, CD8+ T cells become progressively dysfunctional, losing the ability to proliferate, secrete cytokines, and kill target cells. While dysfunctional CD8 T cells have been characterized in infection, studies examining longitudinal responses in tumors have been limited. Here, in an autochthonous model of lung adenocarcinoma using high dimensional flow cytometry and single cell RNA sequencing, we demonstrate that tumor specific CD8 T cell heterogeneity is dynamic, revealing multiple dysfunctional-like CD8 T cell populations. Among these states, we identify TCF-1+ CD8 T cells, a population previously associated with superior functionality. Temporal analysis revealed heterogeneity within the TCF-1+ CD8+ T cell compartment - SlamF6+ CD8 T cells were predominant in early stage disease, while SlamF6- CD8 T cells appeared later and were the majority during progression. Functionally, the SlamF6+ population was proliferative and expressed more inhibitory receptors than SlamF6- cells. However, SlamF6+ CD8 T cells gradually lost the ability to divide and secrete cytokines over the course of tumorigenesis, demonstrating that they become dysfunctional over time. Collectively, our results provide new insights into longitudinal response of TCF-1+ T cells over the course of tumorigenesis and have therapeutic implications for modulating the anti-tumor T cell response.

Extranodal Head and Neck Mantle Cell Lymphoma: Characteristics, Treatment, and Survival

2021 ◽  
pp. 000348942110251
Author(s):  
Christopher T. Breen ◽  
Janet Chao ◽  
Saral Mehra ◽  
Nikita Kohli
Keyword(s):  
Mantle Cell Lymphoma ◽  
Head And Neck ◽  
Cumulative Incidence ◽  
Cell Lymphoma ◽  
Early Stage ◽  
Anatomic Site ◽  
Early Stage Disease ◽  
Stage Disease ◽  
Significant Difference ◽  
Mantle Cell

Objectives: To describe disease characteristics and treatment and to analyze survival and mortality for extranodal mantle cell lymphoma (MCL) of the head and neck. Methods: Patients with extranodal MCL—excluding primary sites in the salivary glands, eye, and adnexa—were identified from the Surveillance, Epidemiology, and End Results (SEER) 18 Registries (2000-2015). Overall survival (OS) and cumulative incidence of MCL and non-MCL mortality were calculated. Factors associated with MCL and non-MCL mortality were analyzed with cause-specific hazard models. Results: Five hundred nine patients met criteria for descriptive analysis and 294 patients met criteria for survival analysis, with a median follow-up of 58 months. The most common sites for MCL were the oropharynx (66.0%), nasopharynx (19.1%), and oral cavity (8.4%). The most common treatment received was chemotherapy alone (48.9%), followed by chemoradiation therapy (16.9%), and radiation therapy alone (10.4%). The proportion of cases diagnosed as early-stage disease ranged from 31% of sinonasal MCLs to 83% of laryngeal MCLs. At 5 years, OS was 63% (95% CI: 57%-69%). There was no significant difference in OS ( P = .79), cumulative incidence of MCL mortality ( P = .76), or cumulative incidence of non-MCL mortality ( P = .98) by anatomic site. Comparing early-stage to late-stage disease, there was no significant difference in OS ( P = .38), cumulative incidence of MCL mortality ( P = .07), or cumulative incidence of non-MCL mortality ( P = .14). Multivariate analysis showed increased hazard of MCL mortality for patients that were older or that presented with stage III or stage IV disease. Conclusion: The oropharynx is the most common subsite of head and neck MCLs, followed by the nasopharynx. Primary head and neck MCLs appear to present at an earlier stage than MCLs of other regions. In particular, laryngeal and hypopharyngeal MCLs may present as stage I or II disease.

scholarly journals High-scatter T cells: a reliable biomarker for malignant T cells in cutaneous T-cell lymphoma

Blood ◽  
2011 ◽  
Vol 117 (6) ◽  
pp. 1966-1976 ◽  
Author(s):  
Rachael A. Clark ◽  
Jeffrey B. Shackelton ◽  
Rei Watanabe ◽  
Adam Calarese ◽  
Kei-ichi Yamanaka ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Skin Diseases ◽  
Cell Lymphoma ◽  
Early Stage ◽  
T Cell Lymphoma ◽  
Cutaneous T Cell Lymphoma ◽  
Inflammatory Skin Diseases ◽  
Inflammatory Skin ◽  
Malignant T Cells

Abstract In early-stage cutaneous T-cell lymphoma (CTCL), malignant T cells are confined to skin and are difficult to isolate and discriminate from benign reactive cells. We found that T cells from CTCL skin lesions contained a population of large, high-scatter, activated skin homing T cells not observed in other inflammatory skin diseases. High-scatter T (THS) cells were CD4+ in CD4+ mycosis fungoides (MF), CD8+ in CD8+ MF, and contained only clonal T cells in patients with identifiable malignant Vβ clones. THS cells were present in the blood of patients with leukemic CTCL, absent in patients without blood involvement, and contained only clonal malignant T cells. The presence of clonal THS cells correlated with skin disease in patients followed longitudinally. Clonal THS cells underwent apoptosis in patients clearing on extracorporeal photopheresis but persisted in nonresponsive patients. Benign clonal T-cell proliferations mapped to the normal low-scatter T-cell population. Thus, the malignant T cells in both MF and leukemic CTCL can be conclusively identified by a unique scatter profile. This observation will allow selective study of malignant T cells, can be used to discriminate patients with MF from patients with other inflammatory skin diseases, to detect peripheral blood involvement, and to monitor responses to therapy.

scholarly journals Diagnostic 2-Gene Classifier in Early-Stage Mycosis Fungoides: A Retrospective Multicenter Study

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2772-2772
Author(s):  
Pia Rude Nielsen ◽  
Jens Ole Eriksen ◽  
Lise M. Lindahl ◽  
Ulrike Wehkamp ◽  
Gitte Rinds Andersen ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Protein Expression ◽  
B Cell ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Early Stage ◽  
Tumor Stage ◽  
Skin Biopsies

Introduction Mycosis fungoides (MF) is the most common type of cutaneous T-cell lymphoma and represents more than 50% of all primary cutaneous lymphomas. It is typically an indolent disorder with limited patches and plaques. One third, however, experience progression with ulcerating tumors and possible further systemic dissemination. Currently, the diagnosis of MF is based on clinical and histological examinations, but this has proven, especially in early-stage disease, to be challenging due to similarities with several benign skin conditions such as psoriasis, pityriasis lichenoides chronica, and dermatitis. Despite intensive research, reliable diagnostic biomarkers for early-stage MF are still needed. This study aims to identify a diagnostic classifier that could support the diagnostic workup leading to an exact diagnosis in the early-stage of this complex and potentially lethal disease. Methods We analyzed 43 formalin-fixed and paraffin-embedded (FFPE) skin biopsies from 36 patients with early-stage MF. Seven patients had 2 longitudinal biopsies available for analysis. These were compared with FFPE skin biopsies from patients with unspecified dermatitis (n=29) and healthy skin (n=12). All samples were collected from the archives of the Department of Pathology, Region Zealand, Denmark in the period 1990-2016. The histological samples were revised and clinical records were reviewed to establish the diagnosis and stage for each patient. Total RNA was extracted from ten 10-μm sections of FFPE tissue, and 50-100 ng of RNA was analyzed on the NanoString nCounter platform by applying the Myeloid Innate Immunity Panel, which quantifies the expression of 800 immune related genes. Differentially expressed genes (DEG, 2-fold change, p<0.05), were assessed by ANOVA, and a Support Vector Machine (SVM) diagnostic classifier was built based on 2-10 DEG and evaluated by 10-fold cross-validation. The classifier was tested on an independent, early-stage MF patient cohort (n=27). Protein expression was validated with immunohistochemistry and digitally analyzed by applying a specifically designed algorithm with the Leica Tissue IA 2.0 software. Double immunofluorescence staining protocols were developed to identify subtypes of TRAF1 positive cells in combination with various macrophage/dendritic cell markers (CD168, CD63, CD11c, CD1a, CD14, and S100) as well as T-cell (CD3) and B-cell (CD20) markers. Results A diagnostic classifier consisting of TOX and TRAF1 was able to distinguish early-stage MF from dermatitis with an overall accuracy of 85% in the discovery cohort and 80% in an independent validation cohort. TOX and TRAF1 protein levels were significantly elevated in early-stage MF compared to the dermatitis group (p < 0.0001). TOX and TRAF1 were also significantly increased in the progression from early-stage MF to tumor stage MF (p=0.003 and p=0.004, respectively). Subtypes of TRAF1-positive dendritic cells in early-stage MF consisted primarily of S100+ cells in both the epidermal and dermal compartment. A few TRAF1+ cells in the Pautrier microabscesses stained double positive with CD11c. In tumor stage MF the majority of TRAF1+ dendritic cells counterstained with CD1a and CD11c. Both neoplastic and reactive T-cells (CD3+) expressed TRAF1 in a minor degree in early-stage MF, while T-cells in tumor stage MF expressed TRAF1 in a much higher degree and the majority of the neoplastic T-cells were TRAF1 positive. No macrophages (CD68+ or CD163+) or B-cells double stained with TRAF1. Conclusion In the present study, we developed a two gene mRNA diagnostic classifier discriminating early-stage MF from dermatitis. The protein expression level of TOX and TRAF1 confirmed our gene expression levels and identified a highly significant difference between early-stage MF and dermatitis, which can prove useful in diagnostics of early-stage MF. Disclosures Andersen: Novo Nordisk: Other: Holds stock in Novo Nordisk; Hologic Deutchland GmbH: Research Funding. Odum:Micreos human Health B.V: Consultancy. Litman:Leo Pharma A/S: Research Funding. Gjerdrum:Nanostring Technologies: Other: Recieves founding from NanoString regarding a B-cell lymphoma research project., Research Funding; Celgene: Other: Celgene has funded the participation in ASH 2019.

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