HLA-DR Helps to Differentiate Erythrodermic Cutaneous T-cell Lymphoma from Erythrodermic Inflammatory Dermatoses in Flow Cytometry


  • Jingru Sun Department of Dermatology and Venereology, Peking University First Hospital, Beijing 100034, China
  • Ran You Department of Clinical Laboratory, Peking University First Hospital, Beijing 100034, China
  • Beini Lyu Peking University Institute for Global Health and Development, Beijing, China
  • Xueying Li Department of Biostatistics, Peking University First Hospital, Beijing 100034, China
  • Yumei Gao Department of Dermatology and Venereology, Peking University First Hospital, Beijing 100034, China
  • Yujie Wen Department of Dermatology and Venereology, Peking University First Hospital, Beijing 100034, China
  • Chenxue Qu Department of Clinical Laboratory, Peking University First Hospital, Beijing 100034, China
  • Yang Wang Department of Dermatology and Venereology, Peking University First Hospital, Beijing 100034, China




Erythroderma, erythrodermic cutaneous T-cell lymphoma, erythrodermic inflammatory dermatoses, flow cytometry, HLA-DR, T helper 17 cells


Differential diagnosis of erythroderma is challenging in dermatology, especially in differentiating erythrodermic cutaneous T-cell lymphoma from erythrodermic inflammatory dermatoses. This study retrospectively reviewed the peripheral blood flow cytometric results of 73 patients diagnosed with erythroderma at Peking University First Hospital from 2014 to 2019. The flow cytometry antibody panel included white blood cell markers, T-cell markers, B-cell markers, T-cell activation markers, and T helper cell differentiation markers. Features of the cell surface antigens were compared between 34 patients with erythrodermic cutaneous T-cell lymphoma and 39 patients with erythrodermic inflammatory dermatoses. The percentage of HLA-DR+/CD4+T cells was the most pronounced marker to distinguish erythrodermic cutaneous T-cell lymphoma from erythrodermic inflammatory dermatoses, with a threshold of 20.85% (sensitivity 96.77%, specificity 70.37%, p = 0.000, area under the curve (AUC) 0.882), suggesting its potential capability in the differential diagnosis of erythrodermic cutaneous T-cell lymphoma from erythrodermic inflammatory dermatoses. Moreover, in contrast to erythrodermic inflammatory dermatoses, the percentage of Th17 cells was significantly downregulated in erythrodermic cutaneous T-cell lymphoma (p = 0.001), demonstrating a dysregulated immune environment in erythrodermic cutaneous T-cell lymphoma.


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Hwang ST, Janik JE, Jaffe ES, Wilson WH. Mycosis fungoides and Sezary syndrome. Lancet 2008; 371: 945-957.

https://doi.org/10.1016/S0140-6736(08)60420-1 DOI: https://doi.org/10.1016/S0140-6736(08)60420-1

Larocca C, Kupper T. Mycosis fungoides and Sezary syndrome: an update. Hematol Oncol Clin North Am 2019; 33: 103-120.

https://doi.org/10.1016/j.hoc.2018.09.001 DOI: https://doi.org/10.1016/j.hoc.2018.09.001

Jawed SI, Myskowski PL, Horwitz S, Moskowitz A, Querfeld C. Primary cutaneous T-cell lymphoma (mycosis fungoides and Sézary syndrome): part I. Diagnosis: clinical and histopathologic features and new molecular and biologic markers. J Am Acad Dermatol 2014; 70: 205.e201-216; quiz 221-202.

https://doi.org/10.1016/j.jaad.2013.07.049 DOI: https://doi.org/10.1016/j.jaad.2013.07.049

Vonderheid EC, Bernengo MG, Burg G, Duvic M, Heald P, Laroche L, et al. Update on erythrodermic cutaneous T-cell lymphoma: report of the International Society for Cutaneous Lymphomas. J Am Acad Dermatol 2002; 46: 95-106.

https://doi.org/10.1067/mjd.2002.118538 DOI: https://doi.org/10.1067/mjd.2002.118538

Scarisbrick JJ, Hodak E, Bagot M, Stranzenbach R, Stadler R, Ortiz-Romero PL, et al. Blood classification and blood response criteria in mycosis fungoides and Sezary syndrome using flow cytometry: recommendations from the EORTC cutaneous lymphoma task force. Eur J Cancer 2018; 93: 47-56.

https://doi.org/10.1016/j.ejca.2018.01.076 DOI: https://doi.org/10.1016/j.ejca.2018.01.076

Hristov AC, Vonderheid EC, Borowitz MJ. Simplified flow cytometric assessment in mycosis fungoides and Sezary syndrome. Am J Clin Pathol 2011; 136: 944-953.

https://doi.org/10.1309/AJCP09OTJOYAVZZK DOI: https://doi.org/10.1309/AJCP09OTJOYAVZZK

Horna P, Wang SA, Wolniak KL, Psarra K, Almeida J, Illingworth AJ, et al. Flow cytometric evaluation of peripheral blood for suspected Sezary syndrome or mycosis fungoides: international guidelines for assay characteristics. Cytometry B Clin Cytom 2021; 100: 142-155.

https://doi.org/10.1002/cyto.b.21878 DOI: https://doi.org/10.1002/cyto.b.21878

Guitart J. Sezary syndrome and mycosis fungoides flow cytometric evaluation:the clinicians' perspective. Cytometry B Clin Cytom 2021; 100: 129-131.

https://doi.org/10.1002/cyto.b.21870 DOI: https://doi.org/10.1002/cyto.b.21870

Olsen E, Vonderheid E, Pimpinelli N, Willemze R, Kim Y, Knobler R, et al. Revisions to the staging and classification of mycosis fungoides and Sezary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the cutaneous lymphoma task force of the European Organization of Research and Treatment of Cancer (EORTC). Blood 2007; 110: 1713-1722.

https://doi.org/10.1182/blood-2007-03-055749 DOI: https://doi.org/10.1182/blood-2007-03-055749

Nagler AR, Samimi S, Schaffer A, Vittorio CC, Kim EJ, Rook AH. Peripheral blood findings in erythrodermic patients: importance for the differential diagnosis of Sezary syndrome. J Am Acad Dermatol 2012; 66: 503-508.

https://doi.org/10.1016/j.jaad.2011.06.014 DOI: https://doi.org/10.1016/j.jaad.2011.06.014

Bernengo MG, Novelli M, Quaglino P, Lisa F, De Matteis A, Savoia P, et al. The relevance of the CD4+ CD26- subset in the identification of circulating Sezary cells. Br J Dermatol 2001; 144: 125-135.

https://doi.org/10.1046/j.1365-2133.2001.04014.x DOI: https://doi.org/10.1046/j.1365-2133.2001.04014.x

Harmon CB, Witzig TE, Katzmann JA, Pittelkow MR. Detection of circulating T cells with CD4+CD7- immunophenotype in patients with benign and malignant lymphoproliferative dermatoses. J Am Acad Dermatol 1996; 35: 404-410.

https://doi.org/10.1016/S0190-9622(96)90605-2 DOI: https://doi.org/10.1016/S0190-9622(96)90605-2

Vonderheid EC, Hou JS. CD4(+)CD26(-) lymphocytes are useful to assess blood involvement and define B ratings in cutaneous T cell lymphoma. Leuk Lymphoma 2018; 59: 330-339.

https://doi.org/10.1080/10428194.2017.1334123 DOI: https://doi.org/10.1080/10428194.2017.1334123

Boonk SE, Zoutman WH, Marie-Cardine A, van der Fits L, Out-Luiting JJ, Mitchell TJ, et al. Evaluation of immunophenotypic and molecular biomarkers for Sezary syndrome using standard operating procedures: a multicenter study of 59 patients. J Invest Dermatol 2016; 136: 1364-1372.

https://doi.org/10.1016/j.jid.2016.01.038 DOI: https://doi.org/10.1016/j.jid.2016.01.038

Murray D, McMurray JL, Eldershaw S, Pearce H, Davies N, Scarisbrick JJ, et al. Progression of mycosis fungoides occurs through divergence of tumor immunophenotype by differential expression of HLA-DR. Blood Advances 2019; 3: 519-530.

https://doi.org/10.1182/bloodadvances.2018025114 DOI: https://doi.org/10.1182/bloodadvances.2018025114

Miyagaki T, Sugaya M. Immunological milieu in mycosis fungoides and Sezary syndrome. J Dermatol 2014; 41: 11-18.

https://doi.org/10.1111/1346-8138.12305 DOI: https://doi.org/10.1111/1346-8138.12305

Krejsgaard T, Litvinov IV, Wang Y, Xia L, Willerslev-Olsen A, Koralov SB, et al. Elucidating the role of interleukin-17F in cutaneous T-cell lymphoma. Blood 2013; 122: 943-950.

https://doi.org/10.1182/blood-2013-01-480889 DOI: https://doi.org/10.1182/blood-2013-01-480889

Chong BF, Wilson AJ, Gibson HM, Hafner MS, Luo Y, Hedgcock CJ, et al. Immune function abnormalities in peripheral blood mononuclear cell cytokine expression differentiates stages of cutaneous T-cell lymphoma/mycosis fungoides. Clin Cancer Res 2008; 14: 646-653.

https://doi.org/10.1158/1078-0432.CCR-07-0610 DOI: https://doi.org/10.1158/1078-0432.CCR-07-0610

Doherty SD, Ni X, Doherty CB, Jones D, Zhao X, Owen LB, et al. Abnormal expression of interleukin-23 in mycosis fungoides/Sézary syndrome lesions. Arch Dermatol Res 2006; 298: 353-356.

https://doi.org/10.1007/s00403-006-0705-x DOI: https://doi.org/10.1007/s00403-006-0705-x

Olsen EA, Whittaker S, Kim YH, Duvic M, Prince HM, Lessin SR, et al. Clinical end points and response criteria in mycosis fungoides and Sezary syndrome: a consensus statement of the International Society for Cutaneous Lymphomas, the United States Cutaneous Lymphoma Consortium, and the Cutaneous Lymphoma Task Force of the European Organisation for Research and Treatment of Cancer. J Clin Oncol 2011; 29: 2598-2607.

https://doi.org/10.1200/JCO.2010.32.0630 DOI: https://doi.org/10.1200/JCO.2010.32.0630

Novelli M, Fava P, Sarda C, Ponti R, Osella-Abate S, Savoia P, et al. Blood flow cytometry in Sezary syndrome: new insights on prognostic relevance and immunophenotypic changes during follow-up. Am J Clin Pathol 2015; 143: 57-69.

https://doi.org/10.1309/AJCP1NA3YCHCDEIG DOI: https://doi.org/10.1309/AJCP1NA3YCHCDEIG

Pitoiset F, Cassard L, El Soufi K, Boselli L, Grivel J, Roux A, et al. Deep phenotyping of immune cell populations by optimized and standardized flow cytometry analyses. Cytometry A 2018; 93: 793-802.

https://doi.org/10.1002/cyto.a.23570 DOI: https://doi.org/10.1002/cyto.a.23570

Wenzel J, Henze S, Brähler S, Bieber T, Tüting T. The expression of human leukocyte antigen-DR and CD25 on circulating T cells in cutaneous lupus erythematosus and correlation with disease activity. Exp Dermatol 2005; 14: 454-459.

https://doi.org/10.1111/j.0906-6705.2005.00301.x DOI: https://doi.org/10.1111/j.0906-6705.2005.00301.x

Wang Y, Su M, Zhou LL, Tu P, Zhang X, Jiang X, et al. Deficiency of SATB1 expression in Sezary cells causes apoptosis resistance by regulating FasL/CD95L transcription. Blood 2011; 117: 3826-3835.

https://doi.org/10.1182/blood-2010-07-294819 DOI: https://doi.org/10.1182/blood-2010-07-294819

Revenfeld AL, Steffensen R, Pugholm LH, Jorgensen MM, Stensballe A, Varming K. Presence of HLA-DR Molecules and HLA-DRB1 mRNA in Circulating CD4(+) T Cells. Scand J Immunol 2016; 84: 211-221.

https://doi.org/10.1111/sji.12462 DOI: https://doi.org/10.1111/sji.12462

Vonderheid EC. On the diagnosis of erythrodermic cutaneous T-cell lymphoma. J Cutan Pathol 2006; 33: 27-42.

https://doi.org/10.1111/j.0303-6987.2006.00541.x DOI: https://doi.org/10.1111/j.0303-6987.2006.00541.x

Miyashiro D, Sanches JA. Erythroderma: a prospective study of 309 patients followed for 12 years in a tertiary center. Sci Rep 2020; 10: 9774.

https://doi.org/10.1038/s41598-020-66040-7 DOI: https://doi.org/10.1038/s41598-020-66040-7

Fierro MT, Novelli M, Quaglino P, Comessatti A, Fava P, Ortoncelli M, et al. Heterogeneity of circulating CD4+ memory T-cell subsets in erythrodermic patients: CD27 analysis can help to distinguish cutaneous T-cell lymphomas from inflammatory erythroderma. Dermatology 2008; 216: 213-221.

https://doi.org/10.1159/000112928 DOI: https://doi.org/10.1159/000112928

Cabrera T, Ruiz-Cabello F, Garrido F. Biological implications of HLA-DR expression in tumours. Scand J Immunol 1995; 41: 398-406.

https://doi.org/10.1111/j.1365-3083.1995.tb03584.x DOI: https://doi.org/10.1111/j.1365-3083.1995.tb03584.x

Dunne MR, Phelan JJ, Michielsen AJ, Maguire AA, Dunne C, Martin P, et al. Characterising the prognostic potential of HLA-DR during colorectal cancer development. Cancer Immunol Immunother 2020; 69: 1577-1588.

https://doi.org/10.1007/s00262-020-02571-2 DOI: https://doi.org/10.1007/s00262-020-02571-2

Dunne MR, Michielsen AJ, O'Sullivan KE, Cathcart MC, Feighery R, Doyle B, et al. HLA-DR expression in tumor epithelium is an independent prognostic indicator in esophageal adenocarcinoma patients. Cancer Immunol Immunother 2017; 66: 841-850.

https://doi.org/10.1007/s00262-017-1983-1 DOI: https://doi.org/10.1007/s00262-017-1983-1

Higashi M, Tokuhira M, Fujino S, Yamashita T, Abe K, Arai E, et al. Loss of HLA-DR expression is related to tumor microenvironment and predicts adverse outcome in diffuse large B-cell lymphoma. Leuk Lymphoma 2016; 57: 161-166.

https://doi.org/10.3109/10428194.2015.1038708 DOI: https://doi.org/10.3109/10428194.2015.1038708

Papadavid E, Economidou J, Psarra A, Kapsimali V, Mantzana V, Antoniou C, et al. The relevance of peripheral blood T-helper 1 and 2 cytokine pattern in the evaluation of patients with mycosis fungoides and Sezary syndrome. Br J Dermatol 2003; 148: 709-718.

https://doi.org/10.1046/j.1365-2133.2003.05224.x DOI: https://doi.org/10.1046/j.1365-2133.2003.05224.x

Moy AP, Murali M, Kroshinsky D, Duncan LM, Nazarian RM. Immunologic overlap of helper T-cell subtypes 17 and 22 in erythrodermic psoriasis and atopic dermatitis. JAMA Dermatol 2015; 151: 753-760.

https://doi.org/10.1001/jamadermatol.2015.2 DOI: https://doi.org/10.1001/jamadermatol.2015.2

Saulite I, Hoetzenecker W, Weidinger S, Cozzio A, Guenova E, Wehkamp U. Sezary syndrome and atopic dermatitis: comparison of immunological aspects and targets. BioMed Res Int 2016; 2016: 9717530.

https://doi.org/10.1155/2016/9717530 DOI: https://doi.org/10.1155/2016/9717530

Papathemeli D, Patsatsi A, Papanastassiou D, Koletsa T, Papathemelis T, Avgeros C, et al. Protein and mRNA expression levels of interleukin-17A, -17F and -22 in blood and skin samples of patients with mycosis fungoides. Acta Derm Venereol 2020; 100: adv00326.

https://doi.org/10.2340/00015555-3688 DOI: https://doi.org/10.2340/00015555-3688

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How to Cite

Sun, J., You, R., Lyu, B., Li, X., Gao, Y., Wen, Y., Qu, C., & Wang, Y. (2023). HLA-DR Helps to Differentiate Erythrodermic Cutaneous T-cell Lymphoma from Erythrodermic Inflammatory Dermatoses in Flow Cytometry. Acta Dermato-Venereologica, 103, adv5668. https://doi.org/10.2340/actadv.v103.5668