{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T10:00:27Z","timestamp":1785837627697,"version":"3.56.0"},"reference-count":36,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2024,2,27]],"date-time":"2024-02-27T00:00:00Z","timestamp":1708992000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Granulomatous Mycosis Fungoides (GMF) is a rare form of mycosis fungoides (MF) characterized by a granulomatous infiltrate associated with the neoplastic lymphoid population and is considered to have a worse prognosis compared with regular MF. The upregulation of the T helper (Th) axis, especially Th17, plays an important role in the pathogenesis of several inflammatory\/infectious granulomatous cutaneous diseases, but its role in GMF is still not elucidated to date. In this study, we evaluated the immunohistochemical expression of Th1 (Tbet), Th2 (GATA-3), Th17 (ROR\u03b3T), T regulatory (Foxp3), and immune checkpoint (IC) (PD-1 and PD-L1) markers in a cohort of patients with GMF and MF with large cell transformation (MFLCT). Skin biopsies from 49 patients (28 GMF and 21 MFLCT) were studied. Patients with GMF were associated with early clinical stage (p = 0.036) and lower levels of lactate dehydrogenase (p = 0.042). An increased percentage of cells positive for Tbet (p = 0.017), ROR\u03b3T (p = 0.001), and PD-L1 (p = 0.011) was also observed among the GMF specimens, while a stronger PD-1 intensity was detected in cases of MFLCT. In this cohort, LCT, ROR\u03b3T &lt; 10%, Foxp3 &lt; 10%, age, and advanced stage were associated with worse overall survival (OS) in univariate analysis. GMF demonstrated Th1 (cellular response) and Th17 (autoimmunity) phenotype, seen in early MF and granulomatous processes, respectively, which may be related to the histopathological appearance and biological behavior of GMF. Further studies involving larger series of cases and more sensitive techniques are warranted.<\/jats:p>","DOI":"10.3390\/cells13050419","type":"journal-article","created":{"date-parts":[[2024,2,27]],"date-time":"2024-02-27T11:52:55Z","timestamp":1709034775000},"page":"419","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Differential Upregulation of Th1\/Th17-Associated Proteins and PD-L1 in Granulomatous Mycosis Fungoides"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6324-2096","authenticated-orcid":false,"given":"Mario L.","family":"Marques-Piubelli","sequence":"first","affiliation":[{"name":"Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jesus","family":"Navarrete","sequence":"additional","affiliation":[{"name":"Department of Anatomical Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6670-7645","authenticated-orcid":false,"given":"Debora A.","family":"Ledesma","sequence":"additional","affiliation":[{"name":"Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Courtney W.","family":"Hudgens","sequence":"additional","affiliation":[{"name":"Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rossana N.","family":"Lazcano","sequence":"additional","affiliation":[{"name":"Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ali","family":"Alani","sequence":"additional","affiliation":[{"name":"Department of Anatomical Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Auris","family":"Huen","sequence":"additional","affiliation":[{"name":"Department of Dermatology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madeleine","family":"Duvic","sequence":"additional","affiliation":[{"name":"Department of Dermatology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Priyadharsini","family":"Nagarajan","sequence":"additional","affiliation":[{"name":"Department of Anatomical Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3398-0573","authenticated-orcid":false,"given":"Phyu P.","family":"Aung","sequence":"additional","affiliation":[{"name":"Department of Anatomical Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ignacio I.","family":"Wistuba","sequence":"additional","affiliation":[{"name":"Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan L.","family":"Curry","sequence":"additional","affiliation":[{"name":"Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA"},{"name":"Department of Anatomical Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA"},{"name":"Department of Dermatology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8467-5464","authenticated-orcid":false,"given":"Roberto N.","family":"Miranda","sequence":"additional","affiliation":[{"name":"Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7422-0661","authenticated-orcid":false,"given":"Carlos A.","family":"Torres-Cabala","sequence":"additional","affiliation":[{"name":"Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA"},{"name":"Department of Anatomical Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA"},{"name":"Department of Dermatology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,2,27]]},"reference":[{"key":"ref_1","first-page":"1609","article-title":"Granulomatous Mycosis Fungoides and Granulomatous Slack Skin: A Multicenter Study of the Cutaneous Lymphoma Histopathology Task Force Group of the European Organization for Research and Treatment of Cancer (Eortc)","volume":"14","author":"Kempf","year":"2008","journal-title":"Arch. Dermatol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1097\/DAD.0000000000002181","article-title":"Subtlety of Granulomatous Mycosis Fungoides: A Retrospective Case Series Study and Proposal of Helpful Multimodal Diagnostic Approach with Literature Review","volume":"44","author":"Lenskaya","year":"2022","journal-title":"Am. J. Dermatopathol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1016\/j.mpdhp.2016.04.004","article-title":"Unusual Variants of Mycosis Fungoides","volume":"22","author":"Virmani","year":"2016","journal-title":"Diagn. Histopathol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1111\/j.1468-3083.2008.03020.x","article-title":"Cutaneous Lymphomas Showing Prominent Granulomatous Component: Clinicopathological Features in a Series of 16 Cases","volume":"23","author":"Gallardo","year":"2009","journal-title":"J. Eur. Acad. Dermatol. Venereol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"610","DOI":"10.1097\/PAT.0000000000000166","article-title":"Mycosis Fungoides with Large Cell Transformation: Clinicopathological Features and Prognostic Factors","volume":"46","author":"Pulitzer","year":"2014","journal-title":"Pathology"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.clml.2015.11.010","article-title":"Retrospective Analysis of Prognostic Factors in 187 Cases of Transformed Mycosis Fungoides","volume":"16","author":"Talpur","year":"2016","journal-title":"Clin. Lymphoma Myeloma Leuk."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1016\/j.jaad.2013.03.036","article-title":"A Case-Control Study of Clinicopathologic Features, Prognosis, and Therapeutic Responses in Patients with Granulomatous Mycosis Fungoides","volume":"69","author":"Li","year":"2013","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"634","DOI":"10.1038\/s41423-019-0220-6","article-title":"Helper T Cell Differentiation","volume":"16","author":"Saravia","year":"2019","journal-title":"Cell. Mol. Immunol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2159","DOI":"10.1182\/blood.2019000779","article-title":"Reproducing the Molecular Subclassification of Peripheral T-Cell Lymphoma-Nos by Immunohistochemistry","volume":"134","author":"Amador","year":"2019","journal-title":"Blood"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"949","DOI":"10.3389\/fimmu.2017.00949","article-title":"Th17-Inducing Cytokines Il-6 and Il-23 Are Crucial for Granuloma Formation During Experimental Paracoccidioidomycosis","volume":"8","author":"Rocha","year":"2017","journal-title":"Front. Immunol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1093\/rheumatology\/ker316","article-title":"Increased Il-17a Expression in Granulomas and in Circulating Memory T Cells in Sarcoidosis","volume":"51","author":"Paats","year":"2012","journal-title":"Rheumatology"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"7529","DOI":"10.1158\/1078-0432.CCR-11-1192","article-title":"Il-22, but Not Il-17, Dominant Environment in Cutaneous T-Cell Lymphoma","volume":"17","author":"Miyagaki","year":"2011","journal-title":"Clin. Cancer Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1072","DOI":"10.1111\/j.1600-0560.2010.01577.x","article-title":"Cd8-Positive Granulomatous Mycosis Fungoides: A Case Report with Review of the Literature","volume":"37","author":"Ishida","year":"2010","journal-title":"J. Cutan. Pathol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1111\/cup.12012","article-title":"Reactive Lymphoid Follicles with Germinal Centers in granulomatous Mycosis Fungoides: A Case Report with Review of the Literature","volume":"40","author":"Ishida","year":"2013","journal-title":"J. Cutan. Pathol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"S69","DOI":"10.1016\/S0959-8049(21)00757-7","article-title":"New Insights into Granulomatous Mycosis Fungoides (Gmf): A Single-Center Experience","volume":"156","author":"Sidiropoulou","year":"2021","journal-title":"Eur. J. Cancer"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1016\/j.jdcr.2015.05.010","article-title":"Granulomatous Mycosis Fungoides, a Rare Subtype of Cutaneous T-Cell Lymphoma","volume":"1","author":"Kogut","year":"2015","journal-title":"JAAD Case Rep."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1007\/s00292-014-2017-9","article-title":"Cutaneous Lymphomas: New Entities and Rare Variants","volume":"36","author":"Kempf","year":"2015","journal-title":"Pathologe"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1590\/abd1806-4841.20153460","article-title":"Granulomatous Mycosis Fungoides\u2014A Diagnostic Challenge","volume":"90","author":"Pousa","year":"2015","journal-title":"Bras. Dermatol."},{"key":"ref_19","first-page":"2772","article-title":"Hodgkin\u2019s Lymphoma with Marked Granulomatous Reaction: A Diagnostic Pitfall","volume":"12","author":"Du","year":"2019","journal-title":"Int. J. Clin. Exp. Pathol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1111\/j.1365-2133.1994.tb08505.x","article-title":"Granulomatous Slack Skin: Report of a Case Associated with Hodgkin\u2019s Disease and a Review of the Literature","volume":"131","author":"Noto","year":"1994","journal-title":"Br. J. Dermatol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1731942","DOI":"10.1080\/2162402X.2020.1731942","article-title":"Lactate Dehydrogenase: A Marker of Diminished Antitumor Immunity","volume":"9","author":"Koornstra","year":"2020","journal-title":"Oncoimmunology"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1016\/j.jdermsci.2017.08.012","article-title":"Differential Expression of Ccr4 in Primary Cutaneous Gamma\/Delta (\u0393\/\u0394) T Cell Lymphomas and Mycosis Fungoides: Significance for Diagnosis and Therapy","volume":"89","author":"Jour","year":"2018","journal-title":"J. Dermatol. Sci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2915","DOI":"10.1182\/blood-2013-11-536359","article-title":"Gene Expression Signatures Delineate Biological and Prognostic Subgroups in Peripheral T-Cell Lymphoma","volume":"123","author":"Iqbal","year":"2014","journal-title":"Blood"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/j.blre.2015.08.003","article-title":"Genomic Signatures in T-Cell Lymphoma: How Can These Improve Precision in Diagnosis and Inform Prognosis?","volume":"30","author":"Iqbal","year":"2016","journal-title":"Blood Rev."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1136\/thx.2010.140319","article-title":"Sarcoidosis Is a Th1\/Th17 Multisystem Disorder","volume":"66","author":"Facco","year":"2011","journal-title":"Thorax"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1002\/path.1508","article-title":"Expression of Il-27 in Human Th1-Associated Granulomatous Diseases","volume":"202","author":"Larousserie","year":"2004","journal-title":"J. Pathol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"943","DOI":"10.1182\/blood-2013-01-480889","article-title":"Elucidating the Role of Interleukin-17f in Cutaneous T-Cell Lymphoma","volume":"122","author":"Krejsgaard","year":"2013","journal-title":"Blood"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"630","DOI":"10.3389\/fimmu.2014.00630","article-title":"Plasticity of Human Cd4 T Cell Subsets","volume":"5","author":"Geginat","year":"2014","journal-title":"Front. Immunol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"adv00777","DOI":"10.2340\/actadv.v102.2416","article-title":"Interleukin-17 Genes Polymorphisms Are Significantly Associated with Cutaneous T-Cell Lymphoma Susceptibility","volume":"102","author":"Jolanta","year":"2022","journal-title":"Acta Derm. Venereol."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Dobos, G., Lazaridou, I., and de Masson, A. (2023). Mycosis Fungoides and S\u00e9zary Syndrome: Microenvironment and Cancer Progression. Cancers, 15.","DOI":"10.3390\/cancers15030746"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"733770","DOI":"10.3389\/fonc.2021.733770","article-title":"Immune Check Point Inhibitors in Primary Cutaneous T-Cell Lymphomas: Biologic Rationale, Clinical Results and Future Perspectives","volume":"11","author":"Roccuzzo","year":"2021","journal-title":"Front. Oncol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1182\/bloodadvances.2020002371","article-title":"Pembrolizumab in Mycosis Fungoides with Pd-L1 Structural Variants","volume":"5","author":"Beygi","year":"2021","journal-title":"Blood Adv."},{"key":"ref_33","first-page":"355","article-title":"Pd-1 and Pd-L1 Expression in Mycosis Fungoides and S\u00e9zary Syndrome","volume":"157","author":"Pileri","year":"2022","journal-title":"Ital. J. Dermatol. Venerol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1200\/JCO.19.01056","article-title":"Pembrolizumab in Relapsed and Refractory Mycosis Fungoides and S\u00e9zary Syndrome: A Multicenter Phase Ii Study","volume":"38","author":"Khodadoust","year":"2020","journal-title":"J. Clin. Oncol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1526","DOI":"10.21037\/atm-20-6719","article-title":"The Role of the Programmed Cell Death Protein-1\/Programmed Death-Ligand 1 Pathway, Regulatory T Cells and T Helper 17 Cells in Tumor Immunity: A Narrative Review","volume":"8","author":"Zhang","year":"2020","journal-title":"Ann. Transl. Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1989","DOI":"10.1056\/NEJMc1703047","article-title":"Reversal of Autoimmune Toxicity and Loss of Tumor Response by Interleukin-17 Blockade","volume":"376","author":"Esfahani","year":"2017","journal-title":"N. Engl. J. Med."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/13\/5\/419\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:05:57Z","timestamp":1760105157000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/13\/5\/419"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,2,27]]},"references-count":36,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2024,3]]}},"alternative-id":["cells13050419"],"URL":"https:\/\/doi.org\/10.3390\/cells13050419","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,2,27]]}}}