Abstract
Primary cutaneous B-cell lymphoma encompass clinically heterogeneous entities. While primary cutaneous diffuse large B-cell lymphoma, leg type (pcDLBCL-LT) is aggressive, primary cutaneous follicle centre lymphoma (pcFCL) and primary cutaneous marginal zone lymphoma (pcMZL) typically follow an indolent course. To clarify their pathophysiological basis, we perform single-cell RNA sequencing on pcFCL, pcMZL, and pcDLBCL-LT, alongside reactive B-cell rich lymphoid proliferations (rB-LP), gastric mucosa-associated lymphoid tissue (MALT) lymphoma, and systemic counterparts. Here we show that the indolent pcMZL, pcFCL, and rB-LP exhibit a persistent germinal centre reaction, not observed in pcDLBCL-LT or gastric MALT lymphoma. Further, pcMZL top expanded clones develop within lesions from naïve and not post-germinal centre B cells as currently presumed. Our data thus indicate that pcMZL and pcFCL, similar to rB-LP may be driven by (a yet unknown) antigen. While our data indicates that pcFCL exhibits some features of true lymphomas, it clearly supports the classification of pcMZL as a lymphoproliferative disease.
Data availability
The processed scRNA-seq data generated in this study have been deposited in the GEO database under accession code GSE218861. Data from healthy control samples are available on GEO under GSE17320580. The raw scRNAs-seq data are protected and are not available due to data privacy laws. The CBCL scRNA-seq data used in this study are available in the European Genome-Phenome Archive (EGA) database under accession code EGAD00001006829. The sFCL scRNA-seq data used in this study are available in the EGA database under accession code EGAS00001006052. The sDLBCL scRNA-seq data used in this study are available in the GEO database under accession code GSE182436. Source data are provided with this paper.
References
Willemze, R. et al. The 2018 update of the WHO-EORTC classification for primary cutaneous lymphomas. Blood 133, 1703–1714 (2019).
Goodlad, J. R., Cerroni, L. & Swerdlow, S. H. Recent advances in cutaneous lymphoma-implications for current and future classifications. Virchows Arch. Int. J. Pathol. 482, 281–298 (2023).
Vitiello, P. et al. Primary cutaneous B-cell lymphomas: an update. Front. Oncol. 10, 651 (2020).
Kempf, W. et al. Classifications of cutaneous lymphomas and lymphoproliferative disorders: an update from the EORTC cutaneous lymphoma histopathology group. J. Eur. Acad. Dermatol. Venereol. https://doi.org/10.1111/jdv.19987 (2024).
Di Napoli, A. et al. Deep sequencing of immunoglobulin genes identifies a very low percentage of monoclonal B cells in primary cutaneous marginal zone lymphomas with CD30-positive Hodgkin/Reed-Sternberg-like cells. Diagn. Basel Switz 12, 290 (2022).
Hristov, A. C., Comfere, N. I., Vidal, C. I. & Sundram, U. Kappa and lambda immunohistochemistry and in situ hybridization in the evaluation of atypical cutaneous lymphoid infiltrates. J. Cutan. Pathol 47, 1103–1110 (2020).
Willemze, R. Cutaneous lymphoproliferative disorders: Back to the future. J. Cutan. Pathol. https://doi.org/10.1111/cup.14609 (2024).
Lima, M. Cutaneous primary B-cell lymphomas: from diagnosis to treatment. An. Bras. Dermatol. 90, 687–706 (2015).
Storz, M. N. et al. Gene expression profiles of cutaneous B cell lymphoma. J. Invest. Dermatol. 120, 865–870 (2003).
Hoefnagel, J. J. et al. Primary cutaneous marginal zone B-cell lymphoma: clinical and therapeutic features in 50 cases. Arch. Dermatol. 141, 1139–1145 (2005).
Nicolay, J. P. & Wobser, M. Cutaneous B-cell lymphomas - pathogenesis, diagnostic workup, and therapy. J. Dtsch. Dermatol. Ges. J. Ger. Soc. Dermatol. JDDG 14, 1207–1224 (2016).
Nakagawa, Y. et al. Analysis of clonality in cutaneous B-cell lymphoma and B-cell pseudolymphoma using skin flow cytometry: comparison of immunophenotyping and gene rearrangement studies. J. Dermatol. 49, 246–252 (2022).
Porkert, S. et al. Patients’ illness perception as a tool to improve individual disease management in primary cutaneous lymphomas. Acta Derm. Venereol. 98, 240–245 (2018).
Schirren, A. E. C. et al. Health-related quality of life and its influencing factors in patients with primary cutaneous B-cell lymphomas: a multicentric study in 100 patients. J. Eur. Acad. Dermatol. Venereol. JEADV 38, 954–966 (2024).
Suryani, S. et al. Differential expression of CD21 identifies developmentally and functionally distinct subsets of human transitional B cells. Blood 115, 519–529 (2010).
Ramelyte, E. et al. Oncolytic virotherapy-mediated anti-tumor response: a single-cell perspective. Cancer Cell 39, 394–406.e4 (2021).
Gibson, S. E. & Swerdlow, S. H. How I diagnose primary cutaneous marginal zone lymphoma. Am. J. Clin. Pathol. 154, 428–449 (2020).
Magro, C. M. & Olson, L. C. Small cell lymphocytic variant of marginal zone lymphoma: a distinct form of marginal zone lymphoma derived from naïve B cells as a cutaneous counterpart to the naïve marginal zone lymphoma of splenic origin. Ann. Diagn. Pathol. 34, 116–121 (2018).
Sagaert, X., Van Cutsem, E., De Hertogh, G., Geboes, K. & Tousseyn, T. Gastric MALT lymphoma: a model of chronic inflammation-induced tumor development. Nat. Rev. Gastroenterol. Hepatol. 7, 336–346 (2010).
Willemze, R. WHO-EORTC classification for cutaneous lymphomas. Blood 105, 3768–3785 (2005).
Han, G. et al. Follicular lymphoma microenvironment characteristics associated with tumor cell mutations and MHC class II expression. Blood Cancer Discov. 3, 428–443 (2022).
Steen, C. B. et al. The landscape of tumor cell states and ecosystems in diffuse large B cell lymphoma. Cancer Cell 39, 1422–1437.e10 (2021).
Dai, D. et al. The transcription factor ZEB2 drives the formation of age-associated B cells. Science 383, 413–421 (2024).
Huang, S. et al. CD1 lipidomes reveal lipid-binding motifs and size-based antigen-display mechanisms. Cell 186, 4583–4596.e13 (2023).
Grosjean, I. et al. CD23/CD21 interaction is required for presentation of soluble protein antigen by lymphoblastoid B cell lines to specific CD4+ T cell clones. Eur. J. Immunol. 24, 2982–2986 (1994).
Wu, L. et al. HMCES protects immunoglobulin genes specifically from deletions during somatic hypermutation. Genes Dev. 36, 433–450 (2022).
Romero, X. et al. CD229 (Ly9) lymphocyte cell surface receptor interacts homophilically through its N-terminal domain and relocalizes to the immunological synapse. J. Immunol. Baltim. Md 174, 7033–7042 (2005).
Stokes, M. E. et al. Transcriptomic classification of diffuse large B-cell lymphoma identifies a high-risk activated B-cell-like subpopulation with targetable MYC dysregulation. Nat. Commun. 15, 6790 (2024).
Arcila, M. E. et al. Establishment of immunoglobulin heavy (IGH) chain clonality testing by next-generation sequencing for routine characterization of B-cell and plasma cell neoplasms. J. Mol. Diagn. JMD 21, 330–342 (2019).
Kuleape, J. A. et al. DNA damage triggers the nuclear accumulation of RASSF6 tumor suppressor protein via CDK9 and BAF53 to regulate p53 target gene transcription. Mol. Cell. Biol. 42, e0031021 (2022).
Odani, K. et al. Insulin-like growth factor II mRNA binding protein 3 is highly expressed in primary diffuse large B-cell lymphoma of the CNS. J. Clin. Exp. Hematop. JCEH 64, 203–207 (2024).
Charfi, C., Levros, L.-C., Edouard, E. & Rassart, E. Characterization and identification of PARM-1 as a new potential oncogene. Mol. Cancer 12, 84 (2013).
Nguyen, L., Papenhausen, P. & Shao, H. The role of c-MYC in B-cell lymphomas: diagnostic and molecular aspects. Genes 8, 116 (2017).
Mestre-Escorihuela, C. et al. Homozygous deletions localize novel tumor suppressor genes in B-cell lymphomas. Blood 109, 271–280 (2007).
Ying, X., Chan, K., Shenoy, P., Hill, M. & Ruddle, N. H. Lymphotoxin plays a crucial role in the development and function of nasal-associated lymphoid tissue through regulation of chemokines and peripheral node addressin. Am. J. Pathol. 166, 135–146 (2005).
Duell, J. et al. Sequential antigen loss and branching evolution in lymphoma after CD19- and CD20-targeted T-cell-redirecting therapy. Blood 143, 685–696 (2024).
Klasen, C. et al. MIF promotes B cell chemotaxis through the receptors CXCR4 and CD74 and ZAP-70 signaling. J. Immunol. Baltim. Md 192, 5273–5284 (2014).
Hu, J. et al. TSP-1-CD47-integrin α4β1 axis drives T cell infiltration and synovial inflammation in rheumatoid arthritis. Front. Immunol. 16, 1524304 (2025).
Kerr, S. C., Fieger, C. B., Snapp, K. R. & Rosen, S. D. Endoglycan, a member of the CD34 family of sialomucins, is a ligand for the vascular selectins. J. Immunol. Baltim. Md 181, 1480–1490 (2008).
Greer, S. F. & Justement, L. B. CD45 regulates tyrosine phosphorylation of CD22 and its association with the protein tyrosine phosphatase SHP-1. J. Immunol. Baltim. Md 162, 5278–5286 (1999).
Duan, L. et al. Follicular dendritic cells restrict interleukin-4 availability in germinal centers and foster memory B cell generation. Immunity 54, 2256–2272.e6 (2021).
Ye, J., Ma, N., Madden, T. L. & Ostell, J. M. IgBLAST: an immunoglobulin variable domain sequence analysis tool. Nucleic Acids Res. 41, W34–W40 (2013).
De Silva, N. S. & Klein, U. Dynamics of B cells in germinal centres. Nat. Rev. Immunol. 15, 137–148 (2015).
Robson, A. et al. Follicular T-helper cells in marginal zone lymphoma: evidence of an organoid immune response. Am. J. Dermatopathol. 43, e197–e203 (2021).
van Nierop, K. & de Groot, C. Human follicular dendritic cells: function, origin and development. Semin. Immunol. 14, 251–257 (2002).
Mechtcheriakova, D. et al. Activation-induced cytidine deaminase (AID)-associated multigene signature to assess impact of AID in etiology of diseases with inflammatory component. PloS One 6, e25611 (2011).
Schumacher, T. N. & Thommen, D. S. Tertiary lymphoid structures in cancer. Science 375, eabf9419 (2022).
Bombardieri, M., Lewis, M. & Pitzalis, C. Ectopic lymphoid neogenesis in rheumatic autoimmune diseases. Nat. Rev. Rheumatol. 13, 141–154 (2017).
Sato, Y., Silina, K., van den Broek, M., Hirahara, K. & Yanagita, M. The roles of tertiary lymphoid structures in chronic diseases. Nat. Rev. Nephrol. 19, 525–537 (2023).
Yu, W.-W. et al. Skin immune-mesenchymal interplay within tertiary lymphoid structures promotes autoimmune pathogenesis in hidradenitis suppurativa. Immunity 57, 2827–2842.e5 (2024).
Travaglino, A. et al. Borrelia burgdorferi in primary cutaneous lymphomas: a systematic review and meta-analysis. J. Dtsch. Dermatol. Ges. J. Ger. Soc. Dermatol. JDDG 18, 1379–1384 (2020).
Cho, W. C. et al. Cutaneous lymphoid hyperplasia with T-cell clonality and monotypic plasma cells secondary to a tick bite: a hidden critter and the power of deeper levels. Am. J. Dermatopathol. 44, 226–229 (2022).
Messina, F., Cicogna, G. T., Salmaso, R., Rondinone, R. & Alaibac, M. Primary cutaneous follicle center B-cell lymphoma at the site of a resolved herpes zoster eruption. Dermatol. Pract. Concept. 12, e2022169 (2022).
Aouali, S., Benkaraache, M., Almheirat, Y., Zizi, N. & Dikhaye, S. Complete remission of primary cutaneous follicle centre cell lymphoma associated with COVID-19 vaccine. J. Eur. Acad. Dermatol. Venereol. JEADV 36, e676–e678 (2022).
Schreidah, C. M. et al. Clinical remission of primary cutaneous marginal zone B-cell lymphoma in a patient with Crohn’s disease after Helicobacter pylori quadruple therapy and vedolizumab. Am. J. Dermatopathol. 45, 572–576 (2023).
Robotis, J., Tsiodras, S. & Rokkas, T. Helicobacter pylori eradication may successfully treat primary cutaneous follicle center lymphoma. Helicobacter 23, e12499 (2018).
Eken, J. A. et al. Antigen-independent, autonomous B cell receptor signaling drives activated B cell DLBCL. J. Exp. Med. 221, e20230941 (2024).
Mareschal, S. et al. Identification of somatic mutations in primary cutaneous diffuse large B-cell lymphoma, leg type by massive parallel sequencing. J. Invest. Dermatol. 137, 1984–1994 (2017).
Zhou, X. A. et al. Genomic landscape of cutaneous follicular lymphomas reveals 2 subgroups with clinically predictive molecular features. Blood Adv. 5, 649–661 (2021).
Barasch, N. J. K. et al. The molecular landscape and other distinctive features of primary cutaneous follicle center lymphoma. Hum. Pathol. 106, 93–105 (2020).
Hadj Khodabakhshi, A. et al. Recurrent targets of aberrant somatic hypermutation in lymphoma. Oncotarget 3, 1308–1319 (2012).
Michaeli, M., Carlotti, E., Hazanov, H., Gribben, J. G. & Mehr, R. Mutational patterns along different evolution paths of follicular lymphoma. Front. Oncol. 12, 1029995 (2022).
Koning, M. T. et al. Acquired N-linked glycosylation motifs in B-cell receptors of primary cutaneous B-cell lymphoma and the normal B-cell repertoire. J. Invest. Dermatol. 139, 2195–2203 (2019).
Senff, N. J., Kluin-Nelemans, H. C. & Willemze, R. Results of bone marrow examination in 275 patients with histological features that suggest an indolent type of cutaneous B-cell lymphoma. Br. J. Haematol. 142, 52–56 (2008).
Porkert, S. et al. Long-term therapeutic success of intravenous rituximab in 26 patients with indolent primary cutaneous B-cell lymphoma. Acta Derm. Venereol. 101, adv00383 (2021).
Valencak, J. et al. Rituximab monotherapy for primary cutaneous B-cell lymphoma: response and follow-up in 16 patients. Ann. Oncol. Off. J. Eur. Soc. Med. Oncol. 20, 326–330 (2009).
Rindler, K. et al. Single-cell RNA sequencing reveals markers of disease progression in primary cutaneous T-cell lymphoma. Mol. Cancer 20, 124 (2021).
Rojahn, T. B. et al. Single-cell transcriptomics combined with interstitial fluid proteomics defines cell type-specific immune regulation in atopic dermatitis. J. Allergy Clin. Immunol 146, 1056–1069 (2020).
Bangert, C. et al. Persistence of mature dendritic cells, TH2A, and Tc2 cells characterize clinically resolved atopic dermatitis under IL-4Rα blockade. Sci. Immunol. 6, eabe2749 (2021).
Biostrings Bioconductor. http://bioconductor.org/packages/Biostrings/ (2024).
Hao, Y. et al. Dictionary learning for integrative, multimodal and scalable single-cell analysis. Nat. Biotechnol. 42, 293–304 (2024).
Yang, S. et al. Decontamination of ambient RNA in single-cell RNA-seq with DecontX. Genome Biol 21, 57 (2020).
Germain, P.-L., Lun, A., Garcia Meixide, C., Macnair, W. & Robinson, M. D. Doublet identification in single-cell sequencing data using scDblFinder. F1000Research 10, 979 (2021).
Haghverdi, L., Lun, A. T. L., Morgan, M. D. & Marioni, J. C. Batch effects in single-cell RNA-sequencing data are corrected by matching mutual nearest neighbors. Nat. Biotechnol. 36, 421–427 (2018).
Heumos, L. et al. Best practices for single-cell analysis across modalities. Nat. Rev. Genet. 24, 550–572 (2023).
Choudhary, S. & Satija, R. Comparison and evaluation of statistical error models for scRNA-seq. Genome Biol. 23, 27 (2022).
Jin, S. et al. Inference and analysis of cell-cell communication using CellChat. Bioinformatics, https://doi.org/10.1101/2020.07.21.214387 (2020).
Griss, J. et al. B cells sustain inflammation and predict response to immune checkpoint blockade in human melanoma. Nat. Commun. 10, 4186 (2019).
Bankhead, P. et al. QuPath: open source software for digital pathology image analysis. Sci. Rep. 7, 16878 (2017).
Bangert, C. et al. Dupilumab-associated head and neck dermatitis shows a pronounced type 22 immune signature mediated by oligoclonally expanded T cells. Nat. Commun. 15, 2839 (2024).
Acknowledgements
This work was funded by research grants from the Austrian Science Fund to P.M.B. (grant number KLI 849-B) and J.G. (grant number P35937). S.N.W. was supported by research grants from the Austrian Science Fund (grant number P31127 and IPPTO project number DOC 59-B33). I.O. was supported by a DOC fellowship from the Austrian Academy of Science (Grant number 27228). The Vienna Scientific Cluster (Project No. 71839) is gratefully acknowledged for providing computational resources.
Author information
Authors and Affiliations
Contributions
Designed research J.G., C.J., S.N.W., P.M.B. Sample acquisition J.G., C.J., P.M.B., S.P., W.D. Histopathological analysis M.D., I.S.K. Sample analysis L.S., U.M., M.F., B.A., B.M.L., M.S., S.Z.S., C.W., S.N.W., W.W. Data analysis J.G., S.G., I.O., V.N. Acquisition of funding J.G., P.M.B. Writing of manuscript J.G., C.J., P.M.B., S.N.W., B.M.L.
Corresponding authors
Ethics declarations
Competing interests
J.G. received personal fees from AbbVie, Eli Lilly, Pfizer, Boehringer Ingelheim and Novartis. C.J. has received personal fees from Boehringer Ingelheim, LEO, Pfizer, Recordati Rare Diseases, Eli Lilly, Novartis, Takeda, Kyowa Kirin, STADA, UCB, BMS, AbbVie, Janssen, Stemline, and Almirall. C.J. is an investigator for Eli Lilly, Novartis, AbbVie, Boehringer Ingelheim, Incyte, 4SC, and Innate Pharma. W.W. has received personal fees from LEO Pharma, Pfizer, Sanofi Genzyme, Eli Lilly, Novartis, Boehringer Ingelheim, AbbVie, and Janssen. W.D. has received personal fees from Boston Scientific, Olympus, Medtronic, Norgine, MSD, Takeda and Ferring. P.M.B. has received personal fees from Almirall, Sanofi, Janssen, Amgen, LEO Pharma, AbbVie, Pfizer, Boehringer Ingelheim, GSK, Regeneron, Eli Lilly, Celgene, Arena Pharma, Novartis, UCB Pharma, Biotest and BMS. P.M.B. is an investigator for Pfizer and Abbvie.
Peer review
Peer review information
Nature Communications thanks Larisa Geskin and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. A peer review file is available.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Source data
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
About this article
Cite this article
Griss, J., Gansberger, S., Oyarzun, I. et al. Indolent primary cutaneous B-cell lymphomas resemble persistent antigen reactions without signs of dedifferentiation. Nat Commun (2026). https://doi.org/10.1038/s41467-026-69210-9
Received:
Accepted:
Published:
DOI: https://doi.org/10.1038/s41467-026-69210-9
