ABSTRACT: Primary cutaneous B-cell lymphomas comprise a heterogeneous group of extranodal non-Hodgkin lymphomas. While primary cutaneous diffuse large B cell lymphoma - leg type (pcDLBCL-LT) is highly aggressive, the two other subtypes, primary cutaneous follicle centre lymphoma (pcFCL) and primary cutaneous marginal zone lymphoma (pcMZL), also termed primary cutaneous marginal zone lymphoproliferative disorder, usually follow an indolent disease course. To better characterise these most common types of primary cutaneous B cell lymphomas, we performed a comprehensive, single-cell RNA-sequencing based analysis of biopsies from pcFCL, pcMZL, and pcDLBCL-LT skin lesions, in comparison to samples from benign reactive B-cell rich lymphoid proliferation (rB-LP) lesions, as well as gastric MALT lymphoma, nodal FCL and nodal DLBCL. Our data show that all non-aggressive forms of primary cutaneous B cell lymphoma, as well as rB-LP, show a persistent germinal centre reaction, with all accessory germinal centre-support cells and continuous somatic hypermutation within the expanded B cell clone. By contrast, malignant clones of pcDLBCL-LT lesions and gastric MALT showed absence of all of these features. Our data further shows that pcMZL originates from naïve and not post-germinal centre B cells as currently believed and observed in gastric MALT. The modest clonal expansion in pcMZL may therefore be the result of a recognition of a distinct (unknown) antigen. Conversely, in pcFCL, B cells show an (antigen-driven) expansion of a single clone with a germinal centre phenotype, presumably through acquisition of a driving mutation. The lack of further differentiation of B cells in pcFCL, in contrast to nodal FCL, may explain its indolent clinical course. Our data indicates that in contrast to highly aggressive cutaneous B cell lymphoma (pcDLBCL-LT), pcMZL, and pcFCL, similar to rB-LP are characterised by a functional germinal centre reaction driven by antigen recognition and supports the classification of pcMZL as a lymphoproliferative disease.
