Mycosis fungoides (MF), the most common cutaneous T-cell lymphoma, is often underdiagnosed in early stages because of similarities with benign dermatoses such as atopic dermatitis (AD). Furthermore, the delineation from what is called “parapsoriasis en plaque”, a disease that can appear either in a small- or large-plaque form, is still controversial.

We sought to characterize the parapsoriasis disease spectrum.

We performed single-cell RNA sequencing of skin biopsies from patients within the parapsoriasis–to–early-stage MF spectrum, stratified for small and large plaques, and compared them to AD, psoriasis, and healthy control skin.

Six of 8 large-plaque lesions harbored either an expanded alpha/beta or gamma/delta T-cell clone with downregulation of CD7 expression, consistent with a diagnosis of early-stage MF. In contrast, 6 of 7 small-plaque lesions were polyclonal in nature, thereby lacking a lymphomatous phenotype, and also revealed a less inflammatory microenvironment than early-stage MF or AD. Of note, polyclonal small- and large-plaque lesions characteristically harbored a population of NPY⁺ innate lymphoid cells and displayed a stromal signature of complement upregulation and antimicrobial hyperresponsiveness in fibroblasts and sweat gland cells, respectively. These conditions were clearly distinct from AD or psoriasis, which uniquely harbored CD3⁺CRTH2⁺ IL-13 expressing “T_H2A” cells, or strong type 17 inflammation, respectively.

These data position polyclonal small- and large-plaque parapsoriasis lesions as a separate disease entity that characteristically harbors a so far undescribed innate lymphoid cell population. We thus propose a new term, “polyclonal parapsoriasis en plaque”, for this kind of lesion because they can be clearly differentiated from early- and advanced-stage MF, psoriasis, and AD on several cellular and molecular levels.