Cellular and molecular profiling of early-stage mycosis fungoides in comparison to parapsoriasis and atopic dermatitis reveals disease-specific markers

The diagnosis of early-stage mycosis fungoides (MF), the most common primary cutaneous T-cell lymphoma, is often delayed due to clinical and histopathological similarities with benign inflammatory dermatoses. Moreover, its delineation from the spectrum of so-called “parapsoriases” is still controversial. For further insight on a molecular level, we performed single-cell RNA sequencing to profile skin biopsies from patients presenting clinically with either “small-“ or “large-patch” dermatitis and compared them to longstanding atopic dermatitis (AD) lesions as well as healthy control (HC) individuals. We found 6 out of 8 large-patch lesions to harbor either an expanded alpha/beta or gamma/delta T-cell clone, consistent with a diagnosis of early-stage MF. By contrast, 6 out of 7 small-patch lesions contained a highly polyclonal T-cell pattern, indistinguishable from AD and HC skin, which we termed as “true” parapsoriasis (PP). Only AD harbored so-called “Th2A” cells, a CD3+CRTH2+ IL13-expressing helper-cell type, previously associated with allergic sensitization and tissue-resident disease memory formation in atopic individuals. Expanded MF clones consistently downregulated CD7, CD27 and EEF1A1 expression, and overexpressed NTRK2, LGALS3, IL26, ANKRD28 and RGS9 in comparison to polyclonal T cells. On a stromal cell level, AD specifically harbored increased numbers of COL6A5+COL6A6+ inflammatory fibroblasts. PP, by contrast, characteristically showed elevated expression of coagulation and complement-related genes including F2R, F3 and C7 in fibroblasts, and expansion of a unique NPY+ innate lymphoid cell population that was not found in other disease groups. These data position classic small-patch PP as a separate entity characterized by expansion of specific ILC subsets, distinct from AD and early MF.