The odyssey of diagnosis of mycosis fungoides: Sailing beyond clonality and histology

The study by Kook et al.¹ addresses the complexities of revisiting the diagnosis of severe atopic dermatitis (AD) in patients who exhibit an insufficient response to dupilumab. This reconsideration is prompted by the necessity to rule out mycosis fungoides (MF). Kook et al. employed comprehensive MF diagnostic criteria, confirming the diagnosis in 19 out of 35 patients. They reported epidermotropic lymphocytes in all patients and atypical lymphocytes in 17 patients. TCR clonality was confirmed in all patients, with 8 showing clonality in multiple biopsies. Immunohistochemical analysis revealed an increased CD4/CD8 ratio and loss of CD7 in all patients.

While approach to diagnosis of MF by Kook et al. is per current standards, it should be noted that clonal T-cell populations and loss of CD7 can also be present in AD, highlighting the diagnostic challenges in these cases. Indeed, studies have shown that TCR clonality is not uncommon in AD, as both lesional and nonlesional AD skin can share identical T-cell clones, complicating the differentiation from MF.² Additionally, the loss of CD7 expression has been observed in atopic dermatitis, further blurring the lines between benign and malignant conditions.³ This traditional approach highlights the limitations of current diagnostic modalities in differentiating between severe AD and MF.

We encountered a similar diagnostic challenge in our study of CD8⁺ hypopigmented MF.⁴ Traditional methods, such as histology and TCR clonality assessments, were insufficient to conclusively identify malignant cells. To overcome this, we developed an alternative approach utilizing single-cell RNA sequencing (scRNA-seq) to create a malignant transcriptome panel. This advanced technique allowed us to precisely distinguish malignant cells from reactive clonal populations, providing a clearer understanding of the disease pathology and guiding more accurate therapeutic interventions.⁴

Incorporating a transcriptomic panel, particularly one tailored to distinguishing between reactive and malignant T-cell populations, could address the diagnostic challenges rise in difficult diagnostic cases similar to what was presented by Kook et al.¹ Our findings with HMF indicate that a small population of malignant cells was obscured by a larger population of clonal reactive cells. Similarly, in AD, a clonal population of CD4⁺ T cells may not be obligatorily malignant. By employing scRNA-seq, distinct transcriptomic signatures can accurately differentiate malignant from reactive clonal T cells, suggesting a path forward for refining the diagnostic approach in MF.

Furthermore, it is notable that treatments utilized for MF, such as methotrexate, retinoids and narrow-band ultraviolet B (NBUVB), have also shown effectiveness in patients with AD, indicating potential overlaps in therapeutic strategies. While those non-specific treatments were sufficient in the cases presented, there are instances where the choice of lymphoma-specific medications is crucial, underscoring the need for accurate diagnosis to guide therapy decisions.

The importance of robust diagnostic tools cannot be overstated, especially in the context of diseases with overlapping features like severe AD and MF. The integration of advanced transcriptomic analysis could provide the specificity needed to distinguish between these conditions, ultimately guiding more precise treatment strategies.

In summary, the study by Kook et al.¹ emphasizes the intricate diagnostic challenges posed by severe AD and MF, especially when patients exhibit insufficient responses to biologics. Traditional diagnostic approaches, while thorough, often fall short in differentiating between these conditions due to overlapping features such as TCR clonality, CD7 loss, exocytosis of lymphocytes in chronically inflamed skin. As we move forward, the integration of comprehensive transcriptomic panels with traditional diagnostic methodst could revolutionize the diagnostic landscape for MF particularly in the setting of non-typical clinical presentation or on the background of concomitant chronic dermatoses, ultimately enhancing patient outcomes in complex dermatological cases.

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Oleg E. Akilov has received research funding/grant support from Actelion, Adaptive Biotechnology, Trillium Therapeutics, Pfizer, Kyowa Kirin, Mallinckrodt; PI on current clinical trials: Tellomak, Corvus, SciTech Development; consultant for Caste Biomarkers, SkinJet, Bioniz, Allmiral, CRISPR Therapeutics; he is a speaker for Kyowa Kirin and Ortho Dermatologics.