Cutaneous Lymphomas Offer Insights Into Chronic Skin Inflammation

At the 2025 Inflammatory Skin Disease Summit, Patrick Brunner, MD, explored how studying cutaneous T-cell lymphomas (CTCL), particularly mycosis fungoides, can deepen our understanding of chronic inflammatory dermatoses such as atopic dermatitis (AD). His presentation bridged 2 domains that are often managed in separate clinical spheres: chronic inflammatory skin disease and skin lymphoproliferative disorders. For clinicians, his message was clear: the biology and clinical behavior of these conditions intersect more often than we realize.¹

CTCL-Dermatology Connection

Brunner began with a challenge: clinicians who treat large volumes of AD and psoriasis should remain vigilant for early CTCL, because clinical and histologic mimicry remains a major diagnostic barrier. As he noted, “mycosis fungoides can, at times, be difficult to differentiate both clinically and histopathologically from either psoriasis or atopic dermatitis or eczema in general.”

This diagnostic overlap has become even more relevant with the rise of targeted immunomodulators. When a patient diagnosed with AD or psoriasis worsens, or fails to improve, on biologic therapy, clinicians must consider whether misdiagnosis or unmasking of occult CTCL could be contributing.

Immune Signatures

Brunner emphasized that AD has a strong and consistent type 2 (Th2) immune signature across phenotypes. In contrast, CTCL evolves over time: early CTCL exhibits type 1 skewing, but later-stage disease often shifts toward a Th2-dominant environment.² However, he cautioned clinicians against assuming that blocking Th2 pathways has therapeutic relevance in CTCL, noting that “although there’s a lot of IL-13 being found… in advanced-stage mycosis fungoides, there was no therapeutic response” to type 2 blockade.

This divergence underlines a critical point: similar cytokine environments in 2 diseases do not imply parallel therapeutic responsiveness.

Disease Memory

One of the most compelling segments of Brunner’s talk addressed why AD relapses so predictably after discontinuing biologic therapy. Pathology may normalize, yet persistent T-cell populations remain. Using patients treated for 1 year with dupilumab, Brunner’s team found that while skin disease cleared both clinically and histologically, a reservoir of tissue-resident immune cells persisted. These cells likely store “disease memory.”

He explained that after prolonged treatment, “the dermatopathology looks completely normal. But when we then did single-cell RNA sequencing… there were fewer cells that were sitting there, that were hibernating there… constituting the skin disease memory.”

These “hibernating” cells continued producing low-level inflammatory mediators (IL-13, IL-22, IL-26) and expressed receptors linked to rapid reactivation when pharmacologic blockade is lifted. This mechanism may explain why AD often returns within months of stopping dupilumab or JAK inhibitors.

Understanding Dupilumab-Associated Dermatoses

Brunner next addressed dupilumab-associated adverse events—particularly ocular inflammation and head/neck dermatitis. These reactions, though uncommon, provide insight into the delicate balance of immune pathways.

According to Brunner, the dupilumab-associated head and neck eruption is not simply undertreated AD. It represents a new inflammatory phenotype. Through single-cell RNA sequencing and T-cell receptor analysis, Brunner’s group found oligoclonal T-cell expansions with a mixed IL-17/IL-22 signature. These T cells were absent in classic AD but appeared consistently in this paradoxical eruption. This suggests that IL-4Rα blockade may unmask or tilt the immune system toward alternative inflammatory routes in a susceptible subset.

“Lymphoma-Like” Hyperplasia Under Dupilumab

One of the more concerning clinical observations Brunner discussed was the development of lymphoma-like skin changes in rare dupilumab-treated AD patients. He described a patient who developed nodular, alopecic, and tumor-like lesions raising alarm for CTCL.

However, when therapy was stopped, the lesions largely resolved. Brunner explained that these cases represent lymphoid hyperplasia, not true CTCL. Importantly, he argued that current evidence linking dupilumab to lymphoma causation is weak, concluding that “to say that dupilumab causes lymphoma… is relatively weak grounds.”

For practicing clinicians, this reinforces the need for careful evaluation—but also caution against over-attributing CTCL to biologic therapy without evidence of clonality or antigen loss.

Lymphomatoid Papulosis

Toward the end of his talk, Brunner pivoted to lymphomatoid papulosis (LyP)—a paradoxical entity that appears malignant under the microscope yet behaves benignly. His group’s sequencing work revealed that LyP lesions show heightened immune activation, especially in IFN-γ and TNF signaling, and richer cross-talk with fibroblasts and endothelial cells.

Unlike aggressive CTCL, LyP lesions appear to “burn out” because the malignant clone becomes too cytotoxic, damaging local vasculature and inducing self-regression. This stands in contrast to advanced CTCL, which develops an immune-protective microenvironment that permits tumor persistence and spread.

These insights may point toward therapeutic strategies that could “sensitize” CTCL lesions toward similar self-destructive pathways.

Clinical Takeaways

• Maintain high suspicion for CTCL in atypical or treatment-refractory AD/psoriasis.
  Early CTCL frequently mimics chronic inflammatory dermatoses.
• Th2 blockade does not improve CTCL, despite overlapping cytokine signatures.
• Disease memory persists despite clinical clearance.
  Residual T-cell populations likely explain relapse after biologic withdrawal.
• Dupilumab-associated eruptions represent distinct immunologic states, not simply poorly controlled AD.
• Not all lymphoma-like reactions are malignant.
  Clonality, antigen loss, and clinical course remain crucial for diagnosis.
• Studying self-resolving conditions like LyP may uncover mechanisms that could be leveraged therapeutically in aggressive CTCL.

Brunner’s presentation underscored the complexity of chronic skin inflammation and its intimate relationship with lymphoproliferative disease biology. For clinicians, understanding these shared pathways and their divergences is essential for accurate diagnosis, safe biologic use, and improved long-term patient outcomes.

References

1. Brunner P. Chronic inflammation – What to learn from cutaneous lymphomas. Oral presentation. Presented at: Inflammatory Skin Disease Summit 2025; November 12-15, 2025; New York, New York.
2. Huang S, Liao M, Chen S, Zhang P, Xu F, Zhang H. Immune signatures of CD4 and CD68 predicts disease progression in cutaneous T cell lymphoma. Am J Transl Res. 2022;14(5):3037-3051. Published 2022 May 15.