Primary cutaneous T-cell lymphomas (CTCL) are a heterogeneous group of non-Hodgkin lymphomas characterized by infiltration of the skin by mature malignant T-cells.9 MF and SS are the most common forms of CTCL accounting for around 50% of the primary CTCLs.10 MF is generally an indolent, progressive monoclonal proliferation of skin-homing memory T-cells with the potential to progress to involve the lymph nodes, blood and viscera.11 MF usually appears in the sixth decade of life with a 1.5-2:1 male/female ratio.12 There is usually a prolonged clinical course with evolution of skin findings that include scaly erythemic patches or plaques that can progress to tumors and may be localized or disseminated. It often begins as a nonspecific dermatitis or is presumed to be AD, with some postulating dermatitis changing into this T-cell lymphoma by virtue of chronic antigen stimulation.13 SS is characterized by the triad of erythroderma, generalized lymphadenopathy and the presence of malignant T-cells with cerebriform nuclei (Sezary cells) in the blood, lymph nodes and skin.9,14
MF and SS show similar features on skin biopsy with epidermotropic lymphoid infiltrates composed of small to medium-sized lymphocytes with cerebriform nuclei. 15 The neoplastic T-cells have a mature T-cell phenotype, CD3+, CD4+, CD45RO+, CD8-. Loss of CD7 or CD5 expression is common.8
In 2019 the first reports of Mycosis fungoides following administration of dupilumab for treatment of AD were published.16 This raised questions and concerns over dupilumab’s safety. The Food and Drug Administration approved dupilumab in 2017 for the treatment of moderate to severe AD in adults, which has been shown to have a strong efficacy in improving cutaneous disease and reducing pruritus.17 Atopic dermatitis (AD) affects approximately 15-20% of children and 1-3% of adults worldwide and is commonly treated with emollients and topical corticosteroids (TCS).18,19 However, new therapies such as dupilumab have arisen in recent years. Dupilumab is a monoclonal antibody directed against the IL-4-receptor-alpha subunit, inhibiting the IL-4 and IL-13 pathways. These pathways play prominent roles in inflammation, epidermal barrier dysfunction, and itch in AD.1
Primary cutaneous T-cell lymphomas (CTCL) lesions have demonstrated a high expression of IL-13 receptors, which lead to hypothesize that dupilumab may also be an effective treatment for mycosis fungoides and Sézary syndrome.20,4 However, with the more widespread use of dupilumab therapy in patients with presumed AD, increased cases of MF and SS have been reported. This raises questions of whether there is a role of IL13 in the pathophysiology of dupilumab/ MF coincidence. In addition, whether dupilumab is safe in AD patients as well as the many others who use dupilumab off label in various other dermatologic conditions21
Multiple theories have been postulated to explain this phenomenon, recognizing dupilumab as a catalyst for the progression of MF. The prevailing theory is that these patients had early-stage MF that was misdiagnosed as AD and that dupilumab exacerbated the MF.5 This theory is plausible due to the difficulty of distinguishing AD from early-stage MF both clinically and histologically. MF patients often present with complaints of pruritic scaly patches or generalized erythema similarly to AD. Additionally, patch stage early MF mimics AD with higher proportions of reactive lymphocytes and a smaller proportion of neoplastic T-lymphocytes. Thus, without a high degree of clinical suspension or classic signs weight loss and lack of atopy, MF may be misdiagnosed as AD. However, the role that dupilumab plays in the evolution of AD into MF remains unknown. One theory behind this worsening is that this specific cohort of patients who later developed MF while on dupilumab had a CTCL resistant to the IL-4 and IL-13 blockade.5Another theory suggests that dupilumab hastens the progression of MF by altering the Th1/Th2 cytokine balance towards a primarily Th1-driven response which is characteristic of early-stage MF.21 Others have suggested that dupilumab promotes the malignant transformation of benign lymphoid infiltrates found in AD, leading to MF. This has been supported by the findings of MF evolving from chronic inflammatory states, such as AD.22 Given the many theories, it is apparent that additional studies are warranted to further elucidate the causes and mechanisms behind the phenomenon, which may include additional malignancies including Hodgkin lymphoma and nodal anaplastic large cell lymphoma.23,24
Our results showed an inverse relationship between the stage of MF at diagnosis and the length of dupilumab treatment (i.e. the higher MF stage at diagnosis the shorter the duration of dupilumab to MF onset. Older age patients correlated significantly with decreased time to MF onset and male gender had a significantly higher risk of MF onset during dupilumab treatment. This suggests that specific populations may be more at risk for quicker disease progression and aggressive forms of MF. Thus, close monitoring both clinically and histologically may be warranted in elderly male patients.
Limitation:
Our study reviewed all published MF cases on dupilumab to our knowledge and provided an exploratory correlation analysis. This analysis was based on limited available observational data. Further studies are necessary to fully understand the relationship between age, gender, and duration of dupilumab treatment in patients who develop MF.