Skin-Directed Therapies in Mycosis Fungoides: An Update.

Key Summary Points

Introduction

Primary cutaneous T cell lymphomas (CTCLs) constitute a diverse group of extranodal lymphoproliferative disorders characterized by the presence of malignant T cells in the skin at diagnosis [ 1 , 2 ]. These neoplasms primarily affect the skin but may progress to involve the blood, lymph nodes, and internal organs in advanced stages. The incidence of CTCLs ranges from 0.29 to 0.87 cases per 100,000 person-years in the USA and Europe, with a rising trend observed in recent epidemiological studies [ 3 – 5 ].

Mycosis fungoides (MF) is the most prevalent subtype of CTCL, accounting for approximately 60% of cases. Clinically, MF typically presents with erythematous, scaly skin patches or plaques that can progress to cutaneous tumors or erythroderma [ 6 ]. Despite extensive research, the precise pathogenesis of MF remains elusive. It involves malignant T cell proliferation, immune evasion, and interactions with the skin microenvironment [ 7 – 9 ]. Current models suggest that disease initiation may be driven by genetic mutations in skin-resident effector memory T cells (TRM) for MF [ 10 ]. However, emerging evidence challenges the conventional mature T cell precursor model, given the multifocal nature of MF, the phenotypic plasticity of malignant cells, and the absence of consistent T cell receptor monoclonality.

Given the skin-restricted nature of early-stage MF, skin-directed therapies (SDTs) play a pivotal role in disease management. Modalities such as topical agents, electron beam radiation therapy, phototherapy, photochemotherapy, and photodynamic therapy effectively target malignant cells within the skin while minimizing systemic toxicity. The primary goals of SDTs are to achieve symptom control, improve skin lesions, delay disease progression, and enhance the patient’s quality of life. Treatment is typically individualized on the basis of the extent of skin involvement, patient preference, tolerability, and comorbidities. In this review, we present an updated overview of SDTs for MF, including topical agents such as corticosteroids, retinoids, mechlorethamine, carmustine, imiquimod, as well as photodynamic therapy (PDT), phototherapy modalities including narrowband UVB (nb-UVB) and psoralen–UVA (PUVA), local radiotherapy, total skin electron beam radiotherapy (TSEBT), and total skin helical tomotherapy (TSHT). Moreover, we summarize ongoing clinical trials on SDTs in MF.

Ethical Approval

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

Brief Introduction to Conventional Therapies and the Need for Innovative Approaches

Topical Corticosteroids

Mechanism of Action

Topical corticosteroids are the primary therapy for early-stage MF, as outlined in the EORTC 2023 consensus recommendation [ 11 ]. Their efficacy is attributed to their ability to induce apoptosis, reduce the adhesion of lymphocytes, and suppress cytokine and growth hormone production [ 12 ]. Corticosteroids exert their effect by binding to the cytoplasmatic glucocorticoid receptor, forming a complex that translocates to the nucleus [ 13 ]. This complex modulates mRNA transcription, regulating the expression of genes encoding pro-inflammatory proteins.

Clobetasol propionate 0.05% and other high-potency corticosteroids are particularly effective, with the ointment formulation demonstrating superior efficacy compared to the cream form, although patient compliance should be a vital factor in therapy selection [ 14 ]. While the use of weaker corticosteroids (e.g., fluocinolone acetonide cream at 0.01% to 0.2%) has demonstrated therapeutic benefit [ 15 ], current guidelines recommend the use of high-potency corticosteroids for optimal outcomes [ 11 ].

Corticosteroids are a reliable therapeutic option as first-line treatment owing to their low price, high availability, and universal anti-inflammatory effect, which allows the use of these agents even before a definitive diagnosis based on histological examination, which is often delayed because of the peculiar and nonspecific nature of the disease.

Efficacy by Clinical Stage of MF

Stage Ia: A high overall response rate (ORR) (75–91%) has been observed in early patch or plaque stage MF [ 14 , 16 , 17 ].

Stage Ib: Response rates (RRs) are comparably lower (62–80%), reflecting decreased efficacy with progressing disease [ 14 , 17 ].

Stage IIb: Efficacy of corticosteroids in monotherapy is significantly diminished (33.3%); however, at least a partial response was noted [ 16 ].

Advanced stages (IIIA–IVA): corticosteroids in monotherapy present little to no efficacy; no changes or disease progression are observed. The initial therapeutic effects are observed in the first 3 months after the initiation of treatment [ 14 ].

Safety Profile

The adverse effects (AEs) of treatment are generally infrequent. Commonly reported reactions include irritant dermatitis, purpura, and striae [ 14 ], while cutaneous atrophy is rare, resolves over time, and rarely requires discontinuation of treatment [ 14 , 18 ]. In a long-term study involving high-potency corticosteroids under occlusion, serum cortisol levels were initially routinely monitored, but monitoring was ceased because no patients developed symptoms of adrenal insufficiency [ 14 ].

Adjunctive and Combination Therapy

Corticosteroids in combination regimens have been employed to mitigate AEs to mechlorethamine gel, such as dermatitis and other severe cutaneous intolerance reactions, and thereby enhance compliance, described in Sect. “ Bifunctional Alkylating Agents: Mechlorethamine and Carmustine in MF Therapy ” [ 19 , 20 ]. Furthermore, in advanced-stage MF, corticosteroids are used supportively to manage symptoms such as pruritus, erythema, and scaling, contributing to improved patient comfort [ 11 , 12 ].

Retinoids—Bexarotene and Tazarotene Gel: Mechanism and Application in Mycosis Fungoides

Retinoids are a group of compounds derived from, or structurally/functionally related to, vitamin A. They bind to two receptor families, retinoic acid receptors (RARs) or retinoid X receptors (RXRs) [ 21 ]. Retinoids selectively activate RXRs, but they do not act like retinoic acid receptor agonists [ 22 ].

Bexarotene is a third-generation retinoid X receptor-selective retinoid [ 23 ]. Bexarotene binds and activate transcription factors RXR-α, -β, and -γ. RXR-α, -β, and -γ modulate several cellular processes including cellular differentiation, proliferation, apoptosis, and insulin sensitization [ 22 ]. Bexarotene can lower serum level of CCL2 through the CCL22:CCR4 axis in patients with CTCL, who respond to bexarotene therapy [ 23 , 24 ]. Moreover, bexarotene increases phosphorylation of ataxia telangiectasia mutated protein (ATM) in vitro—a major activator of p53. Therefore, bexarotene plays an antiproliferative role through p53 activation. However, bexarotene does not fundamentally influence p53 expression [ 25 ]. Notably, bexarotene may cause dose-dependent apoptosis of CTCL cells in patients with CTCL [ 26 ]. Zhang et al. showed that bexarotene induces apoptosis in MJ, Hut78, and HH cell lines through decreased expression of survivin, but not Bcl-2 [ 27 ]. Bexarotene increased Bax expression and caused redistribution of Bax from the cytosol to mitochondria in the Hut-78 and HH CTCL cell lines [ 25 ]. Budgin et al. showed that mitogen stimulation decreased IL-4 expression in peripheral blood mononuclear cells taken from patients with high tumor burden, suggesting that bexarotene may lower Th2 cytokine expression [ 28 ]. Wang et al. showed that retinoids increase integrin β7 expression in CTCL lineages and subsequently increased CTCL adhesion [ 29 ]. Richardson et al. showed that bexarotene causes a reduction of CCR4 expression independent of apoptosis and a reduction in lymphocyte chemotaxis in response to TARC among lymphocytes of patients with Sézary syndrome. Moreover, bexarotene treatment decreased the percentage of CCR4 + T cells in patients with Sézary syndrome [ 30 ] (Fig. 1 ).

Topical bexarotene and tazarotene may be used to treat MF as an alternative to systemic therapy with retinoids [ 31 ]. MF in early stages is treated by bexarotene gel if resistance to other topical therapies occurs [ 21 ]. Wennberg et al. showed that 10–60% of patients treated with topical retinoids achieved complete remission (CR). Nonetheless, this is low certainty evidence [ 32 ]. The most common AEs of topical bexarotene therapy include pruritus, pain, irritant dermatitis, and skin inflammation. In a phase 3 clinical trial, Heald et al. showed that CCR (clinical complete response) or PR (partial response) was seen in 54% of patients treated with topical bexarotene [ 33 , 34 ]. Tazarotene gel is an adjuvant therapy method in refractory MF lesions [ 35 ].

Phototherapy and Photochemotherapy

Phototherapy represents one of the first-line treatment options in the early stages of MF and been used for decades. In some cases, it may be the best treatment option for patients, ensuring CR. Phototherapy involves treatment using UV radiation. It can be divided into two main approaches: narrowband UV-B (nb-UVB) and psoralen–UVA (PUVA) [ 36 ].

Nb-UVB Phototherapy in MF Treatment

Nb-UVB comprises UV-B radiation at a wavelength of 311 nm. The mechanism of nb-UVB is modestly understood. It has an impact on Langerhans cells through a decrease in antigen-presenting capacity. Moreover, nb-UVB upregulates interleukin (IL)-2, IL-6, and tumor necrosis factor (TNF) production by keratinocytes. The aforementioned processes may lead to suppression of skin neoplastic clonal T cell function and upregulation of the immune system [ 36 ]. nb-UVB is primarily recommended in the T1a and T2a phase of MF [ 37 ].

The starting dose of nb-UVB depends on the Fitzpatrick skin phototype. For phototype I, a starting dose of 0.13 J/cm 2 is introduced and progressively increased by 0.015 J/cm 2 each time. For phototype II, dosage starts at 0.22 J/cm 2 and increases by 0.025 J/cm 2 every session. Initiating doses for phototypes III, IV, V, and VI are 0.26 J/cm 2 increasing by 0.04 J/cm 2 ; 0.33 J/cm 2 increasing by 0.045 J/cm 2 ; 0.35 J/cm 2 increasing by 0.06; and 0.4 J/cm 2 increasing 0.065 J/cm 2 each time, respectively [ 38 ].

Currently, as a result of the limited accessibility of PUVA treatment, UVB phototherapy remains an optimal therapeutic option, particularly for superficial skin lesions. However, a disadvantage of this therapy is its time-consuming nature. Patients are required to commute to the phototherapy center multiple times per week, which can be challenging and inconvenient given the demands of modern, busy lifestyles.

PUVA in MF Treatment

PUVA utilizes UV radiation at wavelengths ranging from 320 to 340 nm in combination with topical or systemic psoralen—8-methoxypsoralen or 5-methoxypsoralen [ 39 ]. PUVA penetrates deeper into tissue; thus, it is effective in patients with thick plaques. Some data suggests that this approach may be effective in patients resistant to nb-UVB therapy [ 40 , 41 ]. PUVA blocks the cell cycle in the G2/M phase [ 42 ]. Moreover, it causes the formation of reactive oxygen species (ROS), which damage DNA and cell organelles. The phototoxic effect of PUVA involves selectively neoplastic T lymphocytes in the skin [ 40 , 41 ]. PUVA may cause apoptosis via p53-independent programmed cell death mechanisms [ 40 – 42 ]. However, Wei et al. showed that PUVA upregulates USP2, Mdm2, and p53 [ 43 ]. Apoptosis is caused by increased expression of proapoptotic genes such as Bax , BAK , and PUMA accompanied by decreased expression of anti-apoptotic Bcl-2. Nonetheless, the mechanism of PUVA is poorly understood and requires more studies [ 42 ].

PUVA is a first-line treatment with initial CR for early stages MF [ 40 – 43 ]. Initial doses usually start at 0.5 J/cm 2 in phototype I and 1 J/cm 2 in phototype II, progressively increasing by 0.5 J/cm 2 each time. In phototypes III and IV, the doses start at 1.5 and 2 J/cm 2 respectively, increasing by 1 J/cm 2 . In phototypes V and VI the starting dose may be 2.5 and 3 J/cm 2 respectively, increasing by 1.5 J/cm 2 [ 38 ].

Comparison Between PUVA and nb-UVB in MF Treatment

There is an ongoing debate between clinicians regarding superiority of one approach over another. On the one hand, higher complete response and relapse-free interval were longer for PUVA compared to nb-UVB [ 39 ]. On the other hand, potential AEs are nausea, headaches, and light-headedness. Moreover, this therapy requires wearing of protective glasses after treatment [ 44 ]. PUVA is considered mutagenic and carcinogenic [ 33 , 44 ]. High exposure to PUVA does not significantly elevate the risk of basal cell carcinoma (BCC). However, PUVA may increase the risk of squamous cell carcinoma (SCC) depending on exposure. The risk is greatly elevated if the exposure is more than 350 PUVA treatments, but the risk is minor when exposure is lower than 150 PUVA treatments [ 45 ]. It is well established that nb-UVB may be successfully used in early-stage MF treatment [ 36 , 46 ]. Nonetheless, nb-UVB should be switched to PUVA in case of no response to nb-UVB or progression of the disease [ 46 ]. Breneman et al. suggested that in early-stage MF, patients may be successfully treated using PUVA as an alternative to nb-UVB [ 47 ]. The AEs of nb-UVB therapy include erythema, pruritus, burning, and postinflammatory pigmentation [ 36 , 44 ]. However, nb-UVB therapy has significantly fewer AEs than PUVA as a result of no systemic administration of psoralen. Moreover, nb-UVB therapy has lower irradiation times than PUVA and is safe during pregnancy [ 44 ].

Clinical experience shows that PUVA, when available, is an effective therapeutic option particularly for alleviating superficial skin lesions and, most importantly, pruritus. Its major advantage is compatibility with both SDTs and systemic treatments. However, PUVA application is time-consuming and limited to specialized centers.

Phototherapy-Based Combined Therapies for MF

Besides classic photochemotherapy, early-stage MF may be treated with PUVA combined with oral bexarotene. This therapy is a treatment option for adults with early-stage MF, achieving an ORR of 64.48%. Future research should establish standardized regimens for bexarotene dosage, and phototherapy frequency to facilitate the development of an evidence-based approach for early-stage MF [ 48 ]. PUVA combined with bexarotene or interferon alpha (IFNα) exhibit no difference in ORR compared to PUVA alone [ 49 , 50 ]. Thus, PUVA may be used in monotherapy at the beginning in MF stage IA/IB/II. Moreover, PUVA may be combined with retinoids or IFNα, when patients in MF stage IA/IB/II do not respond sufficiently to PUVA monotherapy. However, evidence for these combinations is weak [ 50 ].

Photodynamic Therapy (PDT) in Treating Mycosis Fungoides

Principle of PDT

Photodynamic therapy (PDT) is a modern, non-invasive treatment modality with applications in both oncological and non-oncological diseases. It is widely used in dermatology, oncology, gynecology, and urology [ 51 ]. The procedure involves administering a photosensitizing prodrug intravenously, orally, or topically, followed by activation with light of a specific wavelength after an appropriate incubation period. This activation, occurring in the presence of oxygen, induces a photodynamic reaction that generates ROS in areas where the photosensitizer has accumulated [ 52 , 53 ]. The antitumor effects of PDT result from a combination of direct cytotoxicity against tumor cells, destruction of tumor vasculature, and stimulation of the immune response (Fig. 2 ). The last of these mechanisms is a key advantage over traditional therapies, as it contributes to long-term disease control [ 53 ].

PDT in the Treatment of Mycosis Fungoides

PDT is primarily used to treat early-stage MF (patches or plaques), unilesional, or paucilesional MF lesions, especially for recurrent or resistant lesions, or in areas such as the face and neck [ 54 ]. The effectiveness of PDT is most likely to be reduced in areas of high sensitivity to touch (e.g., inguinal and gluteal areas, hands, feet). The reason for this is the possibility that the photosensitizer occlusion may be interrupted by the patient’s movement. The total thickness of the skin should also be taken into account when evaluating the effectiveness of PDT [ 55 ].

Choice of Photosensitizer

In dermatology, the most commonly used photosensitizers are topically applied 5-ALA (aminolevulinic acid) or MAL (methyl aminolevulinate) [ 11 ]. MAL is preferred in PDT owing to its higher lipophilicity, deeper skin penetration, and greater specificity for neoplastic cells compared with 5-ALA. Additionally, MAL allows for shorter occlusion times, enabling faster treatment [ 55 ].

The effectiveness of PDT in MF treatment depends on wavelength, penetration depth, and treatment frequency. Red light (630 nm) is more commonly used than blue light (400 nm) (65.9% vs. 34.1%), as longer wavelengths penetrate deeper and may be more effective for thicker lesions. Successful treatment often requires multiple PDT sessions. An analysis of clinical data suggests an average of 9.5 treatments per patient (range 1–46), though the optimal number and frequency remain undefined as a result of the lack of randomized controlled trials [ 55 ].

Overview of Clinical Trials

Aminolevulinic Acid-Based Photodynamic Therapy (ALA-PDT)

The first successful use of ALA-PDT for MF treatment was in 1994 [ 56 ] with multiple subsequent studies confirming its efficacy [ 57 – 59 ]. One study examined three patients with plaque-stage MF who were unresponsive to conventional therapies such as PUVA and IFN. In the first case, a woman with infiltrative plaques on the abdomen and elbows showed only partial improvement after PUVA and IFN therapy. Following two ALA-PDT sessions, CR of the abdominal lesions was achieved. The second patient, presenting with an infiltrative plaque on the buttock, also failed to respond to PUVA and IFN. ALA-PDT was applied biweekly, leading to CR. The third patient, resistant to PUVA and nitrogen mustard therapy, underwent three ALA-PDT sessions, resulting in partial remission with more than 75% lesion reduction. The treatment was generally well tolerated, with localized pain as the primary side effect. One patient experienced transient erythema, blistering, and ulceration, which resolved spontaneously within a week [ 60 ].

ALA-PDT has also been investigated in the treatment of Woringer–Kolopp disease (WKD), a rare variant of MF. A case study described a 10-year-old boy with a single WKD lesion on the foot. Over the course of 13 months, nine ALA-PDT sessions were administered, leading to complete resolution of the lesion and disease-free status at follow-up [ 61 ].

Despite the numerous good results of using ALA in PDT, a number of limitations hinder its continued use. One example is poor tissue penetration, which means that the compound cannot reach tumor tissue thicker than 3 mm to induce sufficient necrosis. In addition, ALA requires an incubation period between application and exposure to light to be metabolically converted to active protoporphyrin IX, causing patients to have to wait a long time during treatment [ 62 ].

Methyl Aminolevulinate-Based Photodynamic Therapy (MAL-PDT)

MAL is more commonly used in PDT, its advantages being increased lipophilicity, deeper skin penetration, and greater specificity for neoplastic cells. With MAL, occlusion times are also shorter, allowing faster treatment [ 55 ]. MAL-PDT has demonstrated efficacy in MF treatment, supported by clinical evidence [ 63 – 65 ].

A case report described a 70-year-old patient with tumor-stage MF presenting with extensive lesions on the face, toes, buttocks, and calcaneus region. Previous therapies, including PUVA, bexarotene, and total-skin electron beam radiation, had yielded poor results. MAL cream was applied to affected areas, except for the face, and occluded for 3 h before red light irradiation. Depending on the site, two to three treatment sessions were conducted biweekly. This approach resulted in complete clinical and histological remission, with no recurrence in treated areas. New lesions that developed in untreated regions responded well to conventional therapies [ 66 ].

A case series further investigated the efficacy of MAL-PDT in four patients with MF. All patients underwent MAL application followed by red light exposure, yielding two CRs and two partial remissions. The therapy was particularly effective in difficult-to-treat areas, such as the feet and pubic region. Side effects were mild, primarily limited to transient burning sensations [ 67 ].

A larger study assessed MAL-PDT in 12 patients with early-stage MF, each receiving six monthly PDT sessions. A clinical response was observed in 75% of cases, including six CRs and three partial remissions, while the remaining three patients exhibited stable disease. Lesions in sheltered areas, such as the torso, buttocks, and thighs, responded more favorably than those on sun-exposed regions like the arms and legs. During therapy, 42% of patients developed new lesions in untreated areas, suggesting the localized nature of MAL-PDT efficacy [ 68 ].

Side Effects and Contraindications

The side effects of PDT are generally transient, with the most common reactions including stinging, erythema, swelling, pruritus, epithelial peeling, pustules, and postinflammatory hyperpigmentation. Among these, pain during phototherapy is the most frequently reported complaint [ 69 ]. Studies suggest that ALA-PDT is often more painful than MAL-PDT [ 70 , 71 ]. Additionally, a case of photocontact urticaria with an intense stinging sensation has been documented following ALA therapy, appearing during the second PDT session and localized to the treated area [ 72 ].

In addition to pain, ALA-PDT has certain limitations that may affect its clinical use. One notable drawback is its relatively poor tissue penetration, restricting its effectiveness in treating deeper lesions. Moreover, ALA requires a prolonged incubation period before activation with light, extending treatment duration and potentially causing discomfort for patients [ 62 ]. These factors can limit its applicability, particularly in cases requiring deeper tissue penetration or shorter procedural times.

Contraindications to PDT include a nonresponsive tumor, a history of porphyria, systemic lupus erythematosus, photosensitive dermatoses, and allergy to the active ingredients in the photosensitizer [ 69 ].

Updates in PDT

A 2022 study evaluated the efficacy and safety of topical, visible light-activated hypericin ointment as a non-mutagenic PDT for early-stage MF [ 73 ]. The FLASH study, a multicenter, placebo-controlled, double-blind, randomized phase 3 clinical trial (2015–2020), enrolled 169 adult patients with stage IA–IIA MF across 39 medical centers in the USA. Patients were randomized (2:1) to receive either hypericin or placebo, applied twice weekly for 6 weeks. In subsequent cycles, all participants received the active drug, with efficacy increasing to 40% and 49% after two and three cycles, respectively. Significant clinical responses were observed across various demographic and disease factors. AEs were mild and primarily skin-related, supporting the safety and efficacy of hypericin PDT for early-stage MF [ 73 ].

A recent case report detailed the treatment of a 57-year-old man with folliculotropic mycosis fungoides (FMF) who experienced relapse after achieving CR with low-dose total skin electron beam therapy (TSEBT). To manage the recurrence, the patient underwent CO 2 laser-assisted PDT using MAL and red light. The procedure consisted of two phases: laser treatment followed by PDT. In the laser phase, hair follicle vaporization and fractional scan microablation were performed to enhance photosensitizer penetration. The PDT phase involved the application of 16% MAL cream for 3 h, followed by an 8-min irradiation session. Post treatment, the patient experienced mild redness and swelling, with pain rated 6/10 on the numeric rating scale (NRS) scale. Four weeks after a single session, the patient achieved CR of facial lesions [ 74 ]. These findings suggest that CO 2 laser-assisted PDT could be a promising therapeutic option for FMF, particularly for lesions in sensitive areas, though further studies are needed to validate its efficacy and optimize treatment protocols.

Imidazoquinolines with Immunomodulatory Properties: Imiquimod and Resiquimod in MF Treatment

Mechanism of Action

Imiquimod, an imidazoquinoline amine compound, serves as an immune response modifier exhibiting significant antiviral and antitumor effects. It enhances the innate immune system by activating Toll-like receptor 7 (TLR7) on plasmacytoid dendritic cells. This activation results in the stimulation of TLR7-mediated MyD88 signaling, the induction of nuclear factor kappa B (NF-κB), and the release of proinflammatory cytokines such as IFNα, IFNγ, and IL-12. These processes collectively promote an innate immune response and establish a Th1-dominant environment [ 75 , 76 ]. Additionally, imiquimod suppresses the anti-apoptotic protein Bcl-2, further contributing to its antitumor effects. Myeloid dendritic cells, which are more prevalent in the skin and express TLR8 instead of TLR7, provide a strong rationale for the use of a TLR8 agonist in therapeutic applications [ 77 , 78 ].

Resiquimod activates both TLR7 on plasmacytoid dendritic cells and TLR8 on myeloid dendritic cells. This dual activation leads to the production of IFNα, TNF, and IL-12, while also stimulating circulating immune cells. Phase I clinical trials have demonstrated activation of both circulating dendritic cells and natural killer (NK) cells in many patients. The capacity of resiquimod to induce systemic immune activation, facilitate cytokine release, and produce an abscopal effect positions it as a promising add-on to immunotherapy strategies for CTCL [ 79 , 80 ]. Resiquimod stimulates both plasmacytoid and myeloid-derived dendritic cells, making it a more effective option than imiquimod in some therapeutic contexts [ 81 – 83 ].

Efficacy of Imiquimod in the Treatment of MF

Several small-scale studies highlight the efficacy of imiquimod in early-stage MF, suggesting that topical imiquimod cream could be a promising option for treating individual lesions [ 84 ]. A 21-year-old with FMF started treatment with topical 5% imiquimod daily. After 1 month, the patient developed an indurated plaque with shallow erosions and mild irritation. Following another month of treatment, shallow ulcerations appeared, prompting the discontinuation of imiquimod. One month after stopping the treatment, the plaque completely resolved, leaving an atrophic pink patch. There was no recurrence at the 5-month follow-up [ 85 ].

Two stage IIB patients with MF, including one with large cell transformation, whose tumors were treated with imiquimod 5% cream after failing prior therapies, demonstrated a complete response to imiquimod 5% cream without recurrence over 8 years and 2 years of follow-up. Both patients were already using oral bexarotene, and imiquimod was added as adjuvant therapy. It is improbable that the resolution of the tumors can be exclusively attributed to bexarotene, as the tumors in both patients had been increasing in size for several months prior to the initiation of imiquimod treatment [ 86 ].

Gordon et al. described cases of stage IB MF successfully treated with topical imiquimod 5% cream, achieving complete clearance in subsets traditionally refractory to conventional therapies [ 87 ]. The first case involved FMF in a challenging area (infiltrated plaques of the left upper and lower eyelid and right nasal sidewall), effectively treated with imiquimod monotherapy without the risk of skin atrophy seen with corticosteroids. The second case demonstrated efficacy of imiquimod in plaque disease progressing to stage IIB MF. Both cases showed good tolerance, with mild macular erythema noted within 2 weeks of treatment, and no maintenance therapy was required after lesion resolution. Tumor MF cleared faster than FMF [ 87 ]. Another case involved a patient with stage IB MF. The treatment was complicated by multiple BCCs and renal cell carcinoma (RCC). Topical imiquimod 5% was initiated, particularly on the genital area. A significant improvement was observed, with the patient achieving prolonged (6 months) clearance. However, the treatment caused notable lethargy, aching, and flu-like symptoms [ 77 ].

Penile involvement in MF is rare. One patient underwent 6 weeks of treatment with topical clobetasol propionate, which failed to provide improvement. He was then switched to 5% imiquimod, and after 4–5 months of therapy, the patient achieved CR. During treatment he developed pain at the application site and a skin erosion requiring cessation of therapy [ 88 , 89 ].

In a study by Chong et al., the intervention group received imiquimod 5%, which was applied daily for a contact duration of 8 h over a period of 16 weeks. AEs reported by patients in the imiquimod group were characterized as mild lesional irritation [ 49 , 90 ]. Additional AEs and reactions include pruritus, burning sensations, erythema, edema, erosion, ulceration, and crusting at the site of application, which are associated with the activation of local immune responses.

Topical imiquimod 5% is an alternative topical agent for early-stage refractory MF and may provide benefit in patients with plaques of MF resistant to other therapies. Similarly to use in BCC and actinic keratosis, an inflammatory reaction occurs. However, the high RR (80%) and possibility of durable CR in refractory disease make it a useful add-on therapy in the management of MF [ 77 ].

Common AEs of imiquimod include skin irritation, pruritus, burning sensations, erythema, edema, erosion, ulceration, and crusting at the site of application, which are associated with the activation of local immune responses. Resiquimod is similarly well tolerated and has been found in clinical trials to generally cause mild AEs. Reported side effects include skin irritation in 25% of patients; skin erosion in 33%; fever in 17%; headaches in 17%; myalgia in 8% of patients [ 80 , 86 ]. Notably, the application of moisturizers or topical steroids may facilitate the recovery process [ 91 ]. Imiquimod functions as a topical irritant, leading to irritant contact dermatitis. Nevertheless, in contrast to other irritants, it promotes considerable exfoliation [ 92 ]. These properties are often utilized in the management of nonmelanoma skin cancers, such as superficial BCC [ 93 ]. Additionally, imiquimod is approved for the treatment of actinic keratosis and condyloma acuminata. Its effectiveness as a topical therapy for MF has been highlighted in numerous reports [ 86 , 94 ].

Efficacy of Resiquimod in the Treatment of MF

Twelve patients diagnosed with stage IA–IIA MF participated in a phase 1 clinical trial assessing the efficacy of 0.03% and 0.06% topical resiquimod gel. Treatment was applied several times per week, increasing to daily use for up to 8 weeks. The treated lesions exhibited significant improvement in 75% of the patients, with 30% experiencing complete clearance of all treated lesions. Resiquimod also induced regression of untreated lesions; 92% of patients had more than a 50% improvement in body surface area involvement by the mSWAT analysis, and two patients experienced complete clearing of disease. TCR sequencing revealed eradication or significant reduction of clonal T cells in several cases, particularly with the higher concentration (0.06%), which also led to faster responses. While local irritation was more frequent at the higher dose, the treatment was generally well tolerated [ 82 ]. One key finding in early-stage disease (stage IA–IIB) is that activation of innate immunity with resiquimod led to a response in a significant number of patients, with treatment-related AEs limited to local irritation [ 83 ].

Bifunctional Alkylating Agents: Mechlorethamine and Carmustine in MF Therapy

Mechlorethamine

Mechlorethamine (NM, nitrogen mustard, chlormethine, 2,2′-dichloro- N -methyldiethylamine) is a synthetic bifunctional DNA-alkylating agent. The antitumor properties of NM arise from its capacity to create DNA–DNA and DNA–protein cross-links (DPCs), which hinder DNA replication, transcription, and damage repair processes, ultimately resulting in genomic instability [ 95 , 96 ] (Fig. 3 .).

NM was utilized as a chemical weapon during World War I (mustard gas). Subsequent investigations revealed that individuals who survived exposure to NM experienced lymphocytopenia. Additionally, it was found that NM can inhibit the proliferation of rapidly dividing malignant T cells [ 97 ]. In 2013, the US Food and Drug Administration (FDA) granted approval for the treatment of stage IA and IB MF with NM in patients who have undergone one prior treatment, with the exception of patients who have been administered NM in the past 2 years or with carmustine ever [ 98 ].

Several clinical trials demonstrated the effectiveness of chlormethine gel formulation in treating MF, with RR for early-stage MF ranging from 58.5% to 83% [ 99 – 101 ]. Regarding the preferred formulation of chlormethine, the gel was superior to ointment owing to higher and faster RR [ 99 , 102 ]. For patients with higher Fitzpatrick skin phototypes, chlormethine gel may be a more suitable option compared to certain other skin-directed therapies, especially topical steroids, which can lead to hypopigmentation in individuals with darker skin tones. Similarly, mechlorethamine surpasses the effectiveness of phototherapy, which was significantly less responsive compared to patients with lower Fitzpatrick skin phototypes [ 103 ]. Additional research is needed to assess the safety, tolerability, and efficacy of chlormethine gel in pediatric populations. The known teratogenic effects of mechlorethamine restrict its use in pregnant or breastfeeding patients [ 104 ].

Contact dermatitis is the primary AE responsible for the early discontinuation of topical chlormethine [ 19 , 99 , 105 ]. To evaluate the effectiveness of topical triamcinolone, 0.1% ointment, in alleviating contact dermatitis that is associated with the application of topical chlormethine gel in the treatment of MF, a randomized Mechlorethamine Induced Dermatitis Avoidance Study (MIDAS) was conducted ( NCT03380026 ). The application of triamcinolone, 0.1% ointment, improved tolerability with preserved efficacy of NM gel. Notably, there was a statistically significant reduction of symptoms, as measured by the 50% reduction in SCORD score observed at the 2-month mark in the group receiving triamcinolone treatment [ 105 ]. The SCORD score, adapted from the SCORAD assessment tool, evaluates the clinical severity of dermatitis through three key criteria: (1) percentage of total lesions exhibiting dermatitis; (2) the severity of various symptoms including redness, swelling, oozing or crusting, scratch marks, skin thickening, and dryness on a scale ranging from 0 to 3; and (3) patients’ self-reported levels of current itchiness on a scale from 0 to 10. Similarly, Kim et al. showed that concomitant steroid therapy and dosage adjustments reduce the risk of dermatitis and skin irritation [ 101 ] (Table 1 ). Overall, mechlorethamine is safe and well tolerated, with no evidence of its systemic absorption [ 99 ]. Concurrent steroid treatment and dosage adjustments may be beneficial in alleviating or preventing AEs.

On the basis of clinical experience, topical treatment with mechlorethamine is a valuable therapeutic option; however, it requires careful instruction of the patient or their caregiver regarding proper storage and application of the medication, as well as clinical expertise in the prevention and management of contact dermatitis.

Carmustine

Carmustine (1,3-bis(2-chloroethyl)-1-nitrosourea, BCNU) is a lipophilic chemotherapeutic prodrug that is metabolized to generate 2-chloroethanol adducts, resulting in cross-links between DNA strands, which inhibits DNA replication and DNA transcription [ 106 ] (Fig. 3 ). BCNU underwent clinical trials in 1964 and received approval from the FDA in 1977 for the treatment of several brain tumors, including glioma, glioblastoma multiforme, medulloblastoma, and astrocytoma, as well as for multiple myeloma and both Hodgkin and non-Hodgkin lymphomas [ 107 ].

Efficacy of Carmustine in the Treatment of MF

The ORR for patients diagnosed with MF treated with conventional topical BCNU therapy ranged from 55% to 80% [ 108 ] (Table 1 ). The administration of dual-dose O 6 -benzylguanine in conjunction with BCNU for the treatment of MF has demonstrated a high ORR of 88%, accompanied by a relatively prolonged mean duration of complete response (CR) of 14.43 months. In comparison to the single-dose O 6 -benzylguanine combined with topical BCNU, the dual-dose regimen resulted in a shorter treatment duration, a reduced mean total dose of BCNU, and an increased incidence of cutaneous AEs. It is recommended to explore alternative formulations of O 6 -benzylguanine, such as oral and patch forms, to enhance the ease of administration. Additionally, authors suggest further studies on the potential unique mechanism of toxicity associated with BCNU, which may involve the hyperactivation of macrophages [ 108 ].

Safety and Adverse Effects of Carmustine

In contrast to NM, there is evidence indicating the systemic absorption of BCNU. Given the potential for BCNU to cause bone marrow suppression due to this systemic absorption, it is recommended to limit the treatment to < 10% of the body surface area and to monitor complete blood counts throughout the course of therapy [ 109 ]. The majority of patients treated with BCNU exhibited erythema, with intense erythema frequently preceding the development of patchy telangiectasia (Table 1 ).

Total Skin Electron Beam Radiotherapy (TSEBT) and Total Skin Helical Tomotherapy (TSHT)

Total skin electron beam therapy (TSEBT) is used when a significant area of the body is affected by the disease. In the therapy, ionizing radiation is used in order to penetrate the skin, targeting pathological tissues while reducing AEs [ 11 , 110 ]. TSEBT is a particularly difficult radiotherapy technique that requires specialist facilities, which is why this therapy is only offered in large clinics where the percentage of patients with MF is significant [ 111 ].

Total skin helical tomotherapy (TSHT) is an advanced radiotherapy technique used for extensive cutaneous involvement in MF. TSHT utilizes photons delivered in a helical pattern, enabling precise dose distribution across the entire skin surface while sparing deeper organs at risk (OARs). This approach is especially beneficial for patients with thicker or recurrent lesions, as photons provide deeper penetration than electrons, ensuring coverage of nodular or tumor-stage disease. However, TSHT is highly specialized and requires a helical tomotherapy unit, a rare and costly technology available only at selected centers. Treatment is delivered with the patient in a supine position, improving comfort compared to standing techniques like TSEBT, but demanding precise planning to minimize dose to underlying tissues [ 112 ]. As bone marrow suppression caused by TSHT was described, patients should be closely monitored for myelosuppression [ 113 , 114 ] (Table 1 ). As a result of its complexity and limited accessibility, TSHT is typically reserved for cases where TSEBT is contraindicated or insufficient.

Mechanism of Action in TSEBT

Ionizing radiation induces T cell apoptosis through damage to double-stranded DNA. This DNA dysfunction activates a cascade of intracellular events, initiating the activation of protein kinases, which phosphorylate proteins localized near the DNA damage. Finally, the protein p53 is phosphorylated, and subsequently it dislocates from the inhibitory complex with MDM2. Apoptosis is initiated by the transcription of proapoptotic genes like BAX and NOXA that are involved in the intrinsic apoptotic pathway as a result of the activity of p53 [ 115 ]. Furthermore, neoplastic T cells exhibit remarkable higher sensitivity to ionizing radiation, allowing one to use lower doses, resulting in toxicity only for malignant cells and sparing the non-neoplastic ones [ 115 , 116 ] (Fig. 4 ).

Techniques Used in TSEBT

The TSEBT can be performed by three primary methods: the large electron field technique (e.g., Stanford technique and its modifications), rotational techniques, and translation techniques, with the Stanford technique being the most common one [ 111 , 117 ]. The conventional dose used in TSEBT ranges from 30 to 36 Gy, delivered over a period of up to 8 weeks [ 111 ]. However, the latest evidence suggests that lower doses may result in comparable efficacy while significantly reducing the risk of toxicity [ 11 , 111 , 118 ].

Efficacy of Conventional-Dose and Low-Dose TSEBT

A study involving 146 patients conducted by Jones et al. evaluated two different TSEBT regimens: group A (25 patients) received a dose of 30 Gy, while group B (121 patients) received a dose of 35 Gy [ 119 ]. Overall, 81.5% of patients achieved CR, with 64% of participants in group A and 85% in group B. The highest rates of CR were observed in T1 stage MF (88%) and T2 (80%). However, in those with T3, RRs were notably lower (62%). An extensive retrospective study evaluating the efficacy of conventional-dose TSEBT (30 Gy) in treating stage T2 and T3 MF between 1970 and 2007 revealed a CR of 75% in patients with T2 MF and 47% in those with T3 [ 110 ]. Results underscore the substantial efficacy of TSEBT in T2 MF, while indicating comparatively lower efficacy in stage T3 disease [ 110 ].

However, recent studies and case reports emphasize the increasing significance of low doses of TSEBT owing to reduced toxicity while preserving comparable therapeutic effects [ 11 , 111 , 118 , 120 , 121 ]. A retrospective study conducted in the Netherlands by Smits et al. compared the efficacy of low dose (12 Gy) and high dose (30 Gy) in patients mainly with T2 and T3 stage MF [ 122 ]. A total of 51 patients were examined during the study. In the study, 31 participants received high-dose and 20 received low-dose TSEBT. The findings demonstrated that both dosing regimens resulted in a high RR. The study reported positive responses to the therapy, with 25.5% of the 51 patients resulting in CR and 54.4% with PR, while no statistical significance was observed between both regime treatments. Likewise, remission outcomes were determined by disease stage rather than dosage, since all patients with progression were classified as stage T3 [ 122 ].

In a study conducted in 2023, TSEBT in low doses (8 Gy in two fractions) was evaluated in the treatment of 18 patients with advanced-stage MF (stages IIb–IV) [ 123 ]. Fifteen out of 18 received prior systemic therapy. The study reported RR of 88.9%, including three cases of CR. The median time to subsequent therapy was 12 months, with a great reduction in mSWAT scores. This research acknowledges the efficacy of TSEBT in disease control and providing palliation in the advanced stages of MF [ 124 ].

Safety and Adverse Effects of TSEBT

A 2022 meta-analysis incorporating 12 studies with a combined total of 616 patients treated with both standard-dose and low-dose TSEBT pointed to a nominal incidence of severe AEs [ 125 ]. However, the analysis showed that nearly all patients experienced at least one AE. The most frequently reported AE was partial or complete reversible alopecia, reported by every patient treated with the standard dose and 44% of those receiving the low dose. Other commonly notified AEs were radiation dermatitis, nail toxicity, xerosis, and limb edema, all of which were more prevalent in the standard-dose TSEBT group [ 41 ].

A significant concern related to TSEBT therapy is the potential long-term risk of developing radiation-associated skin cancer, particularly for patients with early stages of MF and long life expectancy [ 11 ]. However, there are a limited number of long-term studies to assess the impact of TSEBT on the subsequent development of skin cancers. A 1995 study tracking 164 patients treated with TSEBT between 1974 and 1990 noticed the development of various skin cancers over time. Among these patients, six developed melanoma within 12–95 months after TSEBT and 34 developed SCC between 11 months and 10 years post treatment [ 126 ]. Therefore, a significant proportion of patients developed melanoma and non-melanoma skin cancer post TSEBT. In the latest large retrospective study conducted by Lutsyk et al., patients undergoing TSEBT therapy were followed for 36 years to evaluate the development of skin cancers [ 127 ]. Eight cases of melanoma were reported in the group taking radiotherapy, compared to only one case in the non-exposed group. Overall, 33 different types of skin cancers were observed in the TSEBT-treated group, while only three cases were documented in the group where another form of treatment was applied. However, it is worth mentioning that the study highlighted an increased likelihood of developing malignancies in almost every cell in the MF population. Thus, it is demanding to evaluate those findings. Additionally, as a result of the retrospective character of the study, not all major variables could be adequately controlled. While an association between TSEBT and the presence of “skin-related cancers” is implicit, an exact stratification of the risk remains uncertain and requires further investigation in the future [ 127 ].

Local Radiotherapy (RT)

Mechanism of Action

Local RT exerts its therapeutic effects in MF primarily through the induction of DNA damage. Ionizing radiation induces both single- and double-strand DNA breaks directly and indirectly via ROS, which oxidize nucleic acids, proteins, and lipids. The resulting DNA damage activates a cascade of repair mechanisms; however, in radiosensitive neoplastic T cells, such as those in MF, the damage frequently leads to cell death through apoptosis or mitotic catastrophe [ 128 , 129 ].

At low doses, RT also exerts immunomodulatory effects in addition to its direct cytotoxicity. It promotes the polarization of macrophages toward a proinflammatory M1 phenotype and increases the infiltration of NK cells within the tumor microenvironment (TME) [ 130 ]. Furthermore, low-dose RT reprograms the TME, enhancing immune cell trafficking and activity, especially in cutaneous lesions [ 130 ].

RT-induced double-stranded DNA breaks can result in the formation of micronuclei and the release of cytosolic DNA, which activates the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway. This leads to type I interferon release and supports immune activation against tumor cells [ 129 , 131 ]. However, this immunogenic potential is dose-dependent. RT doses exceeding 12–18 Gy upregulate the expression of the DNA exonuclease TREX1, which degrades cytoplasmic single- and double-stranded DNA, thereby suppressing the cGAS-STING pathway and blunting the antitumor immune response [ 128 , 129 , 132 ].

This dose-dependent dichotomy highlights the importance of careful dose selection in clinical practice to optimize both cytotoxic and immune-mediated therapeutic outcomes in MF.

Efficacy of Local RT

Radiotherapy is a well-established and highly effective modality for all stages of MF as a result of the high radiosensitivity of malignant T lymphocytes [ 133 ]. Local RT, using superficial or orthovoltage beams, demonstrates excellent outcomes in early-stage disease (IA–IIB), with CR rates ranging from 88% to 100% depending on dose and lesion type [ 134 , 135 ].

For instance, Neelis et al. reported a 92% CR rate using 8 Gy in two fractions, whereas lower-dose regimens (e.g., 4 Gy in two fractions) achieved significantly reduced response rates (30%) [ 136 ]. Recent evidence from Pena et al. further supports the efficacy of low-dose RT, defined as 2 × 4 Gy over 2 days. In their retrospective study involving 73 lesions in 18 patients, an OR rate was 93%, with a CR rate of 17% in non-tumoral lesions (non-TLs) and only 4% in tumoral lesions (TLs). Local control at 24 months was 100% in non-TLs compared to 61% in TLs, indicating significantly lower long-term efficacy in more aggressive disease phenotypes. These findings suggest that while low-dose RT is effective for palliation, higher doses may be warranted in TLs or lesions with large cell transformation [ 121 ].

For patients with unilesional or minimal stage IA disease, local RT can be curative. Doses between 20 and 30 Gy have consistently achieved CR rates of 95–100% with durable local control and low relapse rates [ 137 , 138 ]. Piccinno et al. observed a CR rate of 88% in a retrospective cohort of 100 patients with MF treated with conventional superficial RT, with a 5-year local control rate of 85% [ 135 ].

Safety and Adverse Effects of Local RT

Radiotherapy for MF is generally well tolerated, with minimal acute and long-term toxicities when appropriately fractionated and targeted. Acute skin reactions, such as erythema, desquamation, or localized ulceration, may occur within the irradiated field but are usually self-limited. Long-term adverse effects include hypopigmentation, alopecia, telangiectasias, and, rarely, radiation-induced secondary malignancies. In the Piccinno et al. study, no serious complications were reported, and cosmetic outcomes were acceptable or good in over 90% of patients [ 134 ].

The choice of dose and fractionation must balance efficacy with potential toxicity, especially in anatomically sensitive areas such as the face, scalp, or genitals. Low-dose regimens (8–12 Gy) are favored in palliative settings because of the possibility of repeat treatments in overlapping fields, particularly for recurrent or difficult-to-treat regions like the lower extremities [ 136 ].

In our clinical practice, we select palliative localized radiotherapy for cases involving solitary tumor lesions coexisting with erythematous and infiltrative lesions. As side effects we notice erythema and desquamation in the area of radiation. Overall, radiotherapy remains one of the most effective and versatile treatment options for MF across its clinical spectrum, with well-documented safety and favorable patient outcomes.

Conclusions and Future Directions

MF remains an incurable malignancy, with treatment strategies focused on symptom control, improving quality of life, and prolonging remission. At the same time MF in early stages is characterized by excellent prognosis. As demonstrated in this review, there are currently promising topical treatment options that may become available in the near future. Moreover, conventional therapies remain effective and readily accessible in routine clinical practice.

Current SDTs, including topical corticosteroids, phototherapy, and topical chemotherapy, play a crucial role in managing early-stage disease with minimal systemic toxicity (Table 2 ). When selecting a treatment modality, it is essential to consider not only the disease stage but also the impact on the patient’s quality of life (QoL). The chosen approach should aim to minimize disruption to daily functioning. For instance, phototherapy requires multiple weekly visits to specialized centers, which may be located hundreds of kilometers away from the patient’s residence. In such cases, less frequent interventions or topical ointments and gels may be more suitable alternatives. However advanced-stage MF often requires combination approaches, integrating systemic agents with SDTs.

In contrast, advanced-stage MF often requires combination approaches, integrating systemic agents with skin-directed modalities. Pruritus remains a significant concern for many patients, highlighting the need to consider this symptom when developing novel therapeutic strategies, including skin-targeted approaches.

Despite progress in therapeutic options, there is still an unmet need for more effective and durable treatments. Future studies should focus on the development of targeted therapies that selectively modulate the TME, immune response, and malignant T cell proliferation. The ideal treatment would provide CR for the longest possible duration. Additionally, further research into the molecular pathogenesis of MF may lead to the identification of novel biomarkers for early diagnosis, prognosis, and therapeutic response prediction.

Ongoing clinical trials and translational research will play a crucial role in improving existing treatment protocols and broadening the range of therapies available for MF. The primary objective is to develop more effective, less toxic, and potentially curative treatment options (Table 3 ).

Acknowledgments

Medical Writing/Editorial Assistance

No medical writing or editorial assistance was received.

Author Contributions

Conceptualization, Maciej Tota, Magdalena Łyko, Julita Kulbacka, Alina Jankowska-Konsur; Writing—original draft preparation, Maciej Tota, Magdalena Łyko, Piotr Misiąg, Julia Łacwik, Julia Laska, Karol Biliński, Julita Kulbacka, Alina Jankowska-Konsur; Writing—review and editing, Maciej Tota, Magdalena Łyko, Julita Kulbacka, Alina Jankowska-Konsur, Visualization—Maciej Tota and Piotr Misiąg; Supervision, Julita Kulbacka and Alina Jankowska-Konsur; Funding acquisition, Julita Kulbacka and Alina Jankowska-Konsur All authors have read and agreed to the published version of the manuscript.

Funding

This research and the Rapid Service Fee was funded by Wroclaw Medical University, grant number SUBZ.A510.25.056.

Data Availability

Data sharing is not applicable to this article as no datasets were generated or analyzed.

Declarations

Conflict of interest

Maciej Tota has nothing to disclose. Magdalena Łyko has nothing to disclose. Piotr Misiąg has nothing to disclose. Julia Łacwik has nothing to disclose. Julia Laska has nothing to disclose. Karol Biliński has nothing to disclose. Julita Kulbacka has nothing to disclose. Alina Jankowska-Konsur has nothing to disclose.

Ethical Approval

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

Footnotes

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Maciej Tota and Magdalena Łyko contributed equally to this work as joint first authors.

Change history

9/14/2025

Layout of Table 3 updated

References

1. Willemze R, Hodak E, Zinzani PL, et al. Primary cutaneous lymphomas: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2018;29:30–40. 10.1093/ANNONC/MDY133.

2. Dummer R, Vermeer MH, Scarisbrick JJ, et al. Cutaneous T cell lymphoma. Nat Rev Dis Primers. 2021. 10.1038/S41572-021-00296-9.

3. Vermeer M. Epidemiology of cutaneous lymphoma. Br J Dermatol. 2021;184:993–4. 10.1111/BJD.19829.

4. Cai ZR, Chen ML, Weinstock MA, et al. Incidence trends of primary cutaneous T-cell lymphoma in the US from 2000 to 2018: a SEER population data analysis. JAMA Oncol. 2022;8:1690–2. 10.1001/JAMAONCOL.2022.3236.

5. Dobos G, Miladi M, Michel L, et al. Recent advances on cutaneous lymphoma epidemiology. Presse Med. 2022. 10.1016/J.LPM.2022.104108.

6. Willemze R, Cerroni L, Kempf W, et al. The 2018 update of the WHO-EORTC classification for primary cutaneous lymphomas. Blood. 2019;133:1703–14. 10.1182/BLOOD-2018-11-881268.

7. Litvinov IV, Shtreis A, Kobayashi K, et al. Investigating potential exogenous tumor initiating and promoting factors for cutaneous T-cell lymphomas (CTCL), a rare skin malignancy. Oncoimmunology. 2016. 10.1080/2162402X.2016.1175799.

8. Krejsgaard T, Lindahl LM, Mongan NP, et al. Malignant inflammation in cutaneous T-cell lymphoma—a hostile takeover. Semin Immunopathol. 2017;39:269. 10.1007/S00281-016-0594-9.

9. Li R, Strobl J, Poyner EFM, et al. Cutaneous T cell lymphoma atlas reveals malignant TH2 cells supported by a B cell-rich tumor microenvironment. Nat Immunol. 2024;25:2320–30. 10.1038/S41590-024-02018-1.

10. Campbell JJ, Clark RA, Watanabe R, Kupper TS. Sezary syndrome and mycosis fungoides arise from distinct T-cell subsets: a biologic rationale for their distinct clinical behaviors. Blood. 2010;116:767–71. 10.1182/BLOOD-2009-11-251926.

11. Latzka J, Assaf C, Bagot M, et al. EORTC consensus recommendations for the treatment of mycosis fungoides/Sézary syndrome - update 2023. Eur J Cancer. 2023. 10.1016/J.EJCA.2023.113343.

12. Jawed SI, Myskowski PL, Horwitz S, et al. Primary cutaneous T-cell lymphoma (mycosis fungoides and Sézary syndrome): Part II. prognosis, management, and future directions. J Am Acad Dermatol. 2014;70:223.e1-223.e17. 10.1016/J.JAAD.2013.08.033.

13. Mehta AB, Nadkarni NJ, Patil SP, et al. Topical corticosteroids in dermatology. Indian J Dermatol Venereol Leprol. 2016;82:371. 10.4103/0378-6323.178903.

14. Zackheim HS. Treatment of patch-stage mycosis fungoides with topical corticosteroids. Dermatol Ther. 2003;16:283–7. 10.1111/J.1396-0296.2003.01639.X.

15. Farber EM, Cox AJ, Steinberg J, McClintock RP. Therapy of mycosis fungoides with topically applied fluocinolone acetonide under occlusive dressing. Cancer. 1966;19(2):237–45.

16. Kartan S, Shalabi D, O’Donnell M, et al. Response to topical corticosteroid monotherapy in mycosis fungoides. J Am Acad Dermatol. 2021;84:615–23. 10.1016/J.JAAD.2020.05.043.

17. Quaglino P, Prince HM, Cowan R, et al. Treatment of early-stage mycosis fungoides: results from the PROspective Cutaneous Lymphoma International Study (PROCLIPI study). Br J Dermatol. 2021;184:722. 10.1111/BJD.19252.

18. Zackheim HS, Kashani-Sabet M, Amin S. Topical corticosteroids for mycosis fungoides: experience in 79 patients. Arch Dermatol. 1998;134:949–54. 10.1001/ARCHDERM.134.8.949.

19. Gilmore ES, Alexander-Savino CV, Chung CG, Poligone B. Evaluation and management of patients with early-stage mycosis fungoides who interrupt or discontinue topical mechlorethamine gel because of dermatitis. JAAD Case Rep. 2020;6:878–81. 10.1016/J.JDCR.2020.05.031.

20. De Quatrebarbes J, Estève E, Bagot M, et al. Treatment of early-stage mycosis fungoides with twice-weekly applications of mechlorethamine and topical corticosteroids: a prospective study. Arch Dermatol. 2005;141:1117–20. 10.1001/ARCHDERM.141.9.1117.

21. Khalil S, Bardawil T, Stephan C, et al. Retinoids: a journey from the molecular structures and mechanisms of action to clinical uses in dermatology and adverse effects. J Dermatolog Treat. 2017;28:684–96. 10.1080/09546634.2017.1309349.

22. Scarisbrick JJ, Morris S, Azurdia R, et al. U.K. consensus statement on safe clinical prescribing of bexarotene for patients with cutaneous T-cell lymphoma. Br J Dermatol. 2013;168:192–200. 10.1111/BJD.12042.

23. Tanita K, Fujimura T, Sato Y, et al. Bexarotene reduces production of CCL22 from tumor-associated macrophages in cutaneous T-cell lymphoma. Front Oncol. 2019;9:468903. 10.3389/FONC.2019.00907.

24. Luna DE, Shinohara MM. New molecular and biological markers in cutaneous T cell lymphoma: therapeutic implications. Curr Hematol Malig Rep. 2023;18:83–8. 10.1007/S11899-023-00692-W.

25. Nieto-Rementería N, Pérez-Yarza G, Boyano MD, et al. Bexarotene activates the p53/p73 pathway in human cutaneous T-cell lymphoma. Br J Dermatol. 2009;160:519–26. 10.1111/J.1365-2133.2008.08931.X.

26. Abbott RA, Whittaker SJ, Morris SL, et al. Bexarotene therapy for mycosis fungoides and Sézary syndrome. Br J Dermatol. 2009;160:1299–307. 10.1111/J.1365-2133.2009.09037.X.

27. Zhang C, Hazarika P, Ni X, Weidner DA, Duvic M. Induction of apoptosis by bexarotene in cutaneous T-cell lymphoma cells. Clin Cancer Res. 2002;8(5):1234–40.

28. Budgin JB, Richardson SK, Newton SB, et al. Biological effects of bexarotene in cutaneous T-cell lymphoma. Arch Dermatol. 2005;141:315–20. 10.1001/ARCHPEDI.161.4.356.

29. Wang L, Demarco SS, Chen J, et al. Retinoids bias integrin expression and function in cutaneous T-cell lymphoma. J Invest Dermatol. 2015;135:2102–8. 10.1038/JID.2015.122.

30. Richardson SK, Newton SB, Bach TL, et al. Bexarotene blunts malignant T-cell chemotaxis in Sezary syndrome: reduction of chemokine receptor 4-positive lymphocytes and decreased chemotaxis to thymus and activation-regulated chemokine. Am J Hematol. 2007;82:792–7. 10.1002/AJH.20952.

31. Kempf W, Mitteldorf C. Cutaneous T-cell lymphomas—an update 2021. Hematol Oncol. 2021;39:46–51. 10.1002/HON.2850.

32. Wennberg E, Richards PQ, Bain PA, et al. Topical treatments for early-stage mycosis fungoides using grading recommendations assessment, development and evaluation (GRADE) criteria: a systematic review. JAAD Int. 2021;3:26–41. 10.1016/J.JDIN.2021.01.002.

33. Michielon E, López González M, Stolk DA, et al. A reconstructed human melanoma-in-skin model to study immune modulatory and angiogenic mechanisms facilitating initial melanoma growth and invasion. Cancers (Basel). 2023;15:2849. 10.3390/CANCERS15102849/S1.

34. Heald P, Mehlmauer M, Martin AG, et al. Topical bexarotene therapy for patients with refractory or persistent early-stage cutaneous T-cell lymphoma: results of the phase III clinical trial. J Am Acad Dermatol. 2003;49:801–15. 10.1016/S0190-9622(03)01475-0.

35. Apisarnthanarax N, Talpur R, Ward S, et al. Tazarotene 0.1% gel for refractory mycosis fungoides lesions: an open-label pilot study. J Am Acad Dermatol. 2004;50:600–7. 10.1016/J.JAAD.2003.09.005.

36. Gökdemir G, Barutcuoǧlu D, Sakiz D, Köşlüt A. Narrowband UVB phototherapy for early-stage mycosis fungoides: evaluation of clinical and histopathological changes. J Eur Acad Dermatol Venereol. 2006;20:804–9. 10.1111/J.1468-3083.2006.01635.X.

37. Şanlı H, Mart HME, Şanlı H, Mart HME. Treatment algorithms for mycosis fungoides and Sézary syndrome. Turk J Dermatol. 2025;19:41–60. 10.4274/TJD.GALENOS.2024.60362.

38. Olsen EA, Hodak E, Anderson T, et al. Guidelines for phototherapy of mycosis fungoides and Sézary syndrome: a consensus statement of the United States Cutaneous Lymphoma Consortium. J Am Acad Dermatol. 2016;74:27–58. 10.1016/J.JAAD.2015.09.033.

39. Phan K, Ramachandran V, Fassihi H, Sebaratnam DF. Comparison of narrowband UV-B with psoralen–UV-A phototherapy for patients with early-stage mycosis fungoides: a systematic review and meta-analysis. JAMA Dermatol. 2019;155:335–41. 10.1001/JAMADERMATOL.2018.5204.

40. Vieyra-Garcia P, Fink-Puches R, Porkert S, et al. Evaluation of low-dose, low-frequency oral psoralen–UV-A treatment with or without maintenance on early-stage mycosis fungoides: a randomized clinical trial. JAMA Dermatol. 2019;155:538–47. 10.1001/JAMADERMATOL.2018.5905.

41. Grandi V, Delfino C, Pileri A, Pimpinelli N. Maintenance phase in psoralen–ultraviolet A phototherapy of early-stage mycosis fungoides. A critically appraised topic. Br J Dermatol. 2017;177:406–10. 10.1111/BJD.15302.

42. Liszewski W, Naym DG, Biskup E, Gniadecki R. Psoralen with ultraviolet A-induced apoptosis of cutaneous lymphoma cell lines is augmented by type I interferons via the JAK1–STAT1 pathway. Photodermatol Photoimmunol Photomed. 2017;33:164–71. 10.1111/PHPP.12302.

43. Wei T, Biskup E, Gjerdrum LMR, et al. Ubiquitin-specific protease 2 decreases p53-dependent apoptosis in cutaneous T-cell lymphoma. Oncotarget. 2016;7:48391–400. 10.18632/ONCOTARGET.10268.

44. Clark C, Dawe RS, Evans AT, et al. Narrowband TL-01 phototherapy for patch-stage mycosis fungoides. Arch Dermatol. 2000;136:748–52. 10.1001/ARCHDERM.136.6.748.

45. Stern RS. The risk of squamous cell and basal cell cancer associated with psoralen and ultraviolet A therapy: a 30-year prospective study. J Am Acad Dermatol. 2012;66:553–62. 10.1016/J.JAAD.2011.04.004.

46. Diederen PVMM, Van Weelden H, Sanders CJG, et al. Narrowband UVB and psoralen-UVA in the treatment of early-stage mycosis fungoides: a retrospective study. J Am Acad Dermatol. 2003;48:215–9. 10.1067/MJD.2003.80.

47. Breneman D, Duvic M, Kuzel T, et al. Phase 1 and 2 trial of bexarotene gel for skin-directed treatment of patients with cutaneous T-cell lymphoma. Arch Dermatol. 2002;138:325–32. 10.1001/ARCHDERM.138.3.325.

48. Ginsburg E, Hennessy K, Mhaskar R, Seminario-Vidal L. Treatment of early-stage mycosis fungoides with oral bexarotene and phototherapy: a systematic review and meta-analysis. Dermatol Ther. 2022;35:e15418. 10.1111/DTH.15418.

49. Valipour A, Jäger M, Wu P, et al. Interventions for mycosis fungoides. Cochrane Database Syst Rev. 2020. 10.1002/14651858.CD008946.PUB3/MEDIA/CDSR/CD008946/URN:X-WILEY:14651858:MEDIA:CD008946:CD008946-CMP-007.03.

50. Humme D, Nast A, Erdmann R, et al. Systematic review of combination therapies for mycosis fungoides. Cancer Treat Rev. 2014;40:927–33. 10.1016/J.CTRV.2014.06.005.

51. Kwiatkowski S, Knap B, Przystupski D, et al. Photodynamic therapy – mechanisms, photosensitizers and combinations. Biomed Pharmacother. 2018;106:1098–107. 10.1016/j.biopha.2018.07.049.

52. Allison RR. Photodynamic therapy: oncologic horizons. Future Oncol. 2014;10:123–4. 10.2217/fon.13.176.

53. Donohoe C, Senge MO, Arnaut LG, Gomes-da-Silva LC. Cell death in photodynamic therapy: from oxidative stress to anti-tumor immunity. Biochim Biophys Acta Rev Cancer. 2019;1872:188308. 10.1016/j.bbcan.2019.07.003.

54. Caccavale S, Tancredi V, Vitiello P, et al. Photodynamic therapy as an effective treatment for cutaneous lymphomas. Pharmaceutics. 2022;15:47. 10.3390/pharmaceutics15010047.

55. Hooper M, Hatch L, Seminario-Vidal L. Photodynamic therapy of mycosis fungoides: a systematic review of case studies. Photodermatol Photoimmunol Photomed. 2021;37:549–52. 10.1111/phpp.12698.

56. Svanberg K, Andersson T, Killander D, et al. Photodynamic therapy of non-melanoma malignant tumours of the skin using topical δ-amino levulinic acid sensitization and laser irradiation. Br J Dermatol. 1994;130:743–51. 10.1111/j.1365-2133.1994.tb03412.x.

57. Díez Recio E, Zambrano B, Alonso ML, et al. Topical 5-aminolevulinic acid photodynamic therapy for the treatment of unilesional mycosis fungoides: a report of two cases and review of the literature. Int J Dermatol. 2008;47:410–3. 10.1111/j.1365-4632.2008.03177.x.

58. Orenstein A, Haik J, Tamir J, et al. Photodynamic therapy of cutaneous lymphoma using 5-aminolevulinic acid topical application. Dermatol Surg. 2000;26:765–70. 10.1046/j.1524-4725.2000.00056.x.

59. Edström DW, Porwit A, Ros AM. Photodynamic therapy with topical 5-aminolevulinic acid for mycosis fungoides: clinical and histological response. Acta Derm Venereol. 2001;81:184–8. 10.1080/000155501750376276.

60. Han D, Xue J, Wang T, Liu Y. Observation of clinical efficacy of photodynamic therapy in 3 patients with refractory plaque-stage mycosis fungoides. Photodiagnosis Photodyn Ther. 2016;16:9–11. 10.1016/j.pdpdt.2016.07.011.

61. Mendese GW, Beckford A, Krejci N, et al. Pagetoid reticulosis in a prepubescent boy successfully treated with photodynamic therapy. Clin Exp Dermatol. 2012;37:759–61. 10.1111/j.1365-2230.2012.04352.x.

62. Vallecorsa P, Di Venosa G, Gola G, et al. Photodynamic therapy of cutaneous T-cell lymphoma cell lines mediated by 5-aminolevulinic acid and derivatives. J Photochem Photobiol B. 2021;221:112244. 10.1016/j.jphotobiol.2021.112244.

63. Zane C, Venturini M, Sala R, Calzavara-Pinton P. Photodynamic therapy with methylaminolevulinate as a valuable treatment option for unilesional cutaneous T-cell lymphoma. Photodermatol Photoimmunol Photomed. 2006;22:254–8. 10.1111/j.1600-0781.2006.00246.x.

64. Kim S, Kang D, Kang J, et al. Photodynamic therapy with methyl-aminolaevulinic acid for mycosis fungoides. Acta Derm Venereol. 2012;92:264–8. 10.2340/00015555-1261.

65. Hegyi J, Frey T, Arenberger P. Unilesional mycosis fungoides treated with photodynamic therapy. A case report. Acta Dermatoven APA. 2008;17:75.

66. Hasson A, Navarrete-Dechent C, Nicklas C, Sazunic I. Topical photodynamic therapy with 5-aminolevulinate for the treatment of tumor-stage mycosis fungoides: a case report. Int J Dermatol. 2013;52:1535–7. 10.1111/j.1365-4632.2011.05427.x.

67. Pileri A, Sgubbi P, Agostinelli C, et al. Photodynamic therapy: an option in mycosis fungoides. Photodiagnosis Photodyn Ther. 2017;20:107–10. 10.1016/j.pdpdt.2017.09.004.

68. Quéreux G, Brocard A, Saint-Jean M, et al. Photodynamic therapy with methyl-aminolevulinic acid for paucilesional mycosis fungoides: a prospective open study and review of the literature. J Am Acad Dermatol. 2013;69:890–7. 10.1016/j.jaad.2013.07.047.

69. Wan MT, Lin JY. Current evidence and applications of photodynamic therapy in dermatology. Clin Cosmet Investig Dermatol. 2014;7:145–63. 10.2147/CCID.S35334.

70. Wiegell SR. Pain associated with photodynamic therapy using 5-aminolevulinic acid or 5-aminolevulinic acid methylester on tape-stripped normal skin. Arch Dermatol. 2003;139:1173. 10.1001/archderm.139.9.1173.

71. Moloney FJ, Collins P. Randomized, double-blind, prospective study to compare topical 5-aminolaevulinic acid methylester with topical 5-aminolaevulinic acid photodynamic therapy for extensive scalp actinic keratosis. Br J Dermatol. 2007;157:87–91. 10.1111/j.1365-2133.2007.07946.x.

72. Yokoyama S, Nakano H, Nishizawa A, et al. A case of photocontact urticaria induced by photodynamic therapy with topical 5-aminolaevulinic acid. J Dermatol. 2005;32:843–7. 10.1111/j.1346-8138.2005.tb00857.x.

73. Kim EJ, Mangold AR, DeSimone JA, et al. Efficacy and safety of topical hypericin photodynamic therapy for early-stage cutaneous T-cell lymphoma (mycosis fungoides). JAMA Dermatol. 2022;158:1031. 10.1001/jamadermatol.2022.2749.

74. Scotti B, Piraccini BM, Pileri A. Folliculotropic mycosis fungoides of the face successfully treated combining CO2 laser and conventional photodynamic therapy (c-PDT). Photodiagnosis Photodyn Ther. 2024;50:104377. 10.1016/j.pdpdt.2024.104377.

75. Sauder DN. Immunomodulatory and pharmacologic properties of imiquimod. J Am Acad Dermatol. 2000;43:10.1067/MJD.2000.107808.

76. Nomura A, Mizuno M, Noto D, et al. Different spatial and temporal roles of monocytes and monocyte-derived cells in the pathogenesis of an Imiquimod induced lupus model. Front Immunol. 2022;13:764557. 10.3389/FIMMU.2022.764557/FULL.

77. Shipman A, Scarisbrick J. New treatment options for mycosis fungoides. Indian J Dermatol. 2016;61:119. 10.4103/0019-5154.174085.

78. Gaurav V, Mehta N, Gupta S. “Immunopeeling” using imiquimod for xeroderma pigmentosum. Indian Dermatol Online J. 2023;15:673. 10.4103/IDOJ.IDOJ_446_23.

79. Huen AO, Rook AH. Toll receptor agonist therapy of skin cancer and cutaneous T-cell lymphoma. Curr Opin Oncol. 2014;26:237–44. 10.1097/CCO.0000000000000048.

80. Weiner DM, Durgin JS, Wysocka M, Rook AH. The immunopathogenesis and immunotherapy of cutaneous T cell lymphoma: current and future approaches. J Am Acad Dermatol. 2021;84:597–604. 10.1016/J.JAAD.2020.12.026.

81. Berg S, Villasenor-Park J, Haun P, Kim EJ. Multidisciplinary management of mycosis fungoides/Sézary syndrome. Curr Hematol Malig Rep. 2017;12:234–43. 10.1007/S11899-017-0387-9.

82. Rook AH, Gelfand JM, Wysocka M, et al. Topical resiquimod can induce disease regression and enhance T-cell effector functions in cutaneous T-cell lymphoma. Blood. 2015;126:1452–61. 10.1182/BLOOD-2015-02-630335.

83. Ramelyte E, Dummer R, Guenova E. Investigative drugs for the treatment of cutaneous T-cell lymphomas (CTCL): an update. Expert Opin Investig Drugs. 2019;28:799–809. 10.1080/13543784.2019.1654995.

84. Freiman A, Sasseville D. Treatment of mycosis fungoides: overview. J Cutan Med Surg. 2006;10:228–33. 10.2310/7750.2006.00051.

85. Shalabi D, Vadalia N, Nikbakht N. Revisiting imiquimod for treatment of folliculotropic mycosis fungoides: a case report and review of the literature. Dermatol Ther (Heidelb). 2019;9:807–14. 10.1007/S13555-019-00317-2.

86. Lewis DJ, Byekova YA, Emge DA, Duvic M. Complete resolution of mycosis fungoides tumors with imiquimod 5% cream: a case series. J Dermatolog Treat. 2017;28:567–9. 10.1080/09546634.2017.1294728.

87. Gordon MC, Sluzevich JC, Jambusaria-Pahlajani A. Clearance of folliculotropic and tumor mycosis fungoides with topical 5% imiquimod. JAAD Case Rep. 2015;1:348. 10.1016/J.JDCR.2015.08.007.

88. Chiam LYT, Chan YC. Solitary plaque mycosis fungoides on the penis responding to topical imiquimod therapy. Br J Dermatol. 2007;156:560–2. 10.1111/J.1365-2133.2006.07599.X.

89. Schaufler C, Ferenczi K, Hegde U, Ristau BT. Complete response of penile mycosis fungoides with systemic brentuximab therapy. Urol Case Rep. 2020;34:101460. 10.1016/J.EUCR.2020.101460.

90. Chong A, Loo WJ, Banney L, et al. Imiquimod 5% cream in the treatment of mycosis fungoides–a pilot study. J Dermatolog Treat. 2004;15:118–9. 10.1080/09546630310019373.

91. Mori H, Arita K, Yamaguchi T, et al. Effects of topical application of betamethasone on imiquimod-induced psoriasis-like skin inflammation in mice. Kobe J Med Sci. 2016;62:E79.

92. Meyer T, Surber C, French LE, Stockfleth E. Resiquimod, a topical drug for viral skin lesions and skin cancer. Expert Opin Investig Drugs. 2013;22:149–59. 10.1517/13543784.2013.749236.

93. Urosevic M, Dummer R, Conrad C, et al. Disease-independent skin recruitment and activation of plasmacytoid predendritic cells following imiquimod treatment. J Natl Cancer Inst. 2005;97:1143–53. 10.1093/JNCI/DJI207.

94. Wagstaff AJ, Perry CM. Topical imiquimod: a review of its use in the management of anogenital warts, actinic keratoses, basal cell carcinoma and other skin lesions. Drugs. 2007;67:2187–210. 10.2165/00003495-200767150-00006.

95. Torrecilla I, Ruggiano A, Kiianitsa K, et al. Isolation and detection of DNA–protein crosslinks in mammalian cells. Nucleic Acids Res. 2024;52:525–47. 10.1093/NAR/GKAD1178.

96. Michaelson-Richie ED, Ming X, Codreanu SG, et al. Mechlorethamine-induced DNA-protein cross-linking in human fibrosarcoma (HT1080) cells. J Proteome Res. 2011;10:2785–96. 10.1021/PR200042U.

97. Guenova E, Ortiz-Romero PL, Poligone B, Querfeld C. Mechanism of action of chlormethine gel in mycosis fungoides. J Eur Acad Dermatol Venereol. 2023;37:1739–48. 10.1111/JDV.19237.

98. Talpur R, Venkatarajan S, Duvic M. Mechlorethamine gel for the topical treatment of stage IA and IB mycosis fungoides-type cutaneous T-cell lymphoma. Expert Rev Clin Pharmacol. 2014;7:591–7. 10.1586/17512433.2014.944500.

99. Lessin SR, Duvic M, Guitart J, et al. Topical chemotherapy in cutaneous T-cell lymphoma: positive results of a randomized, controlled, multicenter trial testing the efficacy and safety of a novel mechlorethamine, 0.02%, gel in mycosis fungoides. JAMA Dermatol. 2013;149:25–32. 10.1001/2013.JAMADERMATOL.541.

100. Kim YH, Martinez G, Varghese A, Hoppe RT. Topical nitrogen mustard in the management of mycosis fungoides: update of the Stanford experience. Arch Dermatol. 2003;139:165–73. 10.1001/ARCHDERM.139.2.165.

101. Kim EJ, Guitart J, Querfeld C, et al. The PROVe study: US real-world experience with chlormethine/mechlorethamine gel in combination with other therapies for patients with mycosis fungoides cutaneous T-cell lymphoma. Am J Clin Dermatol. 2021;22:407–14. 10.1007/S40257-021-00591-X.

102. Querfeld C, Scarisbrick JJ, Assaf C, et al. Post hoc analysis of a randomized, controlled, phase 2 study to assess response rates with chlormethine/mechlorethamine gel in patients with stage IA-IIA mycosis fungoides. Dermatology. 2022;238:347–57. 10.1159/000516138.

103. Jang MS, Baek JW, Park JB, et al. Narrowband ultraviolet B phototherapy of early stage mycosis fungoides in Korean patients. Ann Dermatol. 2011;23:474. 10.5021/AD.2011.23.4.474.

104. Crimp C, Gangal A, Tarabadkar ES, Shinohara MM. Mechlorethamine hydrochloride gel in the treatment of mycosis fungoides-type cutaneous T-cell lymphoma (MF-CTCL): a focus on patient selection and special considerations. Cancer Manag Res. 2022;14:3271–9. 10.2147/CMAR.S351420.

105. Alexander-Savino CV, Chung CG, Gilmore ES, et al. Randomized mechlorethamine/chlormethine induced dermatitis assessment study (MIDAS) establishes benefit of topical triamcinolone 0.1% ointment cotreatment in mycosis fungoides. Dermatol Ther (Heidelb). 2022;12:643–54. 10.1007/S13555-022-00681-6.

106. Faria SHDM, Teleschi JG, Teodoro L, Almeida MO. Computational investigation of the carmustine (BCNU) alkylation mechanism using the QTAIM, IQA, and NBO models. Struct Chem. 2021;32:79–96. 10.1007/S11224-020-01604-X.

107. Andrés CMC, Pérez de la Lastra JM, Munguira EB, et al. Dual-action therapeutics: DNA alkylation and antimicrobial peptides for cancer therapy. Cancers. 2024;2024(16):3123. 10.3390/CANCERS16183123.

108. Tacastacas JD, Chan DV, Carlson S, et al. Evaluation of O6-benzylguanine-potentiated topical carmustine for mycosis fungoides: a phase 1–2 clinical trial. JAMA Dermatol. 2017;153:413–20. 10.1001/JAMADERMATOL.2016.5793.

109. Galper S, Smith B, Wilson L. Diagnosis and management of mycosis fungoides. Oncology (Williston Park). 2010;24:491–501.

110. Navi D, Riaz N, Levin YS, et al. The Stanford University experience with conventional-dose, total skin electron-beam therapy in the treatment of generalized patch or plaque (T2) and tumor (T3) mycosis fungoides. Arch Dermatol. 2011;147:561–7. 10.1001/ARCHDERMATOL.2011.98.

111. Chowdhary M, Song A, Zaorsky NG, Shi W. Total skin electron beam therapy in mycosis fungoides—a shift towards lower dose? Chin Clin Oncol. 2019;8:9–9. 10.21037/CCO.2018.09.02.

112. Wang H, Pi Y, Guo Y, et al. Influencing factors of total skin irradiation with helical tomotherapy. Front Oncol. 2022;12:852345. 10.3389/FONC.2022.852345.

113. Schaff EM, Rosenberg SA, Olson SJ, et al. Bone marrow suppression as a complication of total skin helical tomotherapy in the treatment of mycosis fungoides. Radiat Oncol. 2018;13:1–5. 10.1186/S13014-018-1013-2/TABLES/2.

114. Kitaguchi M, Yamashita H, Takenaka R, et al. Helical skin radiation therapy including total skin radiation therapy using tomotherapy for primary cutaneous lymphoma with bone marrow suppression as a related adverse event. Pract Radiat Oncol. 2021;11:e308–21. 10.1016/j.prro.2020.11.007.

115. Kacinski BM, Flick M. Apoptosis and cutaneous T cell lymphoma. Ann N Y Acad Sci. 2001;941:194–9. 10.1111/J.1749-6632.2001.TB03723.X.

116. Kouhen F, Oqbani K, El Gouach H, et al. Overcoming chemotherapy resistance in cutaneous T-cell lymphoma: a successful case of high-dose radiotherapy management. Cureus. 2023. 10.7759/CUREUS.43959.

117. Diamantopoulos S, Platoni K, Dilvoi M, et al. Clinical implementation of total skin electron beam (TSEB) therapy: a review of the relevant literature. Phys Med. 2011;27:62–8. 10.1016/j.ejmp.2010.09.001.

118. Canu D, Pham-Ledard A, Ouhabrache N, Beylot-Barry M. Changes in total skin electron beam therapy modalities for mycosis fungoides: a single-centre study. Ann Dermatol Venereol. 2022;149:180–4. 10.1016/J.ANNDER.2022.02.006.

119. Jones GW, Tadros A, Hodson DI, et al. Prognosis with newly diagnosed mycosis fungoides after total skin electron radiation of 30 or 35 GY. Int J Radiat Oncol Biol Phys. 1994;28:839–45. 10.1016/0360-3016(94)90103-1.

120. Aral İP, Göçer Gürok N, Konuk AO, Üçer Ö. Ultra-low-dose radiotherapy for palliation of mycosis fungoides. Case Rep Dermatol Med. 2020. 10.1155/2020/4216098.

121. Pena J, Cull D, Strowd LC, et al. Response and local control in patients treated with low-dose radiotherapy for tumoral mycosis fungoides. Leuk Lymphoma. 2023;64:2202–7. 10.1080/10428194.2023.2254435.

122. Smits K, Quint KD, Vermeer MH, et al. Total skin electron beam therapy for cutaneous T-cell lymphomas in the Netherlands: a retrospective analysis of treatment outcomes and selection for high or low dose schedule. Clin Transl Radiat Oncol. 2022;33:77–82. 10.1016/J.CTRO.2021.12.001.

123. Elsayad K, Weishaupt C, Moustakis C, et al. Ultrahypofractionated low-dose total skin electron beam in advanced-stage mycosis fungoides and Sézary syndrome. Int J Radiat Oncol Biol Phys. 2023;117:164–70. 10.1016/j.ijrobp.2023.02.052.

124. Elsayad K, Susek KH, Eich HT. Total skin electron beam therapy as part of multimodal treatment strategies for primary cutaneous T-cell lymphoma. Oncol Res Treat. 2017;40:244–52. 10.1159/000475634.

125. Grandi V, Simontacchi G, Grassi T, et al. Short-term efficacy and safety of total skin electron beam therapy in mycosis fungoides: systematic review and meta-analysis. Dermatol Ther. 2022;35:e15840. 10.1111/DTH.15840.

126. Licata AG, Wilson LD, Braverman IM, et al. Malignant melanoma and other second cutaneous malignancies in cutaneous T-cell lymphoma: the influence of additional therapy after total skin electron beam radiation. Arch Dermatol. 1995;131:432–5. 10.1001/ARCHDERM.1995.01690160060009.

127. Lutsyk M, Ben-Yosef R, Bergman R, et al. Total skin electron irradiation and sequential malignancies in mycosis fungoides patients: longitudinal study. Clin Oncol. 2018;30:618–24. 10.1016/j.clon.2018.06.006.

128. Vanpouille-Box C, Alard A, Aryankalayil MJ, et al. DNA exonuclease Trex1 regulates radiotherapy-induced tumour immunogenicity. Nat Commun. 2017;8:15618. 10.1038/NCOMMS15618.

129. Deng L, Liang H, Xu M, et al. STING-dependent cytosolic DNA sensing promotes radiation-induced type I interferon-dependent antitumor immunity in immunogenic tumors. Immunity. 2014;41:843. 10.1016/J.IMMUNI.2014.10.019.

130. Barsoumian HB, Sezen D, Menon H, et al. High plus low dose radiation strategy in combination with TIGIT and PD1 blockade to promote systemic antitumor responses. Cancers (Basel). 2022;14:221. 10.3390/CANCERS14010221/S1.

131. Harding SM, Benci JL, Irianto J, et al. Mitotic progression following DNA damage enables pattern recognition within micronuclei. Nature. 2017;548:466–70. 10.1038/NATURE23470.

132. Stetson DB, Ko JS, Heidmann T, Medzhitov R. Trex1 prevents cell-intrinsic initiation of autoimmunity. Cell. 2008;134:587–98. 10.1016/J.CELL.2008.06.032/ATTACHMENT/3D1B81B5-3BAC-4034-A470-7EE079A86872/MMC2.XLS.

133. Kirova YM, Piedbois Y, Haddad E, et al. Radiotherapy in the management of mycosis fungoides: indications, results, prognosis. Twenty years experience. Radiother Oncol. 1999;51:147–51. 10.1016/S0167-8140(99)00050-X.

134. Tandberg DJ, Craciunescu O, Kelsey CR. Radiation therapy for cutaneous T-cell lymphomas. Dermatol Clin. 2015;33:703–13. 10.1016/j.det.2015.05.006.

135. Piccinno R, Caccialanza M, Percivalle S. Minimal stage IA mycosis fungoides. Results of radiotherapy in 15 patients. J Dermatolog Treat. 2009;20:165–8. 10.1080/09546630802516571.

136. Neelis KJ, Schimmel EC, Vermeer MH, et al. Low-dose palliative radiotherapy for cutaneous B- and T-cell lymphomas. Int J Radiat Oncol Biol Phys. 2009;74:154–8. 10.1016/j.ijrobp.2008.06.1918.

137. Micaily B, Miyamoto C, Kantor G, et al. Radiotherapy for unilesional mycosis fungoides. Int J Radiat Oncol Biol Phys. 1998;42:361–4. 10.1016/S0360-3016(98)00218-1.

138. Ally MS, Pawade J, Tanaka M, et al. Solitary mycosis fungoides: a distinct clinicopathologic entity with a good prognosis: a series of 15 cases and literature review. J Am Acad Dermatol. 2012;67:736–44. 10.1016/J.JAAD.2012.02.039.

139. Wehkamp U, Jost M, Gosmann J, et al. Management of chlormethine gel treatment in mycosis fungoides patients in two German skin lymphoma centers. J Dtsch Dermatol Ges. 2021;19:1057–9. 10.1111/DDG.14462.

140. Papadavid E, Koumourtzis M, Nikolaou V, et al. Chlormethine gel is effective for the treatment of skin lesions in patients with early- and late-stage mycosis fungoides in clinical practice. J Eur Acad Dermatol Venereol. 2022;36:1751–7. 10.1111/JDV.18183.

141. Macarthur KM, Jariwala N, Kim EJ, Rook AH. Topical carmustine as monotherapy or as multimodality therapy for folliculotropic mycosis fungoides. Acta Derm Venereol. 2017;97:373. 10.2340/00015555-2551.

142. Zackheim HS. Topical carmustine (BCNU) in the treatment of mycosis fungoides. Dermatol Ther. 2003;16:299–302. 10.1111/J.1396-0296.2003.01641.X.

143. Santiago-et-Sanchez-Mateos D, Juarez A, Garcia-Diez A, et al. Topical carmustine in the treatment of mycosis fungoides: efficacy and side effects. J Am Acad Dermatol. 2010;62:AB96. 10.1016/j.jaad.2009.11.651.

144. Zackheim HS, Epstein EH, McNutt NS, et al. Topical carmustine (BCNU) for mycosis fungoides and related disorders: a 10-year experience. J Am Acad Dermatol. 1983;9:363–74. 10.1016/S0190-9622(83)70143-X.

Associated Data

Data Availability Statement

Data sharing is not applicable to this article as no datasets were generated or analyzed.