Version May 2023
INTRODUCTION — Mycosis fungoides (MF) is an extranodal, indolent non-Hodgkin lymphoma of T cell origin that primarily develops in the skin but can ultimately involve the lymph nodes, blood, and visceral organs. Early stage (IA to IIA) disease consists of papules, patches, or plaques, with limited, if any, lymph node involvement and no visceral involvement (table 1A-B). Patients with limited skin involvement plus the more aggressive histopathologic findings of folliculotropism or transformed large cell variants and those with blood involvement are treated similar to patients with more advanced disease. (See 'Special scenarios' below.)
The management of early stage MF will be discussed here. The management of more advanced stage MF and the more aggressive leukemic variant, Sézary syndrome, are presented separately as are the clinical presentation, diagnosis, staging, and prognosis of MF and Sézary syndrome. (See "Treatment of advanced stage (IIB to IV) mycosis fungoides" and "Clinical manifestations, pathologic features, and diagnosis of mycosis fungoides" and "Treatment of Sézary syndrome".)
PRETREATMENT EVALUATION AND STAGING — The staging evaluation of patients with a confirmed diagnosis of MF includes history and careful physical examination; laboratory tests, including complete blood count (CBC) with differential, flow cytometry and/or Sézary cell analysis, and screening serum chemistries (including lactate dehydrogenase [LDH]); and imaging studies in select patients (table 2). The standard staging system for MF is based on involvement of the skin (T), lymph nodes (N), viscera (M), and blood (B) (table 1A-B) [1]. Details are presented separately. (See "Staging and prognosis of mycosis fungoides and Sézary syndrome", section on 'TNMB staging'.)
OUR APPROACH
Goals of treatment — The primary goal of treatment is palliation of symptoms, which may include pruritus, pain, burning, or even cosmetic concerns. In addition, effort is made to minimize the extent of disease within the skin compartment in order to reduce the risk of disease progression.
Patients with MF can have severe pruritus and xerosis (dry skin), either as a result of the disease or therapy. Supportive measures include the aggressive use of emollients, topical corticosteroids, and oral antipruritics/antihistamines. Bathing should be followed immediately with the generous application of an emollient, selected based upon the patient's personal preference for feel and ease of application. (See "Treatment of advanced stage (IIB to IV) mycosis fungoides", section on 'Pruritus'.)
Refractory pruritus is more common in patients with advanced stage disease or Sézary syndrome. Anecdotal responses of refractory pruritus to the single agents aprepitant, gabapentin, and mirtazapine have been reported [2,3]. (See "Pruritus: Therapies for localized pruritus" and "Pruritus: Therapies for generalized pruritus".)
Stage IA disease — Stage IA disease includes patients with patches, plaques, or papules that involve <10 percent of the total skin surface with no involvement of lymph nodes or viscera (table 1A-B). (See "Staging and prognosis of mycosis fungoides and Sézary syndrome", section on 'TNMB staging'.)
For most patients with stage IA MF (table 1A-B), we recommend the use of skin-directed therapies alone or in combination with other skin-directed therapies rather than systemic therapies [4-6]. (See 'Skin-directed therapies' below.)
Patients with stage IA disease who also have an absolute count of circulating atypical lymphocytes (Sézary cells) of 250 to <1000 determined by flow cytometry (ie, those with B1 disease) [7], histologic evidence of the folliculotropic variant, or large cell-transformed MF are treated with more aggressive therapy. (See 'Special scenarios' below.)
Options for localized skin-directed therapies include (see 'Skin-directed therapies' below):
●Topical corticosteroids
●Topical mechlorethamine
●Topical retinoids
●Topical imiquimod
●Localized radiation (x-ray or electron beam)
●Phototherapy (narrowband ultraviolet B [NBUVB] or psoralen plus ultraviolet A [PUVA])
In our practice, topical corticosteroids are the preferred initial treatment option. (See 'Topical corticosteroids' below.)
Other clinicians prefer the initial use of topical mechlorethamine or NBUVB, depending on the distribution and type of lesions as well as the patient's or clinician's preference. (See 'Topical mechlorethamine' below and 'Phototherapy' below.)
If the initial skin-directed therapy fails to obtain an adequate or complete response or is poorly tolerated, a rotation to an alternative skin-directed therapy is attempted before progressing to systemic therapies. In general, patients with stage IA MF will have multiple courses of skin-directed therapies over their lifetime before, if ever, receiving a systemic therapy. The exact sequence should be determined by the expertise of the practitioner and practical concerns for the chosen modality (eg, geographical convenience, costs).
Despite decades of experience in the treatment of MF, evidence from high-quality studies supporting the efficacy of various therapies is limited. The choice among initial skin-directed therapies is made via shared decision making with the individual patient, based on the patient's characteristics and preferences, clinician's experience with these methods, costs of therapy, and side effect profiles.
Stage IB/IIA disease — Stage IB disease includes those patients with patches, plaques, or papules that involve ≥10 percent of the total skin surface with no involvement of lymph nodes or viscera (table 1A-B). Stage IIA disease includes those patients with patches, plaques, or papules of any size with reactive palpable lymph nodes (N1) or with isolated and scattered neoplastic cells in the lymph nodes (N2) on histology (but preservation of the nodal architecture) and no involvement of the viscera (see "Staging and prognosis of mycosis fungoides and Sézary syndrome", section on 'TNMB staging'):
●Skin-directed therapies – For most patients with stage IB or IIA MF, we recommend the use of skin-directed therapies, used alone or in combination, rather than systemic therapies. (See 'Skin-directed therapies' below.)
Options for generalized skin-directed therapy include:
•Topical corticosteroids
•Topical mechlorethamine
•Total skin electron beam therapy (TSEBT)/localized radiation
•Phototherapy (NBUVB or PUVA)
Of note, topical bexarotene and other topical retinoids are not indicated for patients with stage IB/IIA disease. The degree of skin irritation with these agents is too high to allow for large area coverage or total skin therapy:
•Choice of skin-directed therapy – The choice among skin-directed therapies is primarily made based on lesion characteristics:
-For patients with IB or IIA disease demonstrating patches, thin plaques, and an indolent natural history of disease, we suggest initial treatment with topical mechlorethamine, topical corticosteroid, or NBUVB or PUVA phototherapy rather than TSEBT [8,9]. The choice among these treatments is largely dependent on the extent and severity of disease. This preference is principally due to the lower side effect profile of these therapies compared with TSEBT. (See 'Phototherapy' below.)
-For patients who are very symptomatic with rapidly progressive, generalized, thickened plaques in whom a prompt response is needed, we suggest TSEBT rather than topical mechlorethamine or NBUVB or PUVA. The effective depth of treatment of electron beam therapy is more substantial than either topical mechlorethamine or NBUVB/PUVA [10]. TSEBT should also be considered for patients who have failed treatment with either topical mechlorethamine and/or NBUVB/PUVA. TSEBT should be administered at a site with experience in the use of this modality.
Following completion of TSEBT, adjuvant treatment with topical mechlorethamine, NBUVB, or oral bexarotene or other retinoid (ie, acitretin, isotretinoin) is appropriate and may be continued for a minimum of six months [11].
•Inadequate response to initial topical therapy – Patients failing to respond to one topical therapy, or who progress after an initial response, may be treated with an alternative topical therapy or combined modality therapy. There is no evidence that development of resistance to one modality affects subsequent response to an alternative topical modality [12,13]. Potential combinations include [14-17]:
-TSEBT plus topical steroids
-PUVA plus topical steroids
-Phototherapy plus localized electron beam therapy
These treatment options have not been adequately compared in randomized trials. Retrospective analyses have demonstrated varying response rates but no differences in long-term survival [13]. A randomized trial demonstrated that early aggressive therapy with combination chemotherapy plus electron beam radiation therapy does not appear to improve survival when compared with the use of sequential topical regimens [18]. In another small, randomized trial that was closed early for poor accrual, overall response rates and median duration of response were similar in 37 patients receiving the combination of oral bexarotene plus PUVA therapy (77 percent and 5.8 months) and in 32 patients receiving PUVA therapy alone (71 percent and 9.6 months) [19].
●Systemic therapies – Systemic therapies (eg, oral bexarotene, low-dose methotrexate, interferons, oral vorinostat [histone deacetylase inhibitor], mogamulizumab, brentuximab vedotin) are infrequently used as first-line treatment for early stage MF [4]. (See 'Systemic therapies' below and "Treatment of advanced stage (IIB to IV) mycosis fungoides", section on 'Choice among systemic therapies'.)
However, they may be added to skin-directed therapies in the following situations [6]:
•Patients with extensive skin involvement
•Patients with predominantly plaque disease
•Patients with blood involvement
•Patients whose disease is not adequately controlled with skin-directed therapies
•Patients who may not have access to appropriate skin-directed therapies such as phototherapy or TSEBT
•Patients who have a worse prognostic profile, such as folliculotropic MF, large cell transformation, or early blood involvement (>5 percent circulating Sézary cells, B1 disease) [6]
We generally prefer to start treatment with agents with lower toxicity, such as oral bexarotene or low-dose methotrexate, while continuing skin-directed therapies, including topical therapies and phototherapy.
Response assessment — Off of clinical trials, most clinicians assess responses based on general clinical criteria such as visible lesion disappearance or partial regression and relief of symptoms [7]. Use of imaging and frequent biopsies is generally not necessary to assess response.
Special scenarios
Folliculotropic variant — Folliculotropic MF is a histopathologic and clinical variant of MF characterized by follicular papules or plaques often associated with alopecia. Folliculotropic MF has been traditionally considered an aggressive variant of MF with a worse prognosis. Because of the deep, perifollicular localization of the neoplastic infiltrate, patients with stage IA, IB, or IIA folliculotropic MF are treated according to regimens used for stage IIB limited disease. However, studies have shown that patients with early stages of folliculotropic MF have a prognosis similar to that of early MF and may be treated with a less aggressive approach (eg, PUVA, superpotent topical corticosteroids, local radiation therapy) [20,21]. Local radiation is often indicated due to its greater depth of penetration. (See "Treatment of advanced stage (IIB to IV) mycosis fungoides" and "Staging and prognosis of mycosis fungoides and Sézary syndrome", section on 'Folliculotropic variant' and "Variants of mycosis fungoides", section on 'Folliculotropic mycosis fungoides'.)
Large cell transformation — A subgroup of patients with MF will have transformation of their disease to a large T cell lymphoma. This transformation may be associated with an aggressive clinical course and less favorable outcome. However, some patients may meet histopathologic criteria of large cell transformation but may have limited tumor nodules with a more indolent clinical behavior. Thus, the management of these patients labeled with large cell transformation must be individualized according to the clinical behavior. Patients with stage IA, IB, or IIA MF with large cell transformation are treated according to regimens used for stage IIB, limited tumor disease. This is presented separately. (See "Treatment of advanced stage (IIB to IV) mycosis fungoides" and "Staging and prognosis of mycosis fungoides and Sézary syndrome", section on 'Transformation to large-cell histology (LCT)'.)
Blood involvement — Patients with circulating atypical (Sézary) cells are considered to have involvement of the peripheral blood if they show by flow cytometry (table 1A) [7]:
●≥250 Sézary cells/microL
or
●≥15 percent of total CD4+ cells with an abnormal phenotype (CD4+CD26- and/or CD4+CD7-)
Patients with 250 to <1000/microL Sézary cells are designated as having B1 involvement (low blood tumor burden), while patients with ≥1000/microL Sézary cells with positive clonal studies have B2 involvement (ie, Sézary syndrome) with high blood tumor burden. (See "Staging and prognosis of mycosis fungoides and Sézary syndrome", section on 'Flow cytometry'.)
Patients with involvement of the peripheral blood require the inclusion of systemic therapy to clear the circulating tumor cells. Patients with stage IA, IB, or IIA MF with B1 involvement are treated as if they have stage III disease with B1 involvement. This is presented separately. (See "Treatment of advanced stage (IIB to IV) mycosis fungoides", section on 'Peripheral blood involvement'.)
SKIN-DIRECTED THERAPIES
Topical agents
Topical corticosteroids — Topical corticosteroids are effective in early stage MF, with the majority of patients obtaining a complete response [22]. The choice of corticosteroid strength depends on the body area affected and the severity of skin symptoms and signs, but generally, high-potency or super high-potency corticosteroids are used (table 3). A response is typically seen within three months. While there have been some patients who have responded after this time, patients who have no response by the third month should be offered alternative therapies:
●Administration – Topical corticosteroids are applied once or twice daily to all affected areas until the lesions are completely cleared. Plastic film occlusion may enhance the effectiveness [22]. Topical corticosteroids are available in ointments, creams, solutions, foams, and gels. Ointments may be more effective than creams, but some patients prefer the cosmetic appearance of creams. Ointments are preferable for areas of dry skin while foams, solutions, or gels may be more suitable for lesions on the scalp. Gels are useful for treating hairy regions but are generally too drying for routine use otherwise. Plastic film occlusion may enhance the effectiveness [22]. Topical steroids should be discontinued when the lesions are completely cleared. Treatment may be restarted if lesions recur.
●Efficacy – A prospective study of class I corticosteroids in 79 patients with stage T1 (51 patients) or T2 patch or plaque MF followed for a median of nine months reported an overall response rate of 94 percent, with 63 percent complete responses in patients with T1 disease [23]. Further follow-up of approximately 200 patients treated with class I corticosteroids at this same institution reported a continued >90 percent response rate in patients with T1 disease [22].
●Adverse effects – The long-term use of topical corticosteroids may result in skin atrophy and/or striae formation. Caution should be used when applying topical corticosteroids near the eye. As the potency of the steroid increases, the risk of these complications increases as well. High-potency corticosteroids can result in systemic absorption if applied to large skin surfaces, and there have been cases of clinically evident adrenal suppression and Cushing's syndrome. (See "Major side effects of systemic glucocorticoids".)
Topical mechlorethamine — Topical mechlorethamine (chlormethine, nitrogen mustard, HN2) is an alkylating agent that has been used as a skin-directed therapy for MF for decades [24]. It is used as a first- or second-line therapy for early MF or as an adjunctive therapy in patients with advanced stage disease:
●Available formulations – Mechlorethamine can be compounded by a pharmacist as an ointment (10 to 20 mg per 100 grams of petrolatum) or prepared as an aqueous solution (10 to 20 mg in 100 mL of tap water) by the patient themselves. It is also commercially available as a 0.016% gel formulation. The gel formulation, equivalent to 0.02% chlormethine hydrochloride, is approved in the United States, Europe, and several other countries for the treatment of MF.
The choice of preparation is often dependent upon convenience, patient preference, or cost issues (ointment preparation uses less HN2 for a similar response).
●Administration – The preparation is initially applied to the affected anatomical region(s) alone and then to any new areas of involvement noted during clinical follow-up. To increase tolerability, some experts suggest that chlormethine gel be initially applied every other day and combined with the application of topical corticosteroids [25].
Patients themselves do not have to wear protective gloves when applying mechlorethamine, although they are advised to wash their hands afterwards. Mechlorethamine penetrates the thick epidermis of the palms only slowly. When others help the patient apply mechlorethamine, they should use gloves.
If there is no response by three months, the concentration of compounded topical mechlorethamine may be increased every few months until the response is satisfactory (up to concentrations of 30 to 40 mg percent), especially if it is to be applied to small areas.
Treatment is continued on a daily basis for four to six months or until complete skin clearance, followed by a variable duration of maintenance therapy. The standard duration of maintenance therapy used at Stanford University (two of the authors' institution) is one to two months. There is no evidence that more prolonged maintenance therapy is beneficial.
●Efficacy – Observational studies using compounded formulations of topical mechlorethamine reported clinical response rates of 70 to 80 percent in patients with limited patch/plaque (T1) disease, with a median time to skin clearance of six to eight months [12,24,26,27]. A clinical benefit is seen in 50 to 70 percent of patients with T2 disease [13,26,27]. When used as a single agent, approximately 12 and 36 percent of patients with early stage MF will attain complete and partial responses, respectively, as defined by the Composite Assessment of Index Lesion Severity (CAILS) score [28].
In a randomized trial, mechlorethamine gel was noninferior to nitrogen mustard ointment as determined by response rates using the CAILS score (59 versus 48 percent) and the Modified Severity-Weighted Assessment Tool (mSWAT; 47 versus 46 percent) [28]. The efficacy of chlormethine gel has also been evaluated in real-world clinical settings [29-31]. In a two-year, observational study that included 298 patients with MF using chlormethine, the overall response rate in patients with stage IA/IB disease was 43.5 percent at 12 months [29]. The response rate was 36.7 percent after one month of treatment and reached a peak of 66.7 percent at 18 months.
●Adverse effects – Cutaneous adverse effects occur in over 50 percent of patients using topical mechlorethamine [28]. Irritant contact dermatitis is the most common adverse effect of the gel formulation [28-30]. It is usually mild and can be controlled with topical corticosteroids. In more severe cases, the mechlorethamine application can be reduced or temporarily suspended. Delayed hypersensitivity reactions (eg, allergic contact dermatitis) have been reported more frequently with the traditional formulations and, especially, with the aqueous solution [24].
Other cutaneous adverse effects include hypo- or hyperpigmentation of the treated areas. Secondary squamoproliferative lesions have developed primarily in patients treated with multiple sequential topical therapies [32,33]. There does not appear to be an increased risk of development of secondary skin cancers in patients who have used topical mechlorethamine as monotherapy [24]. Because the systemic absorption of topically applied mechlorethamine is minimal, systemic complications (eg, bone marrow suppression or infertility) have not been observed [34].
Topical carmustine — Topical carmustine appears to have similar efficacy to topical mechlorethamine [35-37]. However, topical carmustine is generally not advised for patients with >3 percent skin involvement because systemic absorption can lead to hematologic toxicities, including leukopenia, thrombocytopenia, and anemia. Given the available alternatives, topical carmustine is rarely used in practice.
Topical bexarotene — Topical bexarotene is a synthetic retinoid approved by the US Food and Drug Administration for the topical treatment of early stage cutaneous T cell lymphoma in patients who have refractory or persistent disease after other therapies or who have not tolerated other therapies. Since topical bexarotene is a skin irritant, its use is generally limited to patients with involvement of <15 percent of their body surface area:
●Administration – Topical bexarotene is available in a 1% gel formulation. Generally, bexarotene is applied to lesions nightly for the first week of treatment, then twice daily. To adjust dose intensity, the frequency of application can be increased to up to four times a day, if tolerated.
●Efficacy – Overall response rates of 45 to 65 percent, with 20 percent complete responses, have been reported [38,39]. Complete clearance may take 12 to 16 weeks, and the median response duration (on continuous or maintenance therapy) from start of therapy is estimated at two years [38].
●Adverse effects – Topical bexarotene is generally well tolerated. The most common adverse effects are a mild to moderate irritant dermatitis, pruritus, burning pain at the application site, and skin inflammation [39]. Systemic and topical forms of bexarotene are absolutely contraindicated in pregnancy. All retinoids can also increase sun sensitivity. The use of sun-protective clothing and/or sunscreen is recommended, particularly when prolonged sun exposure is anticipated.
Topical imiquimod — Imiquimod 5% cream is a topical immune response modifier with antiviral and antitumoral activity approved by the US Food and Drug Administration for the treatment of actinic keratosis and superficial basal cell carcinoma. Imiquimod stimulates the local production of multiple proinflammatory cytokines via a toll-like receptor 7 agonistic activity and exerts a proapoptotic activity against tumor cells.
Topical imiquimod may be used "off-label" in patients with solitary or few MF plaques resistant to other skin-directed therapies. However, the evidence supporting its use is limited to a few small case series and single case reports:
●Administration – Imiquimod 5% cream is applied in a thin layer over the affected area once daily. At our institutions, we usually instruct patients to use imiquimod three times per week and gradually increase to daily application (depending upon the degree of inflammatory reaction). Imiquimod is then continued for two to three months before evaluation of response.
●Efficacy – In a review of 20 patients with stage IA to IIB MF treated with imiquimod 5% cream three to seven times per week for up to seven months, a complete clinical response was reported in nine patients, a partial response was reported in seven patients, and no response was reported in four patients [40]. In the largest published series including six patients with stage IA to IIB MF treated with topical imiquimod three times per week for 12 weeks, histologic clearance was demonstrated in three patients [41]. All three patients were concurrently treated with psoralen plus ultraviolet A (PUVA) photochemotherapy, systemic interferon, and PUVA plus systemic retinoids, respectively, suggesting that imiquimod may act synergistically with other systemic or skin-directed therapies.
●Adverse effects – Imiquimod causes a local, inflammatory reaction, with erythema, edema, vesicles, and ulceration/erosion. Severe reactions may be accompanied by systemic, flu-like symptoms (including fever, malaise, and myalgias) that may require treatment interruption.
Phototherapy — Narrowband ultraviolet B (NBUVB) is primarily used for the treatment of MF characterized by patches only (T1a, T2a). Patients with patch/plaque disease (T1b, T2b) can be treated with PUVA, given the ability of ultraviolet A (UVA) to penetrate deeper in the dermis compared with ultraviolet B (UVB). The usual time to skin clearance is two to six months, and the likelihood of clearance is related to the extent of skin involvement. Some patients may obtain a long-term, durable response [42].
Phototherapy may be administered as NBUVB, broadband UVB [43-45], or PUVA photochemotherapy [46-52]. Both NBUVB (311 nm wavelength) and broadband UVB (290 to 320 nm wavelength) have been used as skin-directed treatments for early stage MF, although broadband UVB-emitting sources have mostly been replaced by NBUVB lamps worldwide.
A review of one prospective and two retrospective studies found that short-term maintenance phototherapy does not seem to be effective in reducing the risk of relapse [53]. However, a small, randomized trial reported that maintenance PUVA was associated with longer remission duration and reduced risk of relapse [54]:
●Administration – The treatment dose and schedule and the use of maintenance phototherapy vary among institutions. Although a tapering schedule followed by a maintenance phase is widely used in clinical practice for patients achieving a complete response with PUVA, there is only limited evidence supporting the efficacy of maintenance regimens in prolonging remission. In general, the entire body is treated except for the eyes and genitalia, which are shielded routinely. Other selected areas can be shielded to minimize undesired photodamage. Of note, certain "shadowed" areas, such as the scalp, perineum, axillae, and other skin fold areas, will not receive adequate exposure:
•Narrowband ultraviolet B – Narrowband ultraviolet B (NBUVB) phototherapy is administered in a dermatology office three to five times per week with gradual incremental dose delivery. Improvement is generally seen after 20 to 40 treatments. After a complete response is achieved, the frequency of therapy is tapered very slowly during the maintenance period and then discontinued [55]. The tapering schedule is nonstandardized and differs by institution. As an example of a slow taper, after a complete response or plateau in response, treatments may be decreased from three times a week to twice weekly for one to two months, then decreased to once weekly for one to two months, followed by discontinuation of therapy.
•Psoralen plus ultraviolet A – Psoralen plus ultraviolet A (PUVA; 320 to 400 nm wavelength) treatment consists of a timed exposure to UVA light in a phototherapy unit (PUVA box) administered approximately 1.5 to 2 hours after an oral dose of psoralen. Patients must shield their skin and eyes from the sun for at least 24 hours after ingestion of psoralen. UVA-opaque goggles should be used during therapy and UVA-opaque glasses after therapy. (See "Psoralen plus ultraviolet A (PUVA) photochemotherapy".)
PUVA is administered three times a week until skin clearance is achieved, after which the frequency of treatment is tapered very slowly (in a similar fashion to that done with NBUVB) to as infrequently as once every two weeks. If lesions recur during maintenance therapy, the treatment frequency is increased. Maintenance therapy should be discontinued within one year to minimize the risks of cutaneous carcinogenesis. When maintenance therapy is discontinued, most patients will relapse. However, patients who relapse are likely to respond to retreatment.
●Efficacy – In a meta-analysis of seven observational studies including 778 patients with stage IA to IIA MF of whom 527 were treated with PUVA and 251 were treated with NBUVB, the frequency of any response (complete or partial) was similar for PUVA and NBUVB (91 and 88 percent, respectively; odds ratio [OR] 1.40, 95% CI 0.84-2.34) [56]. However, more patients receiving PUVA achieved a complete response than those receiving NBUVB (74 and 62 percent, respectively; OR 1.68, 95% CI 1.02-2.76). The frequency of adverse effects, including erythema, nausea, pruritus, and phototoxicity, was similar in the two groups.
●Contraindications and adverse effects – Since cumulative doses of ultraviolet light are associated with an increased risk of skin cancer, phototherapy may not be appropriate in patients with a history of multiple nonmelanoma skin cancers or melanoma. (See "Psoralen plus ultraviolet A (PUVA) photochemotherapy" and "UVB phototherapy (broadband and narrowband)".)
Short-term adverse effects of phototherapy include erythema, pruritus, blistering, and skin dryness; nausea is frequently reported with PUVA [8,57]. Potential long-term complications include increased risk of skin cancer and cataracts [58,59]. Among patients treated for MF, this risk is greatest for patients who have undergone long-term treatment with multiple skin-damaging, skin-directed therapies [32]. (See "UVB phototherapy (broadband and narrowband)", section on 'Short- and long-term adverse effects' and "Psoralen plus ultraviolet A (PUVA) photochemotherapy", section on 'Adverse effects'.)
Localized radiation therapy — MF is extremely sensitive to radiation therapy, and ionizing radiation in the form of x-rays or electrons is one of the most effective treatments for localized MF [60,61]. Electron beam therapy is usually used since electrons of appropriate energy can be delivered to the superficial layers of the skin, thus avoiding damage to deeper tissues. Following local electron beam therapy, there are usually no recurrences within the treatment field, but new lesions can develop outside of the field [62]. Other skin-directed therapies, such as topical mechlorethamine or topical corticosteroids, can be used concurrently or as a topical maintenance regimen following localized radiation therapy:
●Administration – For patches or plaques, radiation may be delivered to the lesion with 1 to 1.5 cm margins. Typically, 6 MeV electron energy (with 1 cm bolus to bring the maximum dose to the surface) is sufficient [61]. The usual total dose for local treatment is 8 to 12 Gy administered in one to six fractions. Fraction size and field margins are dependent upon the body surface being treated (ie, smaller size fractions for facial treatment, larger fractions for trunk or extremities) [63].
For the rare patient with a single lesion (unilesional) or localized MF, local radiation can result in efficient disease clearance and permanent disease control [64,65]. Local treatment is delivered to individual lesions with a peripheral margin up to 2 cm, but the exact area treated may be dependent upon the location and proximity to sensitive tissues. To ensure durable local control, the dose is generally 24 to 30 Gy.
●Efficacy – Data on the efficacy of localized radiation therapy for MF are limited. In a study of 31 patients with MF, a complete response was achieved for 60 of 65 lesions (92 percent) treated with 8 Gy in two fractions [63]. In a retrospective, single-center study of 58 patients, a single fraction radiation dose of 4 to 9 Gy produced a complete response in 255 of 270 individual lesions (94 percent) [66]. In another small study of 15 patients with stage IA MF, a complete response was observed in 94 percent of irradiated fields treated with local superficial radiation therapy at a median dose of 22 Gy [62].
●Adverse effects – Treatment-related toxicity is dependent upon the dose of radiation used and the location of the tumor. Side effects may include erythema and hair loss. Lower-dose radiation may have fewer side effects. In one study, irradiation with 4 Gy in two fractions was well tolerated, with only temporary hair loss in the irradiated fields of some patients [63].
Total skin electron beam therapy — Total skin electron beam therapy (TSEBT) is a radiation therapy technique that uses electrons generated by a linear accelerator to treat the entire skin area. TSEBT is indicated for patients with generalized, rapidly progressive, thickened plaques (see 'Stage IB/IIA disease' above):
●Administration and dosing – Patients are usually treated in the standing position, 3 to 4 m distance from a linear accelerator. This distance allows large surfaces to be treated. Patients either stand on a rotating platform or assume several different positions during treatment in order to treat their entire skin surface area [60,61,67]. The conventional ("high") dose is generally 30 to 36 Gy administered over a 10-week period, with a 1-week respite after 15 to 20 Gy to provide for some relief from the generalized skin erythema that often accompanies TSEBT. However, low-dose TSEBT (approximately 10 to 12 Gy) has supplanted high-dose therapy in most situations. Treatment with lower doses limits the duration of therapy, reduces complications, and allows easier retreatment [68-70].
Although selected patients have received a second course of high-dose TSEBT, TSEBT cannot be routinely reused at recurrence. That is why the use of lower-dose TSEBT (12 Gy) is gaining more widespread use. It can be repeated safely and thereby provide a more significant duration of benefit over the lifetime course of a patient's disease.
The eyes are shielded routinely (with either internal or external eye shields). Other shielding may be utilized as needed or as per patient preference, including the scalp, face, fingernails, and male genitalia. With TSEBT, certain portions of the body surface are "shadowed" and receive lower electron doses. These areas include the top of the scalp, the perineum, and the soles of the feet. There may also be relatively shielded areas in individual patients because of body habitus, such as underneath the breasts of some females and under the panniculus of individuals who are obese. These or other shadowed areas may be supplemented with 6 MeV electrons (with bolus) and treated to 12 to 20 Gy [67].
●Efficacy – In a series of 141 patients with MF treated with TSEBT (mean total dose of 30 Gy), the overall response rate was 95 percent [71]. Complete responses were obtained in 85 percent of those with T2 disease. Fifty-four percent of patients demonstrated skin relapse at one year.
In three phase 2 clinical trials evaluating low-dose TSEBT (12 Gy) that included 33 patients with stage IB to IIIA disease (24 patients with stage IB to IIA disease), the overall response rate was 88 percent, with a complete response rate of 27 percent [69]. The toxicities were minor compared with conventional-dose TSEBT, and the duration of clinical benefit (time to requiring another total skin or a systemic therapy) was 70.7 weeks.
●Adverse effects – The likelihood of most complications is related to the dose of radiation (12 or 36 Gy). The most common acute complications of TSEBT are erythema, desquamation, and epilation [72]. Other complications, which are usually mild in severity, include blisters, hyperpigmentation, and skin pain. Lesions may become superinfected in up to one-third of cases. Intermediate-term complications include alopecia, which is incomplete and usually only temporary if the scalp dose is limited to 24 Gy. Most patients experience temporary fingernail and toenail loss two to four months following completion of treatment with doses approximately 30 Gy or greater. Most also report an inability to sweat properly for the first 6 to 12 months following therapy and note chronically dry skin that requires daily use of emollients. In long-term follow-up, occasional patients display scattered telangiectasias, which are rarely evident on casual examination.
Although cutaneous malignancies (eg, squamous cell carcinoma and basal cell carcinoma) are probably increased after the use of TSEBT, the patients in whom these have become problematic are those who have received repeated treatment with multiple therapies, including irradiation, topical HN2, and PUVA [32].
SYSTEMIC THERAPIES — Systemic therapies are infrequently used as first-line treatment of early stage MF [4]. However, they may be used for patients with stage IB or IIA disease who have extensive skin involvement, predominantly plaque disease, and blood involvement, as well as for patients with inadequate response to skin-directed therapies [6]. (See 'Stage IB/IIA disease' above.)
Systemic agents that have been used alone or in combination with skin-directed therapies for early stage MF include bexarotene, low-dose methotrexate, interferons, brentuximab vedotin, mogamulizumab, romidepsin, and vorinostat. In general, agents that have a more favorable safety profile, such as oral bexarotene and low-dose methotrexate, are preferred to more toxic agents as initial treatment. Details on mechanism of action, dosing, efficacy, and adverse effects of systemic therapies for MF are provided separately. (See "Treatment of advanced stage (IIB to IV) mycosis fungoides", section on 'Choice among systemic therapies'.)
INVESTIGATIONAL THERAPIES
Topical resiquimod — Resiquimod is an imidazoquinoline with potent toll-like receptor 7 and toll-like receptor 8 agonistic activity. In a phase 1 trial, 12 patients with stage IA to IIA cutaneous T cell lymphoma who had failed a mean of six previous therapies applied topical resiquimod 0.03% and 0.06% gel to a limited number of target lesions for eight weeks [73]. Treatment was started at three times per week, and the frequency was gradually increased every two weeks, as tolerated. A complete response, as assessed by the Severity-Weighted Assessment Tool (SWAT) score, was achieved in two patients, a partial response was achieved in nine patients, and stable disease was achieved in one patient. Adverse effects were minor and included skin irritations and erosions, low-grade fever, and headache.
Photodynamic therapy — There are a few reports of use of photodynamic therapy (PDT) with topical aminolevulinic acid (ALA) or methyl aminolevulinate (MAL) in patients with stage I paucilesional or unilesional MF unresponsive to other topical treatments [74-76]. However, the role of PDT in the management of early stage MF remains uncertain, and protocols for its use have not been established (see "Photodynamic therapy"):
●In a series of five patients with unilesional MF, MAL-PDT was administered once weekly until complete clearing of the lesion [74]. A complete clinical and histologic remission was observed in four of five patients after a median of six treatments, with no recurrences after a follow-up period of 12 to 34 months.
●In another study, 29 plaque or patch lesions in 12 patients with stage IA and IB MF were treated with monthly MAL-PDT for six months [75]. A complete or partial clinical response was observed in six and three patients, respectively, but new lesions appeared in untreated areas in five patients.
●A multicenter, phase 3, randomized trial evaluated the efficacy and safety of PDT using synthetic hypericin ointment in 169 patients with early stage MF [77]. Treatment was administered twice weekly for each six-week cycle. The primary outcome was the index lesion response rate, defined as ≥50 percent improvement in the modified Composite Assessment of Index Lesion Severity (mCAILS) score from baseline. After six weeks of treatment, hypericin PDT was more effective than placebo (index lesion response rate 16 versus 4 percent, respectively). The index lesion response rate increased to 40 percent in patients who received two cycles of hypericin PDT and to 49 percent after three cycles.
Excimer laser therapy — There are a few reports of the use of targeted phototherapy using excimer lasers emitting narrowband ultraviolet B (NBUVB) at 308 nm for the treatment of localized MF [78-80]. In a series of six patients with early MF involving <10 percent of the body surface area, excimer laser therapy was administered twice weekly for a total of 8 to 24 sessions [78]. Treatment was started at 200 mJ/cm2 and increased by 10 to 20 percent in subsequent sessions. A clinical improvement was seen in five patients, and clinical progression to tumor stage was seen in one. (See "Targeted phototherapy".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Primary cutaneous lymphoma".)
SUMMARY AND RECOMMENDATIONS
●Definition – Early stage mycosis fungoides (MF) is an extranodal, indolent non-Hodgkin lymphoma of T cell origin that primarily develops in the skin but can ultimately involve the lymph nodes, blood, and visceral organs. Early stage (IA to IIA) disease consists of papules, patches, or plaques, with limited, if any, lymph node involvement and no visceral involvement (table 1A-B and table 2). (See "Clinical manifestations, pathologic features, and diagnosis of mycosis fungoides".)
●Treatment – For most patients with early stage MF, we recommend the use of skin-directed therapies rather than systemic therapies (Grade 1B). The choice among skin-directed therapies is made based on the type and extent of skin disease, patient characteristics, clinician's experience with these treatments, and safety profiles (see 'Our approach' above):
•Mild/limited stage IA disease – For patients with mild/limited stage IA MF, we suggest initial treatment with topical corticosteroids (Grade 2C). Topical mechlorethamine can be used as an alternative or as a subsequent therapy if topical corticosteroids are ineffective.
Localized refractory disease can be managed further with topical bexarotene, imiquimod, or local radiation. If a skin-directed therapy fails to obtain a complete response, alternate skin-directed therapies are attempted before progressing to systemic therapies. (See 'Stage IA disease' above.)
•Stage IB or IIA disease – For patients with stage IB or IIA disease demonstrating thin plaques and an indolent natural history of disease, we suggest initial treatment with topical corticosteroids, topical mechlorethamine, or narrowband ultraviolet B (NBUVB) therapy (Grade 2C). A choice among these is largely dependent on the extent and severity of disease. For patients with highly symptomatic, generalized, thickened plaques in whom a prompt response is needed, we suggest total skin electron beam therapy (TSEBT) rather than mechlorethamine or NBUVB alone (Grade 2C).
Systemic therapies (eg, oral bexarotene, low-dose methotrexate, interferons, histone deacetylase inhibitors, mogamulizumab, brentuximab vedotin) are used if skin-directed therapies fail; if skin symptoms are extensive/severe; or if patients have a worse prognostic profile, such as folliculotropic MF, large cell transformation, or early blood involvement. We generally prefer agents that have a more favorable safety profile, such as oral bexarotene and low-dose methotrexate, to more toxic agents as initial treatment. (See 'Stage IB/IIA disease' above.)
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