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 as 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, is 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".)

SPECIAL CONSIDERATIONS DURING THE COVID-19 PANDEMIC — The coronavirus disease 2019 (COVID-19) pandemic has increased the complexity of cancer care. Important issues include balancing the risk from treatment delay versus harm from COVID-19, ways to minimize negative impacts of social distancing during care delivery, and appropriately and fairly allocating limited health care resources. The United States Cutaneous Lymphoma Consortium has published recommendations for the treatment of cutaneous lymphomas during the pandemic, based on disease and treatment risk stratification [1]. General issues and recommendations for cancer care during the COVID-19 pandemic are discussed separately.

●(See "COVID-19: Considerations in patients with cancer".)

PRETREATMENT EVALUATION — The standard staging system for MF is based on an evaluation of the skin (T), lymph nodes (N), visceral involvement (M), and blood (B) (table 1A-B and table 2) [2]. Details are presented separately. (See "Staging and prognosis of mycosis fungoides and Sézary syndrome", section on 'TNMB staging'.)

STAGE IA DISEASE

Overview — Stage IA disease includes those patients with patches, plaques, or papules that involve less than 10 percent of the total skin surface with no involvement of lymph nodes or viscera (table 1A-B). Patients with stage IA disease who also have greater than 5 percent circulating atypical (Sézary) cells as a percentage of circulating lymphocytes (ie, those with B1 disease), histologic evidence of the folliculotropic variant, or large cell transformed MF are treated with more aggressive therapy. (See 'Special scenarios' below.)

Patients with stage IA disease are treated with skin-directed therapies. A randomized trial demonstrated that early aggressive therapy with combination chemotherapy plus total skin electron beam radiation therapy does not appear to improve survival when compared with the use of sequential topical regimens [3].

Skin directed therapies include:

●Topical corticosteroids

●Topical chemotherapy (nitrogen mustard or carmustine)

●Topical retinoids

●Topical imiquimod

●Local radiation (x-ray or electron beam)

●Phototherapy (UVB or PUVA)

Despite decades of experience in the treatment of MF, well-designed, prospective, controlled clinical studies comparing the efficacy of various therapies are lacking.

For most patients with stage IA MF, we recommend the use of skin-directed therapies rather than systemic therapies. The choice among skin-directed therapies is made based on the physician's experience with these methods, patient characteristics, and side effect profiles. In general, topical corticosteroids are the preferred initial treatment option in our practice. Other clinicians prefer the initial use of topical nitrogen mustard. If a 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 will have multiple courses of skin-directed therapies over their lifetime before, if ever, receiving a systemic therapy.

Topical corticosteroids — Topical corticosteroids are effective in early stage MF with the majority of patients obtaining a complete response (CR). The choice of steroid strength depends on the body area affected and the severity of the 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.

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 CRs in patients with T1 disease [4]. Further follow-up of approximately 200 patients treated with class I corticosteroids at this same institution reported a continued greater than 90 percent response rate in patients with T1 disease [5].

Administration — 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. Topical corticosteroids are applied once or twice daily to all affected areas. Caution should be used when applying topical corticosteroids near the eye. Plastic film occlusion may enhance the effectiveness [5]. Topical steroids should be discontinued when the lesions are completely cleared. Maintenance regimens are not used with topical steroids due to the concern of skin atrophy. Treatment may be restarted if lesions recur.

Toxicities — The long-term use of topical corticosteroids may result in skin atrophy and/or striae formation. 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 nitrogen mustard (mechlorethamine, HN2) — Topical nitrogen mustard (mechlorethamine hydrochloride, HN2) produces clinical response in 70 to 80 percent in patients with limited patch/plaque (T1) disease, with a median time to skin clearance of six to eight months [6-9]. When treatment is discontinued, most patients will relapse in the skin at some point, but most will respond to a second course of therapy. Approximately 20 to 25 percent of patients treated with topical HN2 will have a durable CR lasting greater than 10 years. Topical HN2 has also been used safely in pediatric patients with MF [6].

Administration — HN2 is available in a gel, an ointment base, or as a powder to be mixed with tap water and applied daily.

●Nitrogen mustard topical gel is the only topical nitrogen mustard preparation approved by the US Food and Drug Administration for the treatment of MF; it is available in a 0.016% formulation.

●Nitrogen mustard ointment is prepared by the pharmacist at an initial concentration of 10 to 20 mg of HN2 per 100 grams of Aquaphor.

●For the aqueous preparation, patients prepare the solution themselves at a concentration of 10 to 20 mg per 100 mL of tap water and apply it to their skin with a cloth or brush.

In a randomized trial, the gel preparation was noninferior to nitrogen mustard ointment as determined by response rates using the Composite Assessment of Index Lesion Severity (59 versus 48 percent) and the Modified Severity-Weighted Assessment Tool (47 versus 46 percent) [10]. The choice is often dependent upon convenience, patient preference, or cost issues (ointment preparation uses less HN2 for a similar response).

Patients themselves do not have to wear protective gloves when applying the HN2, although they are advised to wash their hands afterwards. The HN2 penetrates the thick epidermis of the palms only slowly. When others help the patient apply the HN2, they should use gloves.

The preparation is initially applied to the entire skin except the genitalia once daily. Areas of disease activity not initially detected may become evident secondary to an inflammatory reaction provoked by the HN2. After a period of several weeks, treatment may then be limited to the affected region. Alternatively, the topical HN2 can be applied initially to the affected anatomical region(s) alone, and then followed clinically for any new areas of involvement. If there is no response by three months, the concentration of the topical HN2 should 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. Alternatively, the frequency of application may be increased to twice daily.

Treatment is continued on a daily basis until complete skin clearance, followed by a variable duration of maintenance therapy. The standard duration of maintenance therapy used at Stanford is one to two months. There is no evidence that more prolonged maintenance therapy is beneficial.

Toxicities — The primary complication of topical HN2 therapy is an acute or delayed hypersensitivity reaction [11]. If a hypersensitivity reaction occurs, a variety of topical or systemic desensitization programs may be used. The aqueous preparation is associated with a much higher incidence of hypersensitivity reactions compared with the ointment preparation (>30 versus <5 percent). In 12 patients with a history of hypersensitivity to topical aqueous HN2, only 3 developed contact dermatitis to the ointment-based preparation [12].

Other side effects include hypo- or hyperpigmentation of treated areas. Secondary squamoproliferative lesions have developed primarily in patients treated with multiple sequential topical therapies [13,14]. There does not appear to be an increased risk of development of secondary skin cancers in patients who have used topical HN2 as monotherapy [6]. In addition, there is minimal systemic absorption of topically applied HN2, thus systemic complications such as bone marrow suppression or infertility have not been observed [15].

Topical carmustine (BCNU) — Topical carmustine (BCNU) appears to have similar efficacy to topical HN2 with a total response rate of 98 percent (86 percent complete) [16,17]. Complete responses generally require 8 to 20 weeks of treatment. Responses appear to be long-lived with approximately 90 percent of patients with T1 disease with disease control at three years.

Topical BCNU is generally not advised for patients with greater than 3 percent skin involvement because systemic absorption can lead to hematologic toxicities. Given the available alternatives, topical carmustine is rarely used in practice.

Administration — BCNU can be mixed in an alcohol solution or incorporated into an ointment with a petrolatum base at a concentration of 10 mg/100 g petrolatum. The ointment appears to be better tolerated than the alcohol solution, but may be less effective [17]. BCNU is applied to affected areas once daily. Patients should take care to avoid exposure to the eyes or orifices. Complete blood counts should be monitored every two weeks to evaluate for marrow suppression that can accompany systemic absorption.

Toxicities — Hematologic toxicities due to systemic absorption include leukopenia, thrombocytopenia, and anemia. Local reactions are common; the majority of patients will develop erythema, often accompanied by a burning sensation, at the areas of application and accentuated in the body folds, groin, and axillae. Erythema usually subsides within a few weeks, but may require localized treatment with cool compresses, cool baths, topical corticosteroids, and/or emollients. Patients may also develop skin thinning, hyperpigmentation, and telangiectasias in areas where the drug is applied. Most telangiectasias will resolve. No cases of skin cancer secondary to topical BCNU have been reported.

Topical bexarotene — Topical bexarotene is a synthetic retinoid that results in overall response rates of 45 to 65 percent with 20 percent complete responses [18,19]. 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 [18]. Since topical bexarotene is a skin irritant, its use is generally limited to patients with involvement of less than 15 percent of their body surface area.

Retinoids have been used primarily in patients with refractory or advanced disease as part of a combination regimen or as adjuvant therapy [20-22]. A phase III trial of topical bexarotene in 50 patients with refractory or persistent early stage disease reported responses in 62 and 50 percent of those with stage IA or stage IB disease, respectively [19]. Three patients with stage IIA or IIB disease did not respond to bexarotene gel.

Bexarotene gel is approved by the US Food and Drug Administration (FDA) for the topical treatment of cutaneous lesions in patients with stages IA and IB cutaneous T cell lymphoma who have refractory or persistent disease after other therapies or who have not tolerated other therapies. Tazarotene gel has been used for the treatment of MF in a pilot study, but other topical retinoids have not yet demonstrated efficacy in clinical trials and are not approved by the FDA [23].

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 (TLR7) 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.

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, a partial response in seven, and no response in four [24]. 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 [25]. All three patients were concurrently treated with PUVA, systemic interferon, and PUVA plus systemic retinoids, respectively, suggesting that imiquimod may act synergistically with other systemic or skin-directed therapies.

Administration — Imiquimod 5% cream is applied in a thin layer over the affected area once daily. At our institution, 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.  

Toxicities — 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.

Administration — Topical bexarotene is available in a 1% formulation. Dose intensity is adjusted by changing the frequency of application. Generally, bexarotene is applied to lesions nightly for the first week of treatment, then twice daily. More frequent application, up to four times a day, can be used, if tolerated.

Toxicities — 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 [19]. 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.

Localized radiation therapy — MF is extremely sensitive to radiation therapy, and ionizing radiation in the form of x-rays is one of the most effective treatments for localized MF [26]. Previously, low energy x-rays (approximately 100 kvp) were used for the treatment of isolated lesions. Unfortunately, short- and long-term toxicities limit its use. Electron beam therapy, now widely available, is usually more appropriate, since electrons of appropriate energy can be used to confine the dose of radiation to the superficial layers of the skin to avoid damage to deeper tissues.

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 [27]. 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 [28].

In a retrospective, single center study, a single fraction radiation dose of 4 to 9 Gy produced a complete response in 255 of 270 individual lesions (94 percent) [29]. Following local EBT, there are usually not recurrences within the treatment field, but new lesions can develop outside of the field. Local radiation may be followed by a topical maintenance regimen such as topical mechlorethamine or topical corticosteroids.

For the rare patient with a single lesion (unilesional) or localized MF, local radiation can result in efficient disease clearance and permanent disease control [30,31]. Local treatment is delivered to individual lesions with a peripheral margin up to two centimeters, 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.

Toxicity — Treatment-related toxicity is dependent upon the dose of radiation used and the location of the tumor. Side effects 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 [28].

Phototherapy

General considerations — Phototherapy may be administered as ultraviolet B (UVB broad or narrow band) [32-34] or PUVA (psoralen + ultraviolet A photochemotherapy) [35-41]. Since cumulative doses of ultraviolet light are associated with an increased risk of certain skin neoplasms, phototherapy may not be appropriate in patients with a history of multiple non-melanoma skin cancers or melanoma. (See "Psoralen plus ultraviolet A (PUVA) photochemotherapy" and "UVB therapy (broadband and narrowband)".)

It is common practice to use UVB for patch disease, reserving PUVA for thicker patch/plaque lesions. Our approach is generally consistent with the guidelines for phototherapy of MF published by the United States Cutaneous Lymphoma Consortium and those of the European Organisation for Research and Treatment of Cancer [42,43].

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.

A review of one prospective and two retrospective studies found that short-term maintenance phototherapy seems not effective in reducing the risk of relapse [44]. However, a small randomized trial reported that maintenance PUVA was associated with longer remission duration and reduced risk of relapse [45].

UVB — Both narrow-band ultraviolet B (NBUVB, 311 nm wavelength) and broad-band (BBUVB; 290 to 320 nm wavelength) have been used as skin-directed treatments for early stage MF, although BBUVB emitting sources have mostly been replaced by NBUVB lamps worldwide. In retrospective cohort studies, NBUVB has demonstrated superior efficacy and decreased toxicity compared with BBUVB, but not PUVA [40,46], with complete response rates ranging from 54 to 90 percent [42,47]. However, there are no randomized trials evaluating the relative efficacy of these phototherapy modalities in patients with early stage MF.

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 with NBUVB, the frequency of any response (complete or partial) was found in a similar proportion of cases (91 and 88 percent, respectively; odds ratio [OR] 1.40, 95% CI, 0.84-2.34) [48]. However, more patients receiving PUVA than those receiving NBUVB achieved a complete response (74 and 62 percent, respectively; OR 1.68, 95% CI 1.02-2.76). Similar results were also found in a subgroup analysis including only patients with stage IA MF. The median relapse-free interval was longer for patients treated with PUVA (33 versus 15 months; hazard ratio of freedom for recurrence 1.93, 95% CI 1.07-3.49). The frequency of adverse effects, including erythema, nausea, pruritus, and phototoxicity, was similar in the two groups.

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 [46]. The tapering schedule is non-standardized 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.

PUVA — Patients with limited patch/plaque (T1) disease treated with PUVA (psoralen + ultraviolet A photochemotherapy) achieve complete response rates as high as 90 percent. 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 [49].

PUVA treatment (320 to 400 nm wavelength) 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 narrow-band ultraviolet B, 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 in order to minimize the risks of cutaneous carcinogenesis. When maintenance therapy is discontinued, the majority of patients will relapse. However, patients who relapse are likely to respond to retreatment.

PUVA 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. 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. Certain "shadowed" areas such as the scalp, perineum, axillae, and other skin fold areas will not receive adequate exposure.

Acute complications of PUVA treatment include erythema, pruritus, blistering, skin dryness, and nausea [42,50]. Potential long-term complications include increased risk of cataracts (requiring the use of UVA-opaque goggles during therapy and glasses after therapy). Patients must shield their skin and eyes from the sun for at least 24 hours after ingestion of psoralen. Patients who undergo long-term continuous treatment with PUVA are at risk for developing secondary cutaneous carcinomas or melanomas [51,52]. Among patients treated for MF, this risk is greatest for patients who have undergone long-term treatment with multiple skin damaging skin-directed therapies [13].

STAGE IB/IIA DISEASE

Overview — Stage IB disease includes those patients with patches, plaques, or papules that involve 10 percent or more 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.

Patients with stage IB/IIA disease who also have greater than 5 percent circulating atypical (Sézary) cells (ie, those with B1 disease), histologic evidence of the folliculotropic variant, or large cell transformed MF are treated with more aggressive therapy. (See 'Special scenarios' below.)

Patients with stage IB/IIA disease are treated with generalized skin-directed therapies, used alone or in combination with other skin-directed therapies. Options for generalized skin-directed therapy include:

●Topical chemotherapy with nitrogen mustard

●Topical corticosteroids

●Total skin electron beam therapy (TSEBT)

●Phototherapy (narrow band ultraviolet B [NBUVB] or psoralen + ultraviolet A photochemotherapy [PUVA])

The degree of skin irritation caused by topical retinoids is too high to allow for total skin therapy. Ointment or aqueous preparations of nitrogen mustard may be used for extensive skin involvement. Localized radiation therapy can be added to any of the above modalities for the adjuvant treatment of poorly responding lesions.

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 [53]. 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 [3]. 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) [54].

For most patients with stage IB or IIA MF, we recommend the use of skin-directed therapies rather than systemic therapies. The choice among skin-directed therapies is primarily made based on lesion characteristics.

●For patients with IB or IIA disease demonstrating thin plaques and an indolent natural history of disease, we suggest the use of topical corticosteroid, topical HN2, or NBUVB therapy. A choice among these is largely dependent upon the extent and severity of disease. This preference is principally due to the lower side effect profile of these therapies compared with TSEBT.

●For patients with rapidly progressive generalized, thickened plaques in whom a prompt response is needed, we suggest TSEBT as initial therapy rather than HN2 or NBUVB alone. This is principally because the effective depth of treatment of electron beam therapy is more substantial. TSEBT should also be considered for patients with a recent history of rapid progression of disease and for those who have failed treatment with either topical HN2 and/or phototherapy.

Systemic biologic therapies, such as retinoids or interferons, histone deacetylase (HDAC) inhibitors, or low-dose methotrexate 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. (See "Treatment of advanced stage (IIB to IV) mycosis fungoides", section on 'Choice among systemic therapies'.)

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 [7,53]. Potential combinations include TSEBT plus topical steroids, PUVA plus topical steroids, or by combining phototherapy with localized EBT [20,21,55,56]. (See "Treatment of advanced stage (IIB to IV) mycosis fungoides".)

Topical nitrogen mustard — Treatment with topical nitrogen mustard (mechlorethamine, HN2) for generalized patch/plaque (T2) disease is similar to that for patients with limited (T1) disease. A clinical benefit is seen in 50 to 70 percent of patients with T2 disease [8,9,53]. 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 score [10]. (See 'Topical nitrogen mustard (mechlorethamine, HN2)' above.)

Total skin electron beam therapy — Overall response rates following TSEBT approach 100 percent and complete responses range from 40 to 89 percent depending upon the extent of skin involvement and dose utilized [26]. It is our preferred initial therapy for patients who are very symptomatic with extensive thickened plaques, since the effective depth of treatment of electron beam therapy is more substantial than either topical HN2 or NBUVB/PUVA [57]. TSEBT should also be considered for patients with a recent history of rapid progression of disease and for those who have failed treatment with either topical HN2 and/or phototherapy. Following completion of TSEBT, adjuvant treatment with topical HN2 is appropriate and may be continued for a minimum of six months. (See 'Topical nitrogen mustard (mechlorethamine, HN2)' above.)

Administration — Patients are usually treated in the standing position, three to four meters distant 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 [26,27,58]. The conventional ("high") dose is generally 30 to 36 Gy administered over a 10-week period, with a one-week respite after 15 to 20 Gy to provide for some relief from the generalized skin erythema that often accompanies TSEBT. However, low dose (approximately 10 to 12 Gy) TSEBT has supplanted high dose therapy in many situations. Treatment with lower doses limits the duration of therapy, reduces complications, and allows easier retreatment [59-61]. 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 women and under the panniculus of obese individuals. These or other shadowed areas may be supplemented with 6 MeV electrons (with bolus) and treated to 12 to 20 Gy [58].

Toxicities — The most common acute complication of TSEBT is erythema and desquamation [62]. 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 such as squamous cell and basal cell carcinomas 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 [13]. 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 life-time course of a patient's disease.

●A series of 141 patients, 25 of whom had received prior treatment with topical agents for MF, treated with TSEBT (mean total dose of 30 Gy) reported an overall response rate of 95 percent [63]. Complete responses were obtained in 85 percent of those with T2 disease. Fifty-four percent of patients demonstrated skin relapse at one year.

●Thirty-three patients with stage IB to IIIA disease, including 24 with stage IB to IIA were treated in three phase II clinical trials evaluating low-dose (12 Gy) TSEBT [60]. The overall response rate was 88 percent, with a complete response rate of 27 percent. The toxicities were minor, compared to conventional dose TSEBT, and the duration of clinical benefit (time to requiring another total-skin or a systemic therapy) was 70.7 weeks.

Phototherapy — Treatment with NBUVB or PUVA for generalized patch/plaque (T2) disease is similar to that for patients with limited (T1) disease. Complete response rates for generalized patch/plaque (T2) disease are 50 to 80 percent for PUVA [35-38,54]. In general, NBUVB is used for most cases and PUVA is reserved for patients with thicker lesions. (See 'UVB' above and 'PUVA' above.)

INVESTIGATIONAL THERAPIES

Topical resiquimod — Resiquimod is an imidazoquinoline with potent TLR7 and TLR8 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 [64]. Treatment was started at three times per week and frequency was gradually increased every two weeks, as tolerated. A complete response, as assessed by the Severity-Weighted Assessment Tool score (SWAT), was achieved in two patients, a partial response in nine, and stable disease in one. 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 [65-67]. (See "Photodynamic therapy".)

In a series of five patients with unilesional MF, MAL-PDT was administered once weekly until complete clearing of the lesion [65]. 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 were treated with monthly MAL-PDT for six months [66]. A complete or partial clinical response was observed in six and three patients, respectively, but new lesions appeared in untreated areas in five patients.

However, the role of PDT in the management of early stage MF remains uncertain and protocols for its use have not been established.

Excimer laser therapy — There are a few reports of the use of targeted phototherapy using excimer lasers emitting NBUVB at 308 nm for the treatment of localized MF [68-70]. In a series of six patients with early MF involving less than 10 percent of the body surface area, excimer laser therapy was administered twice weekly for a total of 8 to 24 sessions [68]. 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 in one. (See "Targeted phototherapy".)

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 favorable prognosis, similar to that of early MF, and may be treated with a less aggressive approach (eg, PUVA, superpotent topical corticosteroids, local radiation therapy) [71,72]. (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 atypical (Sézary) cells ≥5 percent of circulating lymphocytes are considered to have involvement of the peripheral blood. Blood involvement may also be defined as ≥250/microL Sézary cells; CD4+CD26– or CD4+CD7– cells or CD4+CD26– and CD4+CD7– cells ≥15 percent by flow cytometry.

Of those with blood involvement, patients with less than 1000/microL Sézary cells are designated as having B1 involvement, while patients with 1000/microL Sézary cells or more with positive clonal studies have B2 involvement (ie, Sézary syndrome). 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".)

Pruritus — 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 their personal preference for feel and ease of application.

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 [73,74]. (See "Pruritus: Therapies for localized pruritus".)

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

●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".)

●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 physician's experience with these methods, patient characteristics, side effect profiles, and tumor characteristics.

•For patients with mild/limited stage IA MF, we suggest treatment with topical corticosteroid (Grade 2C). Topical nitrogen mustard (mechlorethamine, HN2) can be used as an alternative or as a subsequent therapy if topical steroid is 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.)

•For patients with stage IB or IIA disease demonstrating thin plaques and an indolent natural history of disease, we suggest the use of topical corticosteroids, topical HN2, or narrow-band ultraviolet B (NBUVB) therapy (Grade 2C). A choice among these is largely dependent on the extent and severity of disease. (See 'Stage IB/IIA disease' above.)

•For patients with highly symptomatic, generalized thickened plaques in whom a prompt response is needed, we suggest total skin electron beam therapy (TSEBT) or skin-directed therapies in combination with systemic biologic therapies rather than HN2 or NBUVB alone (Grade 2C). Systemic biologic therapies, such as retinoids or interferons, histone deacetylase (HDAC) inhibitors, or low-dose methotrexate 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. (See 'Stage IB/IIA disease' above.)