Observations  Eight white patients (4 men, 4 women; age range, 66-83 years) with histologically proven patch-stage MF received TL-01 phototherapy 3 times weekly using a standard protocol. Complete clearance of MF was achieved in 6 cases in a mean of 9 weeks or 26 treatments (range, 20-37 weeks) and 4 patients have had prolonged remissions. Mean duration of clinical improvement has been 20 months (range, 11-40 months). Partial response to TL-01 or poor histologic improvement was associated with rapid relapse.

Conclusions  TL-01 is an effective, convenient therapy that may have less risk of long-term adverse effects than current alternatives. Although larger prospective studies are necessary, for some patients intermittent courses of TL-01 may offer effective long-term therapy.

Commonly used treatments for early MF include photochemotherapy (psoralen UV-A [PUVA]) and topical nitrogen mustard (mechlorethamine) or carmustine chemotherapy. Total-skin electron-beam radiation therapy is also used in some centers.² All have been reported to have equal efficacy in stage 1 MF with a complete response to treatment in more than 70% of cases.³ Although the median duration of disease-free remissions reported for these therapies is variable, the long-term survival rates are not significantly different.³ Broadband UV-B has also been shown to have similar efficacy for skin clearance, with a 23% sustained disease-free remission on discontinuation of maintenance therapy in stage 1a disease (mainly patch-stage disease).⁴ Although several studies have suggested that narrowband TL-01 is more effective than broadband UV-B in the treatment of psoriasis,^5-8 there is only 1 report of its use in MF.⁹

PATIENTS AND METHODS

View this table: [in this window] [in a new window] Table 1. TNMB Classification for Mycosis Fungoides*

View this table: [in this window] [in a new window] Table 2. Clinical Staging System for Mycosis Fungoides*

View this table: [in this window] [in a new window] Table 3. Clinical Characteristics of Study Patients With Patch-Stage Mycosis Fungoides (MF)*

All treatments were carried out in a purpose-built cubicle constructed by the medical physics department of Ninewells Hospital, Dundee, Scotland, containing 50,100-W TL-01 fluorescent lamps (Philips Electronics, New York, NY). The irradiance within the cubicle changed from 3.53 mW/cm² to 2.22 mW/cm² during the study period, and exposure times were adjusted accordingly. Irradiance was measured monthly, by a standard protocol, with an international light meter (IL-4000; Able Instruments, Reading, England) calibrated using a spectroradiometer.

Patients received TL-01 phototherapy by our standard protocol.¹³ The minimum erythemal dose for each patient was determined prior to starting treatment by irradiation of a template of eight 1 x 1-cm² apertures on the upper back with a TL-01 source 20 cm from the patient. Two standard ranges of doses were administered: 25 to 390 mJ/cm² for phototypes 1 and 2 or 70 to 770 mJ/cm² for phototypes 3 and 4.¹⁴ Therapy commenced with 70% of the minimum erythemal dose. Treatment was administered 3 times weekly with 20% increment at each exposure unless modified by the erythemal response assessed at 48 hours after treatment. Phototherapy was continued until complete clinical clearance or minimal residual activity was achieved. Minimal residual activity and partial response were defined as a greater than 90% and 50% improvement, respectively, with persistent skin disease despite continuing treatment (ie, sanctuary sites). Relapse was defined as clinically significant disease requiring further therapy. A face shield and gloves were used to minimize UV-B exposure to areas habitually exposed to sunlight but unaffected by MF (cases 2, 3, 5, and 7).

RESULTS

View larger version (105K): [in this window] [in a new window] Figure 1. Left, Patch-stage mycosis fungoides (case 2) with pruritic, superficial, scaly, erythematous patches on the lower trunk. Right, Complete clinical remission in the same patient following narrowband TL-01 phototherapy.

Pretherapy and posttherapy biopsy results were available for study except for patient 5, who relapsed rapidly and extensively and on whom a posttherapy biopsy was not done. Diagnosis relied on the presence of typical histologic features on hematoxylin-eosin–stained sections. All pretherapy specimens demonstrated a superficial dermal mononuclear cell inflammatory infiltrate containing phenotypically abnormal lymphocytes (Figure 2). All showed epidermotropism, Pautrier microabcesses, and variable acanthosis. T-cell marker studies were available in 4 cases, showing predominant T helper (CD4+) cell infiltrates (cases 2, 3, 4, and 6). T-cell receptor gene rearrangement studies were not routinely performed.

View larger version (85K): [in this window] [in a new window] Figure 2. Left, Patch-stage mycosis fungoides pretreatment histologic photomicrograph (case 2) showing acanthosis, a superficial dermal mononuclear cell inflammatory infiltrate containing phenotypically abnormal lymphocytes that demonstrate epidermotropism. Right, Marked reduction of the atypical lymphocytic infiltrate in the same patient following narrowband TL-01 phototherapy. (Hematoxylin-eosin; original magnification x 166 for both photographs.)

Although no posttreatment biopsy findings showed entirely normal histologic characteristics, most showed a reduction of the inflammatory infiltrate (cases 1, 2, 3, 6, 7, and 8). Marked reduction of the inflammatory infiltrate with loss of epidermotropism and Pautrier microabcesses was found in those who achieved a prolonged remission (patients 1 and 2), but acanthosis and a mild chronic atypical dermal inflammatory infiltrate remained (Figure 2). In case 3, despite apparent clinical clearance, the atypical lymphocytic infiltrate was only moderately reduced after treatment, and the subsequent remission was short lived. Partial response (case 4) was associated with a persistent, atypical lymphoid cell infiltrate, epidermotropism, Pautrier microabcesses, and acanthosis.

COMMENT

Although the ability of UV-B to clear patch-stage MF has been known since the 1950s, it seems to have been rarely studied.¹⁷ Two reports of broadband UV-B phototherapy for "early" MF have shown similar effectiveness. Most of these patients had limited patch-stage disease, and complete remission was achieved in more than 80% in a median of 5 months to clearance, results comparable with other topical therapies.^{4, 18-19} Both studies used maintenance regimens following complete remission and noted high relapse rates when this treatment was stopped. Nevertheless, 23% of patients in 1 study had a long-term sustained remission (>58 months).⁴ Ultraviolet-B phototherapy was most effective with patch-stage or thin-plaque disease, and the authors concluded that this might be due to the limited ability of UV-B to penetrate thicker lesions. This may also be reflected in an Italian retrospective study where PUVA was reported to be more effective than broadband UV-B for stage 1 MF.²⁰

Narrowband phototherapy uses the Philips TL-01 lamp, which has an emission spectrum (311-313 nm) within the therapeutic action spectrum for psoriasis. In many centers it has replaced traditional broadband UV-B phototherapy as the treatment of choice for psoriasis and other dermatoses.

In this study, the response to TL-01 was best when there was a long history of premycotic eruption suggestive of an indolent and less aggressive disease more susceptible to this therapy. No correlation between skin phototype and therapeutic response was found (Table 3 and Table 4). Although persistent histologic abnormalities were demonstrated in all cases, similar findings have been reported with PUVA.²¹ Without maintenance therapy, 3 patients relapsed rapidly and required alternative therapy. One patient had extensive, indurated MF patches and her partial response to TL-01 and subsequent relapse was, perhaps, predictable (case 4).

View this table: [in this window] [in a new window] Table 4. Response to TI-01 Phototherapy in Patch-Stage Mycosis Fungoides*

Although current topical therapies are effective, they can have clinically significant adverse effects. High cumulative numbers of PUVA treatments in patients with psoriasis have been associated not only with an increased incidence of nonmelanoma cutaneous carcinomas,²² but also a small but important increase in malignant melanomas.²³ Topical nitrogen mustard causes a high incidence of allergic contact dermatitis, an increased incidence of cutaneous and internal malignancies, and environmental contamination.²⁴ Carmustine is associated with marrow suppression, intertrigo, and telangectasia.²⁵ Total-skin electron-beam radiation therapy can produce serious adverse effects including erythema, edema, desquamation, total alopecia and nail loss, blistering, pigmentation, telangectasias, and chronic xerosis.²⁶

When compared with PUVA, TL-01 phototherapy has several advantages. As systemic psoralen is not required, related acute adverse effects (nausea, headaches, and light-headedness) and the need for protective glasses after treatment are avoided. TL-01 phototherapy usually has shorter irradiation times, which aids compliance since patients with MF are often elderly and infirm. It can also be used in the rare instance where therapy is required during pregnancy.

Although we have achieved sustained remissions in 50% of our patients (mean, 20 months), others have reported more transient remissions.⁹ Unlike PUVA, with which maintainance is effective, once-weekly treatment with TL-01, attempted for 1 patient (case 3), proved difficult because painful posttreatment erythema developed despite UV-B dose reduction.

Acute adverse effects from TL-01 phototherapy can include erythema and pruritus. The major chronic adverse effects are photoaging and photocarcinogenisis. Despite the absence of long-term prospective studies, the photocarcinogenic risk of TL-01 seems to be less than that associated with PUVA.^27-28 Of concern is the recent discovery of p53 tumor suppressor gene mutations in some MF tumors (40%).²⁹ These mutations were predominantly in C:T and CC:TT transitions, which are characteristic of UV-B–induced DNA damage and were not found in plaque-stage disease. This might suggest a role for UV radiation therapy in the progression of the later stages of MF. However, in the absence of epidemiological evidence for the association of UV radiation and MF progression, further work is necessary to determine the significance of these findings.^30-31

Narrowband phototherapy offers the potential for prolonged remission for some patients with patch-stage MF. Although our study cohort was small (8 patients), we believe TL-01 treatment should be included among the initial therapeutic options in view of its efficacy, convenience, and likelihood of fewer long-term adverse effects. Clearly, larger prospective, long-term follow-up studies are necessary to define the role of TL-01 in patch-stage MF. However, our experience has shown TL-01 to be effective when PUVA therapy has been unsatisfactory or curtailed because of adverse effects. The optimum therapeutic regimen for TL-01 therapy in MF is still to be determined, but a more prolonged induction phase or the use of maintenance therapy may improve its efficacy while retaining a favorable adverse-effect profile.

Presented to the British Photodermatology Group at the British Association of Dermatologists meeting, Edinburgh, Scotland, June 30, 1999.

Corresponding author: Colin Clark, MRCP, Photobiology Unit, Department of Dermatology, Ninewells Hospital, Dundee, DD1 9SY, Scotland (e-mail: cclark35{at}hotmail.com).